4p Syndrome 5p Deletion Syndrome 5p Monosomy

P

4p Syndrome ▶Wolf-Hirschhorn Syndrome

5p Deletion Syndrome ▶Cri-du Chat Syndrome

5p Monosomy ▶Cri-du Chat Syndrome

5p Syndrome ▶Cri-du Chat Syndrome

8p Inverted Duplication ▶Inv Dup Del (8p)

8p Mirror Duplication ▶Inv Dup Del (8p)

9p Monosomy ▶Deletion 9p Syndrome

9p Syndrome ▶Deletion 9p Syndrome

P. Jiroveci Pneumonia ▶Pneumocystis Pneumonia

PA/IVS ▶Pulmonary Atresia

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PACD

PACD ▶Corneal Dystrophy, Posterior Amorphous

boundary motifs known to be involved in the filament assembly. The helix boundary motifs represent mutational high spots for keratin disorders. Any substitution or deletion within the rod domain is expected to cause distortion of the α-helix structure, and thus lead to instability of the heteropolymeric intermediated filaments. In PC, the majority of mutations are confined to the helix boundary motifs of either K6a and K16 in PC-1 or K6b and K17 in PC-2 [2,3].

Pachydermoperiostosis Diagnostic Principles ▶Touraine-Solente-Golé Syndrome ▶Clubbing

If clinically suspicious for PC, mutational analysis should focus on exons 1 and 6 in K16 and K17, and exons 1 and 7 in K6.

Therapeutic Principles

Pachyonychia Congenita M ARKUS B RAUN -FALCO Department of Dermatology, University of Freiburg, Freiburg, Germany

Treatment options are purely symptomatic. Nail care is compulsory. The hyperkeratotic nail plates have been milled down regularly. A last option would be nail extraction followed by destruction of the nail matrix. For skin and mucosa changes, oral retinoids were occasionally beneficial. Gene therapy is not jet available.

References Synonyms Pachyonychia congenita type I (PC-I) JadassohnLewandowsky (MIM 167200); PC-II Jackson-Lawler (MIM 167210)

Definition and Characteristics Group of four autosomal dominant inherited ectodermal dysplasias, with hypertrophic nail dystrophy (pachyonychia) as the constant main feature [1]. In addition, type I reveals palmoplantar hyperkeratosis, follicular hyperkeratosis, and oral leukoplakia; type II multiple pilosebaceous cysts, palmoplantar blisters, hyperhidrosis, and neonatal teeth; and type III and type IVear–nose and throat abnormalities and mental retardation.

1. Feinstein A, Friedman J, Schewach-Millet M (1988) Pachyonychia congenita. J Am Acad Dermatol 19:705–711 2. Feng Y-G, Xiao S-X, Ren X-R, Wang W-Q, Liu A, Pan M (2003) Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. Br J Dermatol 148:452–455 3. Terrinoni A, Smith FJD, Didona B, Canzona F, Paradisi M, Huber M, Hohl D, David A, Verloes A, Leigh IM, Munro CS, Melino G, McLean WHI (2001) Novel and recurrent mutations in the genes encoding keratins K6a, K16, K17 in 13 cases of pachyonychia congenita. J Invest Dermatol 117:1391–1396

Prevalence Overall very rare; distribution among different PC-types: PC-1 > 50%; PC-2 ≈ 25%; PC-3 and PC-4 < 25%.

Genes PC-1: Keratin (K) 6a and K16; PC-2: K6b and K17.

Pachyonychia Congenita Type I ▶Pachyonychia Congenita

Molecular and Systemic Pathophysiology Keratin intermediate filaments belong to the cytoskeletal system within the cytoplasm of epithelial cells. They consist of type I and II proteins, which assemble into 10-nm intermediate filaments. The central coiled-coil α-helical rod domain of each keratin contains highly Hconserved sequences at both ends, termed helix

PACNS ▶Vasculitis, Cerebral Forms

Paget’s Disease of Bone

PAD ▶Peripheral Artery Disease

PAF ▶Pure Autonomic Failure ▶Catecholamine Deficiency

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Zealand origin being much more likely to have the disease than native-Americans, Eskimos, Africans, Indians or Orientals.

Genes The causes of Paget’s disease of bone have always been obscure. Because the disease appeared to occur in patients mostly after the age of 50, genetic causes initially seemed unacceptable and the etiology related to parvomyxovirus infection was proposed but could not be confirmed. The racial and ethnic distribution seemed to strongly support the occurrence of the disease in patients of British origin and the relative rarity of the presentation in persons from Sweden, the Netherlands, Africa, India, Japan and China supported this view. Gene studies have recently disclosed modifications of tseqestosome 1 gene (also known as p 62); modifications in the RANKL, RANK and OPG systems with alterations in Bcl-2, an apoptotic suppressor; or finding of alterations in chromosome 9p13.3–p12 or 18g21.1–q22 or 6p21.3 [4].

Paget’s Disease of Bone Molecular and Systemic Pathophysiology H ENRY J. M ANKIN Orthopedic Surgery, Massachusetts General Hospital, Boston, MA, USA

Synonyms Osteitis deformans

Definition and Characteristics Paget’s disease of bone is a mysterious entity with no readily identifiable cause and an array of different presentations. Although suggestions of viral and genetic possible causes have been made, there is still no clear definition as to the origin of the disease [1,2]. The first description of Paget’s disease was by Sir Samuel Wilks in 1869, who reported a case of 60-year-old man who died and at autopsy, was found to have enlarged and very thick bones [3]. Sir James Paget became intrigued by the syndrome and in 1877 described 11 cases of the same disease and named it “osteitis deformans.” In 1888, Jonathan Hutchinson changed the name of osteitis deformans to “Paget’s Disease of Bone.”

Prevalence The disorder is common and its frequency range is approximately 3% of the population over the age of 50, many of whom are asymptomatic. There is a strong difference in ethnic frequency with Caucasians and particularly persons of English, Australian or New

In patients with Paget’s disease bone is both synthesized and destroyed equally at extremely rapid rates. Because of this rapid turnover, the affected bone becomes markedly enlarged with very thick cortices, coarse but purposeful trabeculae and irregular lytic areas in some parts of the bone. Bowing of the affected bone is common (Fig. 1). Because of the marked increment in synthetic activity, the bone scan is almost always intensely positive over the site and the serum alkaline phosphatase and the hydroxyproline peptides become markedly increased. Histologically in active sites, one sees an extraordinary vascularity and an enormous collection of osteoblasts making irregular columns of mature bone, which are simultaneously being destroyed by an equal number of osteoclasts (Fig. 2). With time the bone becomes less active in terms of turnover and develops cement lines separating the segments of bone.

Diagnostic Principles The findings that distinguish Paget’s disease from almost all other disorders are four in number: the bone is larger in width (and often in length) than normal; the cortices are wider than normal; the trabeculae in the medullary cavity are coarse but purposeful; and the medullary bone often contains sometimes large lytic areas. In addition there are several changes that are sometimes present. These include: the “advancing wedge” of the disease; “stress lines” on the convex side of the bone; changes in the skull structure (“osteoporosis

P

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Paget’s Disease of Bone

Paget’s Disease of Bone. Figure 3 X-ray of the skull of a patient with extensive Paget’s disease. Note the enlargement of the bone and the marked sclerosis, which is quite irregular in distribution. Paget’s Disease of Bone. Figure 1 Classic radiographic appearance of a femur of a patient with severe Pagetoid bone changes. Note the bowing, the increased bone width, the thickening of cortices, the coarse but purposeful trabeculae and the lytic areas.

an imaging study for some other problem. It is often the complications of the disease that produce symptoms. The complications include the following: bone pain over the site of the lesion; bone deformities which may cause severe disability; osteoarthritis in the hip, knee or spine; foraminal encroachment which leads to deafness, blindness or Bell’s palsy; pathologic fractures which heal poorly and are difficult to treat surgically; high output left heart cardiac failure; and Paget’s sarcoma which occurs in 10% of patients with diffuse disease and is usually fatal.

Therapeutic Principles

Paget’s Disease of Bone. Figure 2 Histologic picture of the bone from a patient with severe Paget’s disease. Note the increased vascularity and the irregular structure of the bone. Numerous osteoblasts and osteoclasts are present. (Hematoxylin and eosin × 200).

cicrumscripta cranii”) (Fig. 3); large vertebra with coarse trabeculae (“ivory vertebra”); and an enlarged jaw with “floating teeth” on imaging studies. Many patients with Paget’s disease at a single site are asymptomatic and the diagnosis is made on the basis of

Until relatively recently there was very little treatment available for patients with Paget’s disease. Those patients who have a solitary focus with little or no discomfort or deformity may be watched periodically with serial X-rays, bone scans and assays for serum alkaline phosphatase. Patients who develop osteoarthritis or fractures can be treated by appropriate surgery which is sometimes difficult because of excessive blood loss and problems with getting hardware to work effectively, and high output cardiac disease making anesthesia complicated. The newest systems of treatment for patients with extensive Paget’s disease are based on medications that diminish the bone turnover. These include calcitonin and bisphosphonates which act principally by inhibiting osteoclastic activity and causing a “remission” in bone pain, cardiac problems, arthritis difficulty, hearing loss and fracture rate [5].

Pallister-Killian Syndrome

References 1. Barry HC (1969) Paget’s disease of bone. William and Wilkins Co., Baltimore 2. Altman RD (1992) Paget’s disease of bone. In: Coe FL, Favus MJ (eds) Disorders of bone and mineral metabolism. Raven Press, New York, pp 1027–1064 3. Mankin HJ, Hornicek FJ (2005) Paget’s sarcoma: a historical and outcome review. Clin Orthop 438:97–102 4. Layfield R, Ciani B, Ralston SH et al. (2004) Structural and functional studies of mutation affecting the UA domain of SQSTM1 (p62) which cause Paget’s disease of bone. Biochem Soc Trans 32:728–730 5. Devogelear JP (2002) Modern therapy for Paget’s disease of bone: focus on bisphosphonates. Treat Endocrinol 1:241–257

PAH1 ▶Hypotension, Hereditary ▶Pseudohypoaldosteronism Type I

Painful Plantar Warts or Vegetative Warts ▶Human Papilloma Virus

PAIS

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Pallister-Killian Syndrome S HARON L. W ENGER Department of Pathology, West Virginia University, Morgantown, WV, USA

Synonyms Tetrasomy 12p mosaicism; Isochromosome 12p [i(12) (p10)] syndrome

Definition and Characteristics The additional chromosome consists of two short arms of chromosome 12, resulting in four copies of 12p (Fig. 1). Individuals with Pallister-Killian syndrome show tissue-limited mosaicism of the isochromosome, rarely seen in cultured peripheral blood lymphocytes, but present in fibroblasts and bone marrow [1]. The i(12p) cell line decreases in fibroblasts with increased age of patient, in vivo, and with serial passaging of fibroblasts, in vitro [2]. This is thought to be due to growth disadvantage of the cells containing the isochromosome. The isochromosome may be lost more quickly in some cells due to greater somatic selection against cells containing the i(12p).

Prevalence This is a rare sporadic chromosomal abnormality with over 100 cases reported in the literature.

Molecular and Systemic Pathophysiology The isochromosome 12p is a mosaic condition with tissue-limited mosaicism. Molecular studies have demonstrated that almost always the isochromosome is maternal in origin, with the majority suggesting second meiosis error [3]. This is supported by increased risk with advanced maternal age [4]. While a variety of methods have been proposed, the majority support a meiotic error

▶Androgen Insensitivity Syndrome

PAIVS ▶Pulmonary Atresia

Pallister-Killian Syndrome. Figure 1 Partial G-banded karyotype showing normal chromosomes 12 (left and center) and isochromosome 12 (right).

P

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Palmitoylcarnitine Transferase

Pallister-Killian Syndrome. Figure 2 Alpha-satellite FISH probe for centromere of chromosome 12 showing three signals in an amniocyte nucleus.

of nondisjunction followed by centromere mis-division. FISH probes for the centromere of chromosome 12 show the isochromosome to have a single centromeric signal, suggestive of mis-division of the centromere. Some isochromosomes have been reported to have a smaller signal, which may predispose to mitotic loss. While the zygote contains the isochromosome, the presence of two cell lines indicates a mitotic loss during early fetal development. A common finding on prenatal ultrasound is a diaphragmatic hernia, the major cause of perinatal death. Characteristics in liveborn infants include hypotonia, profound mental retardation, seizures, hypertelorism, prominent lower lip and cupid-bow shaped upper lip with long philtrum, large ears, macrostomia, prominent forehead, flat nasal bridge, and sparse temporal scalp hair in young patients. Adults have a coarse facial appearance with prominent mandible. Pigmentary streaks of skin can demonstrate hyper/hypo pigmentation, most likely related to the mosaicism [5].

Diagnostic Principles Diagnosis is made by cytogenetics with use of a DNA centromeric probe for chromosome 12 by fluorescence in situ hybridization (FISH), which can confirm the isochromosome origin in metaphase and in interphase cells (Fig. 2).

Therapeutic Principles If miscarriage did not occur, management after birth is aimed at seizure control and physical and speech therapy.

2. Peltomaki P, Knuutila S, Ritvanen A, Kaitila I, De la Chapelle A De la (1987) Pallister-Killian syndrome: cytogenetic and molecular studies. Clin Genet 31:399–405 3. Dutly F, Balmer D, Baumer A, Binkert F, Schinzel A (1998) Isochromosomes 12p and 9p: parental origin and possible mechanisms of formation. Eur J Hum Genet 6:140–144 4. Wenger SL, Steele MW, Yu W-D (1988) Risk effect of maternal age in Pallister i(12p) syndrome. Clin Genet 34:181–184 5. Reynolds JF, Daniel A, Kelly TE, Gollin SM, Stephan MJ, Carey J, Adkins WN, Webb MJ, Char F, Jimenez JF, Opitz JM (1987) Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases. Am J Med Genet 27:257–274

Palmitoylcarnitine Transferase ▶Carnitine PalmitoyltransferaseI Deficiency

Palmoplantar Keratoderma ▶Hypotrichosis - Osteolysis - Peridontitis - Palmoplantar Keratoderma Syndrome

Palmoplantar Keratoderma Vo¨rner-Unna-Thost M ARKUS B RAUN -FALCO Department of Dermatology, University of Freiburg, Freiburg, Germany

Synonyms Keratosis palmoplantaris diffusa; Epidermolytic palmoplantar keratoderma

Definition and Characteristics References 1. Ward BE, Hayden MW, Robinson A (1988) Isochromosome 12p mosaicism (Pallister-Killian syndrome): newborn diagnosis by direct bone marrow analysis. Am J Med Genet 31:835–839

Autosomal dominant defect in keratin 9 (K9) leading to diffuse, non-transgredient keratoderma of the entire surface of palms and soles with red margins and histologically with or without epidermolytic hyperkeratosis. Additional features are clubbing of nails and knuckle pad-like keratoses.

Pancreatic Cancer

Prevalence The most common palmoplantar keratoderma (PPK) with approximately 1 in 100,000.

Genes Keratin 9 (MIM 144200) on chromosome 17q21 (very rarely keratin 1 in mild or atypical variants).

Molecular and Systemic Pathophysiology Keratin intermediate filaments belong to the cytoskeletal system within the cytoplasm of epithelial cells. They consist of type I and II proteins, which assembly into 10-nm intermediate filaments. The central coiled-coil α-helical rod domain of each keratin contains highly conserved sequences at both ends, termed helix boundary motifs known to be involved in the filament assembly. The helix boundary motifs represent mutational high spots for keratin disorders. K9 belongs to the type I keratins. In contrast to other keratins, K9 is exclusively synthesized in suprabasal keratinocytes of palmoplantar skin. K9 pairs with K1. To date, approximately 14 different mutations have been described. The majority of them were missense mutations in the highly conserved coil-A segment within the α-helical rod domain of K9. Most prevalent are mutations at codon 160 or 162 within the helix boundary motifs. The primary structure is characterized by “heptad” substructure (a-b-c-d-e-f-g)m, which are involved in the formation of heterodimers. Each residue has its specific properties, for instance in the polar interaction with neighboring keratin molecules. Mutations in these segments are thought to have a dominant negative effect on the assembly of keratin intermediate filaments and cause their instability.

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2. Hamada T, Ishii N, Karshima T, Kawano Y, Yasumoto S, Hashimoto T (2005) The common KRT9 gene mutation in a Japanese patient with epidermolytic palmoplantar keratoderma and knuckle pad-like keratose. J Dermatol 32:500–502 3. Zhang XN, He XH, Lai Z, Yin WG, Le YP, Guo JM, Mao W, He XL, Li JC (2005) An insertion-deletion mutation in keratin 9 in three Chinese families with epidermolytic palmoplantar keratoderma. Br J Dermatol 152:804–806 4. Terron-Kwiatkowski A, Terrinoni A, Didona B, Melino G, Atherton DJ, Irvine AD, McLean WHI (2004) Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene. Br J Dermatol 150:1096–1103 5. Kimyai-Asadi A, Kotcher LB, Jih MH (2002) The molecular basis of hereditary palmoplantar keratodermas. J Am Acad Dermatol 47:327–343

PAN ▶Polyarteritis Nodosa Group

Pancreas Annulare ▶Annular Pancreas

P Pancreatic Adenocarcinoma

Diagnostic Principles The clinical picture of diffuse palmoplantar hyperkeratosis with a red margin should lead to mutational analysis within keratin 9.

▶Pancreatic Cancer

Therapeutic Principles Treatment options are purely symptomatic and focus on the reduction of hyperkeratosis by using urea containing ointments, topical calcipotriol, or mechanic keratolysis by rubbing with pumice stones. Gene therapy is not yet available.

Pancreatic Cancer S TEPHAN D I S EAN K ENDALL , G ERARD C. B LOBE Medicine, Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

References 1. Küster W, Reis A, Hennies HC (2002) Epidermolytic palmoplantar keratoderma of Vörner: re-evaluation of Vörner’s original family and identification of a novel keratin 9 mutation. Arch Dermatol Res 294:268–272

Synonyms Exocrine pancreatic cancer; Pancreatic carcinoma; Pancreatic adenocarcinoma

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Pancreatic Cancer

Definition and Characteristics Includes cancers of the exocrine pancreas, excluding tumors derived from the pancreatic islets. Pancreatic cancer has an extremely poor prognosis, with mortality rates nearly matching incidence rates [1]. Incidence is rare before age 45, but increases steadily thereafter. The majority of patients have regional or distant spread at diagnosis. Risk factors include cigarette smoking, diabetes mellitus, obesity, and chronic pancreatitis. Multiple hereditary syndromes increase the risk for pancreatic cancer as well, including hereditary chronic pancreatitis, Peutz-Jeghers syndrome, BRCA2, ataxiatelangectasia, and familial atypical multiple-mole melanoma (FAMMM) [1]. Patients with hereditary pancreatic cancer develop pancreatic cancer earlier in life compared to sporadic cases.

Prevalence 232,241 new cases and 226,949 deaths yearly worldwide [2].

Genes Multiple genetic alterations, both germline and somatic, are associated with the development of pancreatic carcinoma (Table 1). The primary oncogenic mutation in pancreatic cancer, found in over 90% of tumors, is a

mutation in codon 12 of the K-Ras gene. K-Ras mutations occur more frequently in pancreatic cancer than any other human cancer, and the mutation of K-Ras codon 12 is considered a molecular hallmark of pancreatic cancer. The ErbB-2 proto-oncogene, also known as Her-2/neu, is a receptor of the epidermal growth factor family, and is amplified in approximately 65% of pancreatic carcinomas. Multiple tumor suppressor genes are inactivated in pancreatic cancer, including the p16 gene, the p53 gene, and the deleted in pancreatic cancer 4 (DPC4) gene, also known as SMAD4. p16 inactivation occurs in 95% of pancreatic cancers, and p53 inactivation occurs in 50–75% of pancreatic cancers. In the pancreas, the loss of p16 and p53 appear to be specific to the development of malignant disease; they are rarely inactivated in chronic pancreatitis or other nonmalignant pancreatic diseases. Loss of DPC4 is relatively specific for pancreatic cancer, although it does occur at low rates in other malignancies. Of note, the combination of K-Ras activation and p16 inactivation occurs almost exclusively in pancreatic cancer, and there is interest in using this combination of genetic mutations as a pancreatic cancer signature. In addition to somatic mutations, there are multiple germline mutations that increase pancreatic cancer risk [3]; these are detailed in Table 1.

Pancreatic Cancer. Table 1 Common genetic mutations in pancreatic carcinoma Somatic mutations Mutation

Gene type

Mutation timing

K-Ras

Oncogene

Early

ErbB2 (Her-2/neu)

Oncogene

Early

p16 (CDKN2A)

Tumor suppressor

Middle

p53

Tumor suppressor

Late

DPC4 (SMAD4)

Tumor suppressor

Late

Description Activating somatic mutation occurs in 90% of pancreatic carcinomas Amplified in 65% of pancreatic carcinomas Somatic inactivation occurs in 95% of pancreatic carcinomas Somatic inactivation occurs in 50–75% of pancreatic carcinomas Somatic inactivation occurs in 55% of pancreatic carcinomas

Germline mutations Mutation

Gene type

Genetic syndrome

STK11 p16 (CDKN2A)

Tumor suppressor Tumor suppressor

BRCA2 ATM MLH1, MSH2

Tumor suppressor Tumor suppressor DNA mismatch repair

Peutz-Jeghers syndrome Familial atypical multiple mole melanoma syndrome Familial breast cancer Ataxia-telangectasia Hereditary nonpolyposis colon cancer

Lifetime risk 36% 19% 5% Unknown Unknown

Pancreatic Nesidioblastosis

Molecular and Systemic Pathophysiology In general, pancreatic oncogenesis is caused by the accumulation of multiple genetic alterations. Similarly to colorectal cancer, pancreatic cancer progresses in a stepwise manner from normal epithelium to progressive stages of pancreatic intraepithelial neoplasia (PanIN) to neoplastic tissue [4]. PanIN lesions are divided into four categories: PanIN-1A, a flat duct lesion; PanIN-1B, a papillary lesion; PanIN-2, an atypical papillary lesion; and PanIN-3, a severely atypical papillary lesion. In general, the activation of both K-Ras and ErbB-2 occur early in PanIN development (PanIN-1A and PanIN-1B). Inactivation of p16 occurs later in pancreatic neoplastic development, being initially found in PanIN-1B and PanIN-2 lesions. Loss of p53 and DPC4 tend to occur later in pancreatic cancer development, usually appearing initially in PanIN-3 lesions.

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gemcitabine is the standard for metastatic disease; the addition of the EGFR inhibitor erlotinib modestly improves overall survival. Median survival for patients with metastatic disease is approximately 6 months with therapy, and 4 months in the absence of therapy.

References 1. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Lancet 363:1049–1057 2. Kamangar F, Dores GM, Anderson WF (2006) J Clin Oncol 24:2137–2150 3. Brentnall TA (2005) Curr Treat Options Oncol 6:437–445 4. Talar-Wojnarowska R, Malecka-Panas E (2006) Med Sci Monit 12:186–193 5. Lockhart AC, Rothenberg ML, Berlin JD (2005) Gastroenterology 128:1642–1654

Diagnostic Principles Due to a lack of specific signs, symptoms or an effective screening test, pancreatic cancer is difficult to diagnose at an early stage; most patients are diagnosed with advanced disease. Presenting symptoms also tend to be nonspecific including abdominal pain that radiates to the back, anorexia, weight loss and obstructive jaundice. Ascites or an abdominal mass may be present on examination. Tumors which present in the head of the pancreas tend to cause jaundice and anorexia, while tumors in the body or tail of the pancreas tend to cause pain. The initial workup for suspected pancreatic cancer are imaging studies, including ultrasound (transabdominal or endoscopic), CT scan, MRI, or endoscopic retrograde cholangiopancreatography (ERCP). ERCP offers the potential advantage of relieving a biliary obstruction through stent placement. The suspicion of disease must be confirmed by biopsy, which can be done using a needle guided by CT or ultrasound, endoscopic ultrasound (EUS), ERCP, or laparoscopy.

Pancreatic ß-cell Tumor ▶Insulinoma

Pancreatic Carcinoma ▶Pancreatic Cancer

P Pancreatic Cholera Syndrome ▶VIPoma

Therapeutic Principles Therapy for pancreatic cancer depends on the extent of the disease [5]. About 20% of patients have tumor localized to the pancreas that is resectable, offering the only potential for cure. However, most have recurrence of their disease, with 5-year survival ranges of 10–25%. For this reason adjuvant chemoradiation with 5-fluorouracil or gemcitabine (before or after surgery) followed by adjuvant gemcitabine is recommended. Approximately 40% of patients present with locally advanced disease, indicating either unresectable disease or local lymph node involvement. Optimal treatment for these patients has not been completely defined, but chemoradiation with 5-fluorouracil or gemcitabine is recommended. Median survival for these patients is approximately one year. Finally, approximately 40% of patients present with metastatic disease, primarily to the liver. Treatment with

Pancreatic Insufficiency and Bone Marrow Dysfunction ▶Shwachman Diamond Syndrome

Pancreatic Nesidioblastosis ▶Persistent Hyperinsulinemic Hypoglycemia

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Pancreatitis, Acute

Pancreatitis, Acute C HRISTOPH K. W EBER 1 , R ICHARD L ORENZ 2 1

Department of Gastroenterology, Klinik Sonnenhof, Bern, Switzerland 2 Department of Internal Medicine, Ulm University, Ulm, Germany

Genes Genetic alterations have been identified in the context of chronic or recurrent acute pancreatitis, i.e., patients suffering from a hereditary form of pancreatitis express mutations in the cationic trypsinogen gene PRSS1 (e.g., R122H or N29I). Only a subgroup of patients with recurrent idiopathic acute pancreatitis has mutations of the cystic fibrosis gene CFTR.

Molecular and Systemic Pathophysiology Definition and Characteristics Acute pancreatitis (AP) is characterized by a rapid onset of inflammation of the pancreas. The disease is mainly associated with biliary duct obstruction or alcohol consumption. Rare causes of AP include drugs, hypercalcemia, hyperlipidemia, trauma, endoscopic interventions, autoimmune response, infections or genetic predisposition. In up to 25% the cause cannot be determined. In about 80% of the cases inflammation is limited to the pancreatic gland resulting in mild pancreatitis with little mortality. Severe pancreatitis usually includes necrosis of pancreatic tissue with a generalized inflammatory state involving failure of distant organ systems such as kidney, lungs and liver.

Prevalence The prevalence in Europe and the USA of acute pancreatitis is constantly increasing and reaches about 24–75 cases per 100,000 adults [1].

Most investigators believe that the key factor in AP is the uncontrolled, premature activation of intracellular trypsin from trypsinogen in the acinar cell. This process can be triggered by increased pressure in the biliary or pancreatic duct (i.e., in gallstone disease) or alcohol consumption. In animal models acinar hyperstimulation (i.e., with excessive doses of cholezystokinine, CCK) or the inhibition of the serine protease inhibitor Kazal type 1 (SPINK1) lead to activation of acinar trypsin [2]. Moreover, defense mechanisms such as controlled low intracellular calcium levels, cellular compartmentalization and the autodigestion of trypsin have to be overcome. Together with trypsin, inflammatory mediations such as phospholipase A2 and elastase are activated. These events trigger the release of IL-1, IL-6 and IL-8 mainly from local inflammatory cells. This cascade of events results in local damage such as edema, necrosis, abscess or cyst formation of the pancreas. The process further triggers activation of inflammatory mediators in i.e., the liver causing a generalized inflammatory state with distant organ failure [3].

Diagnostic Principles

Pancreatitis, Acute. Figure 1 Overview of molecular processes in acute pancreatitis in an schematic acinar cell: Increased mechanical pressure in the biliary duct, alcohol, cholecytokinine (CCK) overstimulation, inhibition of SPINK1 or increase in calcium level lead to intracellular activation of trypsinogen to active trypsin.

Acute pancreatitis starts with abdominal pain often accompanied by nausea, vomiting and fever. Elevated serum levels of amylase or lipase may support the clinical diagnosis; they rise within a few hours after onset of symptoms. Serum levels of ASAT (>3-fold of normal limit) indicate biliary pancreatitis. Standard diagnostic procedures to rule out biliary pancreatitis include detection of gallstones by ultrasonography or endosonography. The alcoholic form of pancreatitis is likely if alcohol is drunken regularly. To assess the severity of the inflammatory process measurement of the C-reactive protein (CRP) is applied, multi-score-systems (Ranson-Score, Imrie-Score, APACHE II-Score) may be useful to predict clinical outcome. If diagnosis is unclear or complications are suspected computer tomography is performed.

Therapeutic Principles Therapeutic principles in AP include supportive therapy, sufficient intravenous fluid administration and adequate pain control. If signs of respiratory

Pancreatitis, Autoimmune

insufficiency, renal failure or metabolic complications are present, intensive care is necessary. Enteric feeding should be administered in the early course of the disease either by a nasogastric or jejunal feeding tube [3]. In case of biliary pancreatitis, endoscopic retrograde cholangiography should be performed within the first 72 h to remove stones from the bile duct. Infection of pancreatic necrosis is a major complication in acute pancreatitis. In the case of infected necrosis, abscess, cholangitis, sepsis or extrapancreatic manifestations intravenous antibiotic therapy should be initiated, the use of prophylactic antibiotic administration is unclear.

References 1. Yadav D, Lowenfels AB (2006) Trends in the epidemiology of the first attack of acute pancreatitis: a systematic review. Pancreas 33:323–330 2. Ohmuraya M, Hirota M, Araki M, Mizushima N, Matsui M, Mizumoto T, Haruna K, Kume S, Takeya M, Ogawa M, Araki K, Yamamura K (2005) Autophagic cell death of pancreatic acinar cells in serine protease inhibitor kazal type 3 – deficient mice. Gastroenterology 129:696–705 3. Weber CK, Adler G (2003) Acute pancreatitis. Curr Opin Gastroenterol 19:447–450

Pancreatitis, Autoimmune G UIDO A DLER Department of Internal Medicine I, Ulm University, Ulm, Germany

Synonyms Lymphoplasmacytic sclerosing pancreatitis; LPSP; IgG4-related sclerosing disease

Definition and Characteristics Autoimmune pancreatitis is a benign chronic disease of the pancreas characterized by lymphoplasmacytic infiltration, diffuse organ enlargement, irregular narrowing of the pancreatic duct and a favourable response to glucocorticoid treatment. The inflammatory process is usually focal and mainly involves the head of the pancreas and the distal bile duct. Intense cellular infiltration is observed around medium-sized and large interlobular ducts [1]. Infiltrating cells are mainly CD8 and CD4 positive T lymphocytes. Periductal fibrosis increases with duration of disease. Inflammatory pseudotumors in the head of the pancreas may represent advanced stages of fibrosing autoimmune

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pancreatitis. High serum concentrations of the IgG4 subclass of immunoglobulins are closely related to disease activity. Patients with autoimmune pancreatitis often have extrapancreatic diseases like sclerosing cholangitis, retroperitoneal fibrosis, sialadenitis and lymphadenopathy. At the onset of disease patients present with unspecific symptoms like obstructive jaundice, abdominal or back pain, new-onset diabetes, or pancreatic mass. The severity of acute attacks of pancreatitis and the intensity of pain is mild [2].

Prevalence The exact occurrence rate of autoimmune pancreatitis is still unknown. Most cases have been published in the Japanese literature. Males (83%) are clearly predominant over females. The published mean age at diagnosis was between 54.7 and 63 years [2].

Molecular and Systemic Pathophysiology IgG4 plays a major role in the pathogenesis of autoimmune pancreatitis. This concept is supported by the specific rise of serum levels of IgG4, the close association with disease activity and the abundance of IgG4-positive cells infiltrating the pancreas (Fig. 1B). Recent studies suggested that autoimmune pancreatitis causes several extrapancreatic manifestations (see above) that are characterized by IgG4 cell infiltration. It is suggested that potential antigens within the duct epithelium are the targets of the autoimmune process [3]. The frequent occurrence of antibodies against pancreatic proteins like carboanhydrase, pancreatic secretory trypsin inhibitor and lactoferrin support this concept. Similar to other autoimmune diseases the HLA haplotype DRB1*0405-DQB1*0401 is associated with autoimmune pancreatitis. Only recently an association of polymorphisms of the Fc receptor-like genes (FCRLs) with autoimmune diseases has been demonstrated. FCRL 3 expression on B cells is suggested to increase autoantigen production. In patients with autoimmune pancreatitis the frequency of the FCRL3– 110A/A alleles was significantly increased compared with controls [4]. It is now suggested that both the HLA DRB1*0405-DQB1*0401 haplotype and FCRL3–110 alleles are related to susceptibility for autoimmune pancreatitis.

Diagnostic Principles At present no unanimously accepted diagnostic scoring system exists. Essential are imaging, serology and in some scoring systems the response to steroid therapy (Table 1). Typically the pancreas is diffusely enlarged on CT or MR imaging and ultrasonography. On contrastenhanced CT a low attenuation rim surrounded the pancreas. A focal mass lesion could be detected in

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Pancreatitis, Autoimmune

Pancreatitis, Autoimmune. Figure 1 Morphology of autoimmune pancreatitis. (a) CT scan demonstrating low density lesion in the tail of the pancreas (arrowheads), (b) Pancreatic biopsy shows abundant IgG4-positive cells on immunostaining, (c) Resolution of changes in pancreatic tail after prednisone therapy ([2] with permission).

Pancreatitis, Autoimmune. Table 1 Diagnostic criteria for autoimmune pancreatitis (from [2]) Category

Criteria

Histology

At least one of the following: 1. Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis (LPSP) 2. Lymphoplasmacytic infiltrate with storiform fibrosis showing abundant (≥10 cells/HPF) IgG4-positive cells Typical: diffusely enlarged gland with delayed (rim) enhancement; diffusely irregular, attenuated main pancreatic duct Othersa: Focal pancreatic mass/enlargement; focal pancreatic duct stricture; pancreatic atrophy; pancreatic calcification; or pancreatitis Elevated serum IgG4 level (normal, 8–140 mg/dL) Hilar/intrahepatic biliary strictures, persisent distal biliary stricture, parotid/lacrimal gland involvement, mediastinal lymphadenopathy, retroperitoneal fibrosis Resolution/marked improvement of pancreatic/extrapancreatic manifestation with steroid therapy

Pancreatic imaging

Serology Other organ involvementb Response to steroid therapyc a

With negative work-up for known etiologies for pancreatic disease, especially pancreatic/biliary cancer. Radiologic evidence of organ involvement can be confirmed by biopsy showing lymphoplasmacytic infiltrate with abundant IgG4-positive cells or its resolution/improvement with steroid therapy. c Resolution/marked improvement of pancreatic/extrapancreatic manifestation with steroid therapy. b

few patients only. ERCP images demonstrated focal (90% of patients) or diffuse (10% of patients) narrowing of main pancreatic duct and narrowing of distal bile duct. In patients with autoimmune pancreatitis serum levels of pancreatic enzymes, IgG and IgG4

are increased. In addition several autoantibodies are detected like antinuclear antibody (ANA), antilactoferrin antibody (ALF), anti-carbonic anhydrase – II-antibody (ACA-II), rheumatoid factor and only recently antibodies against pancreatic secretory trypsin

Pancreatitis, Chronic

inhibitor (PSTI). Serum IgG4 concentrations are closely associated with disease activity and distinguish autoimmune pancreatitis from other pancreatic disorders with a high sensitivity (95%) and specificity (97%). Recently a role for pancreatic biopsy was suggested in diagnosing autoimmune pancreatitis, however, the values and risks of this procedure need further confirmation.

Therapeutic Principles While a few patients improve without any treatment, in different series almost every patient responded to glucocorticoid therapy. Without establishment of a detailed treatment schedule, oral prednisolone is initiated at 40 mg/day. After confirmation of the response prednisolone is tapered during a period of 12–16 weeks to a dose of 2.5–5 mg/day. Therapy may be maintained at this dose or discontinued completely. This regimen caused significant improvement in clinical symptoms, negative conversion of detected autoantibodies, normalization of elevated levels of IgG and IgG4, regression of pancreatic enlargement, resolution of pancreatic ductal narrowing and improvement of bile duct stricture. Associated type 2 diabetes may improve after glucocorticoid therapy. In some diagnostic scoring systems response to glucocorticoid therapy is included as a criterium for definite diagnosis. The response within two weeks of therapy could help to differentiate autoimmune pancreatitis from pancreatic cancer.

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usually abdominal pain [1]. Anatomic features include inflammatory cell infiltration, fibrosis, loss of acinar and islet cells, dilated ducts, enlarged and inflamed nerve trunks and calcifications. The etiologies of chronic pancreatitis are nearly all complex, requiring combinations of interacting and sequential genetic, environmental and metabolic risk factors for the pathological features to develop. Alcohol abuse and tobacco smoking are major environmental risk factors but are not sufficient to cause chronic pancreatitis alone. Genetic polymorphisms, autoimmune disorders, recurrent and severe acute pancreatitis attacks and duct obstruction are also important risk factors but many cases remain idiopathic.

Prevalence Accurate data on the prevalence of chronic pancreatitis is lacking due to poor definition of early chronic pancreatitis and the lack of high quality of abdominal imaging techniques in older studies. Older studies from Europe, the United States and Mexico suggest a prevalence of 10–15 cases per 100,000 people, but more sensitive approaches used recently in Japan suggest a prevalence of 45 per 100,000 in males, and 12.4 per 100,000 in females. Incidence rates vary widely between countries, primarily due to differences in risk factor prevalence and criteria used for case-definition/acquisition. Longitudinal data from Western countries (United States, United Kingdom and Denmark) suggests an increase in incidence over time.

References

Genes

1. Klöppel G, Lüttges J et al. (2004) JOP 6(Suppl 1):97–101 2. Chari ST, Smyrk TC et al. (2006) Clin Gastroenterol Hepatol 4:1010–1016 3. Asada M, Nishio A et al. (2006) Pancreas 33:20–26 4. Umemura T, Ota M et al. (2006) Gut 55:1367–1368

Chronic pancreatitis, as a complex inflammatory process, is associated with a variety of genes affecting susceptibility to injury, genes modifying the inflammatory response, and genes associated with other complications of recurrent injury or linked with specific types of environmental factors. The most widely studied susceptibility genes include PRSS1 coding for cationic trypsinogen (the cause of autosomal dominant hereditary pancreatitis [2]), SPINK1 coding for pancreatic secretory trypsin inhibitor (PSTI) [3], and CFTR coding for the cystic fibrosis transmembrane conductance regulator [4].

Pancreatitis, Chronic DAVID C. W HITCOMB , D HIRAJ YADAV

Molecular and Systemic Pathophysiology

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA

In most cases chronic pancreatitis is linked to recurrent trypsin-initiated pancreatic injury. Normally, the exocrine pancreas synthesizes digestive enzymes in inactive forms and secretes them into the duodenum during a meal where they are activated by trypsin after enterokinase (a duodenal brush border enzyme) initiates the activation cascade by converting trypsinogen to trypsin. Since trypsin also activates trypsinogen to more trypsin, prematurely activated trypsin within

Definition and Characteristics Chronic pancreatitis is a syndrome of recurrent and chronic pancreatic inflammation and progressive fibrosis, with eventual loss of exocrine and endocrine function and

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the pancreas can trigger the digestive enzyme activation cascade leading to pancreatic injury and an inflammatory response. Recurrent injury leads to chronic inflammation and fibrosis – the hallmarks of chronic pancreatitis. Different pathologic conditions leads to premature activation of trypsinogen inside the acinar cell and inside the pancreatic ducts [5]. Acinar cell protection from trypsin is dependent on low calcium concentrations because they retard trypsinogen activation and facilitate autolysis thru calcium binding sites on the trypsinogen molecule. Mutations in PRSS1 (the trypsinogen gene) effecting calcium-regulated trypsin activity predispose to recurrent acute and chronic pancreatitis. The duct cells protect the pancreas from trypsin by flushing enzymes out of the duct. Secretion is driven by ion secretion through CFTR channels. Mutations in CFTR, or other factors that limit duct drainage, lead to trypsinrelated injury of ductal origin. Biallelic severe CFTR mutations affect other organs, including lungs and intestines, causing cystic fibrosis. PSTI, an acute phase protein and specific trypsin inhibitor, is markedly up regulated in inflammation. Mutations in the PSTI gene, SPINK1, are associated with early onset chronic pancreatitis and tropical pancreatitis.

References 1. Etemad B, Whitcomb DC (2001) Gastroenterology 120:682–707 2. Whitcomb DC, Gorry MC, Preston RA et al. (1996) Nature Genet 14(2):141–145 3. Witt H, Luck W, Hennies HC et al. (2000) Nature Genet 25(2):21321–21326 4. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS (1998) New Engl J Med 339(10):653–658 5. Whitcomb DC (2004) Nat Clin Pract Gastroenterol Hepatol 1(1):46–52

Pancreatitis, Hereditary J OHANNES B ODE Department of Gastroenterology, Hepatology and Infectiology, University-Hospital, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany

Definition and Characteristics Diagnostic Principles Because of the current risk of pancreatic biopsy the diagnosis of chronic pancreatitis is usually inferred from imaging studies demonstrating gland atrophy and distortion, dilation of the duct system, calcifications, pseudocysts or persistent inflammatory masses. Pancreatic insufficiency alone is not diagnostic. Genetic testing is available for the major genes (e.g. PRSS1, SPINK1 and CFTR). Some pancreatitis-associated CFTR mutations do not cause cystic fibrosis, so screening of the entire gene may be indicated.

Therapeutic Principles Chronic pancreatitis is a complex process with many complications, so no single therapy will be effective. Gene therapy is not currently available, but advances in cystic fibrosis therapy may benefit the subset of pancreatitis patients with CFTR mutations. The use of vitamins and antioxidants appears to benefit some patients with hereditary pancreatitis. Dietary recommendations are usually for multiple, small, low fat meals. Lost exocrine function is replaced with pancreatic enzyme supplements, with or without gastric acid suppression. Diabetes is managed with diet, pancreatic enzyme supplements, oral hypoglycemic agents and insulin. Early intervention with prevention of organ injury and fibrosis appears to be the best approach to chronic pancreatitis in the future.

Hereditary pancreatitis is characterized by recurrent episodes of acute pancreatitis or a priori as chronic pancreatitis in several members of one family in the absence of other causes of pancreatitis. Classical hereditary pancreatitis follows an autosomal dominant expression pattern with incomplete penetrance of approximately 80%. The onset of hereditary pancreatitis is bimodal with a first peak of onset at 1–6 years and a second at 18–24 years of age. The median age of onset is 10–13 years. Apart from hereditary pancreatitis, cystic fibrosis is another inherited cause of chronic pancreatitis and mutations within the CFTR gene have been associated with an increased risk for the onset of pancreatitis [1,2].

Prevalence The incidence in Western Europe and North America of acute pancreatitis varies from 4.8 to 24.2 per 100.000 and of chronic pancreatitis from 3.5 to 7.7 per 100.000. Less than 2% of all these cases are related to hereditary pancreatitis with cationic trypsinogen or SPINK mutations or to cystic fibrosis with mutations of the CFTR gene [3].

Genes The disease gene for the classical hereditary pancreatitis phenotype is located on the long arm of chromosome 7. Among the eight trypsinogen genes identified in the T-cell receptor β-chain locus in 7q35 three generate

Pancreatitis, Hereditary

functional proteins: the cationic trypsinogen gene, the anionic trypsinogen gene and the mesotrypsinogen gene. Particularly mutations (A16V, D22G, K23R, N29I, R122H and R122C) of the cationic trypsinogen gene significantly correlate with hereditary pancreatitis. Apart from the cationic trypsinogen gene mutations of the SPINK1 gene (M1T and N34S) and the CFTR gene have been associated with an increased risk for the onset of pancreatitis. Of note, many of these mutations have also been detected in patients with idiopathic chronic pancreatitis that has no obvious hereditary basis. Hence, hereditary pancreatitis should be particularly considered if a positive family history for pancreatitis is reported [1,2,4,5].

Molecular and Systemic Pathophysiology Auto-digestion of the pancreas by various proteases that are activated in response to ectopic activation of trypsinogen is thought to be an important mechanism in the onset of pancreatitis. Pancreatic enzymes are stored as inactive precursors in pancreatic zymogen granules. Normally activation is strictly controlled in order to prevent premature intra-pancreatic activation and subsequent autodigestion. Triggers which impair these protective mechanisms and lead to activation of trypsinogen and of other downstream zymogens include excessive pancreatic exocrine stimulation, reflux of bile, duodenal fluid, disturbance of pancreatic duct flow, alcohol, and inflammation. Control of premature intra-pancreatic activation in particular of cationic trypsinogen is disturbed in patients with inherited pancreatitis, resulting in a higher susceptibility to respective triggers. A relationship between mutations of the cationic trypsinogen gene and pancreatitis was initially reported 1996 [1,2,5], whereas the effect of mutations in the pancreatic secretory trypsin inhibitor (also known as serine protease inhibitor Kazal type [SPINK]1) on the onset of pancreatitis was first reported in 2000. Four mechanisms have been proposed to explain how mutations in the cationic trypsinogen gene can lead to an increase in trypsin activity: 1. Mutation of the cationic trypsinogen protein (R122H and R122C) prevents inactivation of activated trypsin1 by autolysis and results in increased auto-activation. 2. The mutation (N29I) leads to changes of the higher order structure of trypsin, resulting in decreased inactivation by SPINK1 binding, increased stability of trypsin and auto-activation. 3. Increased auto-activation of trypsinogen to trypsin by mutations of the trypsinogen N-terminal peptide (A16V, D22G and K23R) which changes the signal peptide cleavage site of trypsin and increases the susceptibility to trypsin-mediated auto-cleavage.

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4. Enhanced transcriptional activation (228delTCC) of the cationic trypsinogen gene and subsequent increased expression of trypsinogen, facilitating its activation. SPINK1 is a major inhibitor of trypsin in the pancreas. Hence, functional alterations of the SPINK1 gene would result in an imbalance of trypsin activation and its inhibition and may predispose for the development of pancreatitis. Two mutations of the SPINK1 gene at positions 1 (M1T) and 34 (N34S) have been identified which are correlated with increased susceptibility to develop chronic pancreatitis. The M1T mutation eliminates the SPINK start codon leading to an overall loss of SPINK1 activity. Family members carrying this mutation have pancreatitis as dominant trait, indicating that the absence of one functional SPINK1 allele is sufficient to induce pancreatitis. The importance and the functional implication of the N34S mutant is less clear. The N34S mutation in SPINK1 has been reported in familial pancreatitis and in children with idiopathic chronic pancreatitis, but also in 2% of control populations. However, patients homzygous for the N34S mutant of SPINK have an almost 100% risk (98%; 49/50) to develop pancreatitis, which suggests that this mutations may be a recessive inherited trait. An increased prevalence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been reported for patients with idiopathic pancreatitis. CFTR conducts both chloride and bicarbonate, and largely controls pancreatic fluid secretion. Mutations of this gene, together with other genetic and environmental factors, are risk factors for chronic pancreatitis, by altering the ability to clear digestive enzymes from the pancreatic duct.

Diagnostic Principles Genetic testing for inherited pancreatitis should be considered in patients with onset of symptoms of idiopathic pancreatitis at a young age (37.8°C (oral measurement) or >38.4°C (rectal measurement). Diagnosis of endocrine paraneoplastic syndromes can be done on the basis of biological

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criteria (neoplastic tissue which expresses hormones) or clinical criteria (association between tumor and endocrine syndrome). Most frequent syndromes are caused by an ectopic ACTH production, an HCG production, and an inadequate ADH secretion. Metabolic paraneoplastic syndromes are characterized by an alteration of glucose, lipid, and electrolyte metabolism. The parameters for diagnosis of hypercalcemia are A calcium level >10.5 mEq/l, clinical symptoms (i.e., asthenia, anorexia, itch, polydipsia, and dehydration), organ-related signs, in particular renal signs (polyuria, lithiasis, variable grade of renal failure), gastrointestinal signs (nausea, vomiting, constipation, paralytic ileum), cardiac signs (arrhythmia, bradycardia, P-R elongation), and neuromuscular signs (hyporeflexia, somnolence, obfuscation). The diagnosis of hypoglycemia is clinical and it is based on asthenia, confusion, swelling, and shudder. Hyperuricemia can lead to an acute uratic nephropathy. Hematologic Paraneoplastic Syndromes: In chronic anemia the hemoglobin level is usually not inferior to 9 g/dL. Laboratory examinations show reduced levels of iron and hyper-transferrinemia. Clinical characteristics are fatigue, dyspnoea, tachycardia, and all the other typical signs and symptoms of anemia [4,5]. Leukocytosis is characterized by an increase of leukocytes. Differential diagnosis with chronic myeloid leukemia consists in detecting myeloid blasts in the peripheral smear, with the absence of splenomegaly, thrombocytosis, and Philadelphia chromosome. On the other hand, leukopenia is characterized by a decrease of leukocytes with subsequent susceptibility to infections. Coagulation: VTE may be asymptomatic; in some cases, it can be characterized by edema and pain. Clinical features of pulmonary embolism are dyspnoea, tachypnoea, pain, and cough. DIC may be characterized by hemorrhage that can be acute or subacute and generally involves the CNS, the gastrointestinal tract, and the urinary tract. Laboratory examination shows low levels of platelets, fibrinogen, pro-thrombin, and coagulation factors, as well as a PT and a PTT extension.

Therapeutic Principles In all the cases, the best therapy is represented by the tumor treatment. Epoetin can be employed in the treatment of anemia [4,5]. Heparin is used in the treatment of thrombosis.

References 1. Carsons S (1997) The association of malignancy with rheumatic and connective tissue diseases. Semin Oncol 24(3):360–372 2. Voltz R (2002) Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy. Lancet Neurol 1(5):294–305

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3. Tisdale MJ (2001) Cancer anorexia and cachexia. Nutrition 17(5):438–442 4. Manegold C (1998) The causes and prognostic significance of low haemoglobinin levels in tumor patients. Strahlenther Onk 174:17–19 5. Berardi R, Tamburrano T, Fianchini A, et al. (2005) Perioperative anemia and blood transfusions as prognostic factors in patients undergoing resection for non-small cell lung cancer. Lung cancer 49:371–376

Parasternal Chondrodynia ▶Tietze's Syndrome

Parathyroid Hormone and Related Peptides G EOFFREY N. H ENDY Departments of Medicine, Physiology and Human Genetics, McGill University; Calcium Research Laboratory; Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, QC, Canada

Definition and Characteristics Parathyroid hormone (PTH) is essential for the maintenance of calcium homeostasis, and an excess or deficiency can cause severe and potentially fatal illness. PTH is synthesized in the parathyroid glands in the neck, and after secretion, PTH exerts its effects directly on the skeleton and kidneys.

Prevalence Primary hyperparathyroidism, 1 in 1,000; secondary (renal) hyperparathyroidism, 1 in 1,000; and hypoparathyroidism, between 1 in 1,000 and 1 in 10,000.

Genes PTH is the product of a single-copy gene and in mammals has 84 amino acids. The gene, which encodes a larger precursor molecule of 115 amino acids, preproPTH, is organized into three exons. Exon I encodes the 5′ untranslated region (UTR) of the messenger RNA; exon II encodes the NH2-terminal pre- or signal peptide and part of the short propeptide; and exon III

encodes the Lys−2-Arg−1 of the prohormone cleavage site, the 84 amino acids of the mature hormone, and the 3′-UTR of the mRNA (Fig. 1). The gene for PTH-related peptide (PTHrP), a widely expressed cytokine, has a similar organization with the same functional domains – the UTR, preprosequence of the precursor peptide, and the prohormone cleavage site and most or all of the mature peptide – being encoded by single exons. For the PTHrP gene, exons encoding alternative 5′ UTRs, carboxyl-terminal peptides, and 3′ UTRs may also be present depending on the species. The PTH and PTHrP genes map to chromosome 11p15 and chromosome 12p12.1–11.2, respectively. Because of the similarity in NH2-terminal sequence of their mature peptides, their gene organization, and chromosomal locations, it is likely that the PTH and PTHrP genes evolved from a single ancestral gene. The gene for the neuromodulator, tuberoinfundibular peptide of 39 residues (TIP39), a more distantly related member of the gene family, resides on chromosome 19q13.33. The TIP39 gene shares organizational features with the PTH and PTHrP genes having one exon encoding the 5′ UTR, one encoding the precursor leader sequence, and one encoding the prohormone cleavage site and the mature peptide.

Molecular and Systemic Pathophysiology Hyperparathyroidism: Abnormally increased parathyroid gland activity may be primary or secondary. Primary hyperparathyroidism is associated with hyperplasia and neoplasia, the latter predominantly adenomas; parathyroid carcinoma is extremely rare. Parathyroid adenomas are monoclonal, involving molecular genetic derangements, such as loss of the multiple endocrine neoplasia (MEN) type 1 gene on chromosome 11q13, which encodes a tumor suppressor called menin, or overexpression of the cyclin D1 gene on chromosome 11q. Hyperparathyroidism may occur as part of rare familial syndromes including MEN 1, MEN 2A, familial hypocalciuric hypercalcemia (FHH), and neonatal severe hyperparathyroidism (NSHPT). Heterozygous and homozygous inactivating mutations in the parathyroid calcium-sensing receptor (CASR) gene, located on chromosome 3q13.3–21, cause FHH and NSHPT, respectively. Mutations in the CASR gene itself do not contribute to sporadic parathyroid tumorigenesis, although CASR expression is often reduced in parathyroid tumors, Parafibromin, the product of the tumor suppressor gene associated with the hyperparathyroidism-jaw tumor syndrome and some cases of familial isolated hyperparathyroidism, is implicated in sporadic parathyroid carcinoma. Secondary hyperparathyroidism occurs when extracellular calcium and/or 1,25-dihydroxyvitamin D levels fall

Parathyroid Hormone and Related Peptides

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Parathyroid Hormone and Related Peptides. Figure 1 Comparison of the structural organization of the human PTH, PTHrP, and TIP39 genes. Exons are boxed: from left to right, stippled and hatched boxes denote 5′UTRs, white boxes denote presequences, black boxes denote prosequences, light gray stippled boxes denote mature polypeptide sequences, and dark gray stippled boxes denote 3′UTRs. +1 denotes the beginning of the mature polypeptide. [From Hendy GN (2005) Calcium-regulating hormones. Vitamin D and parathyroid hormone. In: Melmed S, Conn PM (eds) Endocrinology: basic and clinical principles, 2nd edn. Humana Press Inc., Totowa, NJ pp 283–299.]

below normal, as in chronic renal disease or vitamin D deficiency. Tertiary hyperparathyroidism ensues when a parathyroid adenoma arises from the secondary hyperplasia caused by chronic renal failure. Excess circulating PTH leads to altered function of bone cells, renal tubules, and gastrointestinal (GI) mucosa. This may result in kidney stones and calcium deposits in renal tubules, and decalcification of bone, resulting in bone pain and tenderness and spontaneous fractures. The hypercalcemia may also lead to muscle weakness and GI symptoms. Hypoparathyroidism: The most common cause of hypoparathyroidism, in which the deficiency of PTH secretion results in hypocalcemia and hyperphosphatemia, is surgical excision of, or damage to, the parathyroid glands. Hypoparathyroidism may be due to metabolic disease such as mitochondrial myoneuropathies, inborn error of oxidative fatty acid metabolism or metal storage disorders. Isolated or idiopathic hypoparathyroidism develops as a solitary endocrinopathy: familial forms occur with either autosomaldominant, autosomal-recessive, or X-linked recessive modes of inheritance. Familial autosomal hypoparathyroidism can be due to inactivating mutations in the PTH gene, activating mutations in the CASR gene, or inactivation of the gene encoding the transcription factor glial cell missing-2. Hypoparathyroidism may also occur as part of a pluriglandular autoimmune disorder (AIRE gene) or as a complex congenital defect, including the DiGeorge (Tbx1 transcription factor and other genes), autosomal-recessive Kenny-Caffey or Sanjad-Sakati (tubulin-specific chaperone E gene), and Barakat or HDR (hypoparathyroidism, nerve deafness, and renal dysplasia) (GATA3 transcription factor gene) syndromes.

Diagnostic Principles Primary Hyperparathyroidism: Primary hyperparathyroidism must be differentiated from other causes of hypercalcemia such as humoral hypercalcemia of malignancy, vitamin D or vitamin A intoxication, milk-alkali syndrome, granulomatous disorders (especially sarcoidosis), immobilization of patients with a pre-existing high bone turnover state such as adolescence, thyrotoxicosis, Paget’s disease and treatment with thiazide diuretics or lithium. PTHrP is the major (although not the only) causative agent in the humoral hypercalcemia of malignancy. Hypoparathyroidism: Acute hypocalcemia can be life threatening and present with seizures, tetany or cardiac arrhythmias.

Therapeutic Principles Hyperparathyroidism: Criteria for surgery in hyperparathyroidism have been established by a consensus conference and a follow-up workshop of the National Institutes of Health. Candidates for surgery are those having one or more of the following: hypercalcemia >11.6 mg/dL; hypercalciuria >400 mg/day; kidney stones; reduced bone density or age 25% of patients with parkinsonism and disease onset before age 30. Clinical symptoms also include focal dystonia and diurnal fluctuations. The locus PARK5 on chromosome 4p is very rarely associated with autosomal-dominant PD, and a mutation of an ubiquitin C-terminal hydrolase gene which is located within this locus was detected in one family with PD. The PD locus PARK6 on chromosome 1p35–36 relates to mutations of a mitochondrial kinase gene (PINK1). First mutations were identified in patients with early onset autosomal-recessive inheritance. However, heterozygous gene carriers may develop late onset parkinsonism.

Parkinson’s Disease

Parkinson’s Disease. Table 1

Synopsis of familial (monogenetic) parkinsonian syndromes

Name of the locus

Locus

PARK1 [OMIM: 168601] PARK2 [OMIM: 600116] PARK3 [OMIM: 602404] PARK4 PARK5 [OMIM: 191342] PARK6 [OMIM: 605909] PARK7 [OMIM: 606324] PARK8 [OMIM: 607060]

4q21– 23 6q25– 27 2p13

SNCA, ad α-Synuklein Parkin, Parkin ar –

ad

4p14

UCH-L1, UCH-L1 PINK1, PINK1 DJ-1, DJ-1

ar

Early

ar

Early

ad, sporadic

Early

Ar

Early

PARK9 [OMIM: 606693] PARK10 [OMIM: 606852] PARK11 [OMIM: 607688] Nurr1 [OMIM: 601828] Synphilin-1 [OMIM: 603779] NF-M Mitochondrium [OMIM: 252010]

1p35– p36 1p36

Gene, protein

12p11– LRRK2, q13 Dardara (LRRK2) 1p36 –

Mode of inheritance

Age at onseta

Comments

Middle

Lewy bodies (diffuse pattern), fast progression, postural tremor, late onset dementia Juvenile Unspecific nigral degeneration, rare Lewy boy pathology, slow progression, focal dystonia Late Lewy bodies (typical pattern in brain stem), dementia Same gene as PARK1 locus, refer to PARK1 locus Middle No neuropathological data, only one family No neuropathological data, slow progression, tremor, dystonia Heterozygous cases with Lewy bodies, slo progression, focal dystonia Lewy bodies, tauopathy, levodopa responsive

1p32

–

Late

Spasticity, supranuclear palsy, dementia, also: Kufor-Rakeb-Syndrome Iceland population study

2q36– 37 2q22– 23 5q23

–

Late

Sibling study

NR4A2, Nurr1 Ad

Late

Lewy bodies (brain stem)

SNCAIP, Synphilin-1 NF-M, NF-M NADH Komplex 1

Late

–

8p21

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Juvenile Only one family, late-onset dementia Mitochondrial Late –

P

ad, autosomal-dominant; ar, autosomal-recessive; Nurr1, Nuclear receptor-related 1, UCH-L1, Ubiquitine C-terminal hydrolase L1, NF-M, neurofilament medium, LRRK2, Leucine-rich repeat kinase 2; juvenile onset (mean age at onset 60 years).

The frequency of these mutations is not yet clear. Clinical symptoms seem to be similar to those elicited by parkin mutations, although focal dystonia may be less frequent. PARK7 was mapped to chromosome 1p36. The gene product is an RNA binding protein termed DJ-1, which is activated by oxidative stress. Mutations in this gene are rare and induce early onset and slowly progressive autosomal-recessive parkinsonism. PARK8 seems to be the locus most relevant to sporadic PD. Many mutations in the respective gene, leucine rich repeat kinase 2 (LRRK2), have been identified in families with autosomal-dominant late onset parkinsonism. Up to 70% of families with late onset parkinsonism may carry mutations in this gene. Due to a limited penetrance also 2% of patients with sporadic disease carry such mutations. LRRK2 is a so-called ROCO gene with many different functional domains. The most frequent mutation

(Gly2019Ser) occurs within a MAP kinase kinase kinase domain. Clinical symptoms are variable with many patients presenting with a typical PD syndrome, but others may present with predominant dementia, dystonia, etc. Also neuropathological findings may vary within the same family from classical Lewy body disease to abnormal Tau pathology. PD has been associated with genetic polymorphisms of various genes, including genes of the dopamine metabolism, the dopamine transporter gene and the gene encoding for α–synuclein (SNCA gene). However, most of these results were not confirmed by other association studies.

Molecular and Systemic Pathophysiology The hallmark of PD is a loss of dopaminergic neurons within the substantia nigra pars compacta with

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cytoplasmic inclusions in the remaining cells and a subsequent dopamine deficiency in the striatum. This dopamine deficiency leads to an increased activity of inhibitory output neurons of the basal ganglia loop located in the medial segment of the globus pallidus. Except for familial syndromes, the pathogenesis remains unclear, although there are also patients with parkinsonism following specific infections (vonEconomo encephalitis) or intoxications (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; MPTP). The latter compound induces mitochondrial dysfunction via blockade of complex I in dopaminergic neurons. Whether this mechanism is also relevant to patients with sporadic disease is still not clear. However, several lines of evidence exist for a pivotal role of reduced mitochondrial activity, increased oxidative stress, and impaired function of the ubiquitin-proteasome system in the pathogenesis of PD. It is in contrast unclear how these mechanisms fit into a global pathogenetic concept.

Diagnostic Principles The diagnosis is primarily clinical. Established criteria are based on the cardinal symptoms bradykinesia, resting tremor, rigidity and loss of postural reflexes as well as asymmetry and responsiveness to levodopa [4,5]. Degeneration of dopaminergic neurons in the substantia nigra may be proven by nuclear medicine techniques and ligands that specifically bind to these neurons.

Therapeutic Principles At present, dopamine replacement therapy remains the gold standard. Levodopa as a metabolic precursor of dopamine is the most frequently used antiparkinsonian drug. It is very effective and well tolerated, but during long-term treatment several side effects occur including motor fluctuations, dyskineasias and psychiatric symptoms. Dopamine agonists are chemical compounds which directly act on dopamine receptors, while MAO-B inhibitors and COMT-inhibitors block levodopa and/or dopamine catabolism. Amantadine as an inhibitor of glutamate receptors of the NMDA type and displays mild antiparkinsonian effects and additionally some antidyskinetic activity. The use of anticholinergics seems obsolete. Advanced patients can be treated via modulation of the neuronal activity in the subthalamic nucleus using deep brain stimulation.

References 1. Lang AE, Lozano AM (1998) Parkinson’s disease. Second of two parts. N Engl J Med 339(16):1130–1143 2. Lang AE, Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339(15):1044–1053

3. Tanner CM, Goldman SM, Aston DA, Ottman R, Ellenberg J, Mayeux R et al. (2002) Smoking and Parkinson’s disease in twins. Neurology 58(4):581–588 4. Hughes AJ, Daniel SE, Blankson S, Lees AJ (1993) A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 50(2):140–148 5. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125 (Pt 4):861–870

Paroxismal Nocturnal Hemoglobinuria J OHN -J OHN B. S CHNOG 1 , V ICTOR E. A. G ERDES 2 1

Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands 2 Amsterdam Vascular Medicine Group, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Definition and Characteristics Acquired hematologic disorder. The mean age at presentation is 30–40 years (range 6–82) and the median survival at diagnosis is 10–15 years. A deficiency of the glycosylphosphatidylinositol (GPI) anchor in red blood cells leads to the absence of several GPI-linked proteins, which makes these cells more sensitive to the lytic effect of complement. Frequent hemolytic episodes and thrombosis in hepatic, other intraabdominal, cerebral, and peripheral veins as well as marrow aplasia are clinical manifestations of the disease. Progression to leukemia or a myelodysplastic syndrome may occur.

Prevalence The prevalence is estimated a few cases per million.

Genes Phosphorylinositol glycan class A (PIG-A), Xp22.1.

Molecular and Systemic Pathophysiology A number of cell surface proteins are missing in PNH. Some of these, CD59 and CD55, protect red blood cells against the hemolytic action of complement. The GPI anchor is essential for a number of proteins to attach to the cell membrane. The observation that all missing proteins in PNH are GPI related implicates that a defect in the complex biosynthesis of GPI must be involved in PNH pathogenesis. The first step in GPI synthesis, the transfer of N-acetylglucosamine to phosphatidylinositol, is defective in PNH patients. The PIG-A gene and

Paroxysmal Dyskinesias

three other genes are involved in this transfer. A number of mutations in the PIG-A gene, which led to partial or complete GPI deficiency, have been observed in PNH patients. In some patients, multiple erythroid clones have been identified. All patients with PNH have mutations of the PIG-A gene in hematopoietic stem cells, but a certain predisposition (which is yet to be identified) is needed for the expansion of PNH cells. The pathophysiology of thrombosis in PNH is not fully understood, but may involve pro-coagulant platelet microvesicle formation (platelets in PNH lack complement activation regulatory proteins as well), increased prothrombinase activity as well as impaired fibrinolysis (due to deficiency of the GPIlinked urokinase plasminogen activator receptor of monocytes).

Diagnostic Principles Lysis of erythrocytes by acidified serum is demonstrated in the Ham test, the classic test that is still a specific and relatively sensitive test. With the use of flow cytometry quantification of specific GPI-anchor binding using fluorescent-labeled inactive toxin aerolysin (FLAER), it is possible to detect small PNH clones.

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5. Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP (2004) Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. NEJM 350:552–559

Paroxysmal Cold Hemoglobinuria ▶Anemia, Hemolytic Autoimmune

Paroxysmal Dyskinesias S USANNE A. S CHNEIDER , K AILASH P. B HATIA Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, UK

Synonyms Therapeutic Principles The treatment of anemia is supportive. Iron supplementation, to compensate the iron loss due to hemosiderinuria, and folic acid supplementation are recommended, with red blood cell transfusions only when necessary. Prednisone reduces the rate of hemolysis. Also androgens are effective in reducing anemia. Treatment with an antibody against terminal complement protein C5, eculizumab, reduced intravascular hemolysis, hemoglobinuria, and the need for transfusion in a recent study. Bone marrow transplantation is generally reserved for patients with life-threatening disease.

References 1. Hillmen P, Richards SJ (2000) Implications of recent insights into the pathophysiology of paroxismal nocturnal haemoglobinuria. Br J Haemat 108:470–479 2. McKusick VA (2005) Phosphatidylinositol glycan, class A; PIGA. Online Mendelian Inheritance in Man 3. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV (1995) Natural history of paroxismal nocturnal hemoglobinuria. NEJM 333:1253–1258 4. Socie G, Mary JY, De Gramont A, Rio B, Leporrier M, Rose C, Heudier P, Rochant H, Cahn JY, Gluckman E (1996) Paroxismal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet 348:573–577

Paroxysmal dystonic choreoathetosis; PDC; historically: Extrapyramidal epilepsy; Striatal epilepsy; Tonic seizures; Reflex epilepsy; Periodic dystonia

Definition and Characteristics Intermittent attacks of involuntary movements, usually dystonia, chorea or ballism, induced by trigger factors including sudden movements (paroxysmal kinesigenic dyskinesia, PKD), prolonged exercise (paroxysmal exercise-induced dyskinesia, PED) or alcohol and coffee (paroxysmal non-kinesigenic dyskinesia, PNKD) or during sleep (nocturnal hypnogenic dyskinesia, PHD) according to the Demirkiran and Jankovic classification [1,2]. Onset of primary forms is usually in childhood. PKD: up to 30–100 very brief (seconds) attacks per day triggered typically by sudden movement or sudden increase in speed, amplitude, force or strength, startle, sound, photo stimulation, vestibular stimulation, hyperventilation or stress. Speech disturbance in 30%. Sometimes aura. Refractory period (20 min). PNKD: attacks (30 min–6 h) induced by alcohol, coffee, coke, tobacco, emotional excitement, hunger, concentration or fatigue several times per week or per year. 1/3 secondary cause. PED: Attacks (2 min–2 h) induced by prolonged or sustained exercise usually affecting the feet (80%).

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PHD: Intermittent (sometimes complex) attacks (30–60 s) often in clusters during non-REM sleep, particularly stages 2–3, causing sleep fragmentation. Manifestation of nocturnal frontal lobe epilepsy (NFLE). Other paroxysmal disorders: Paroxysmal ataxias (episodic ataxia 1 and 2); tonic spasms in MS; torticollis in infancy; Sandifer’s syndrome; paroxysmal superior oblique myokymia; paroxysmal tonic conjugate deviation of the eyes.

Prevalence Data limited, overall rare. One report states 92 cases among 12,063 patients (0.76%) seen over 19 years.

Genes PKD: 70% familial, autosomal dominant. Heterogeneity. Linkage to at least two loci on chromosome 16. A third locus must exist as not all cases link to chromosome 16. Proximity or overlap with infantile convulsions (ICCA syndrome) and rolandic epilepsy, paroxysmal exercise-induced dyskinesia and writer’s cramp (RE-PED-WC). PNKD: autosomal dominant. Missense mutation (A7V and A9V) in the myofibrillogenesis regulator gene (MR-1) (2q33–35), associated with the myofibril contractile apparatus. A separate condition “paroxysmal choreoathetosis/spasticity” has been mapped to a region of 2 cM between D1S443 and D1S197 on chromosome 1p. PHD: NFLE (eponym “autosomal dominant nocturnal frontal lobe epilepsy” (ADNFLE)), see chapter on “Idiopathic focal epilepsies.” PED: genetic defects not known.

Molecular and Systemic Pathophysiology PNKD: Mutations cause alteration in the aminoterminal α-helix [3]. There are two isoforms, MR-1S and MR-1L. The MR-1S isoform is ubiquitously expressed in peripheral tissues and the brain and shows diffuse cytoplasmic and nuclear localization. The MR1L isoform is exclusively expressed in the cell membrane of the brain. Within the mouse brain, mRNA expression (detected by BRP17) was allocated to the substantia nigra, albeit at low levels, apart from other areas (red nucleus, mammillary nucleus, raphe nucleus, interpeduncular nucleus, the periaqueductal grey, forebrain areas (cortex, hippocampus, dentate gyrus and medial and lateral habenula) and ventral regions including the piriform cortex, amygdala and the ventromedial hypothalamic nucleus, cerebellum (granule cells and Purkinje cell layers, particularly in the lateral lobules and the paraflocculus) and the spinal cord) [3]. It has been suggested that the regions involved in motor control (basal ganglia, motor cortex

and cerebellum) or rather their dys-function may play an important role in PNKD [3]. There is no published information on human gene function but homology of MR-1L with the hydroxyacylgluthatione hydrolase (HAGH), a member of the zinc metallohydrolase enzyme family, was found by gene bioformatic analysis (41% identity) [3]. All zincbinding residues were conserved. HAGH plays a role in the detoxification pathway of methylglyoxal, a compound present in coffee and alcoholic beverages both of which can induce attacks in patients with PNKD. PHD [4]: see chapter on ▶Idiopathic focal epilepsies.

Diagnostic Principles Diagnosis depends on a detailed history, family history and clinical characterization of the type of dyskinesias. Secondary causes, i.e. demyelination, vasculopathy, infectious disease (HIV, CMV), cerebral and peripheral trauma, neurodegenerative disease, hormonal and metabolic dysfunction (diabetes mellitus, hyperthyroidism, hypoparathyroidism, pseudohypoparathyroidism), neoplasm, Chiari malformation, cervical syringomyelia and cerebral palsy must be excluded. Ictal and interictal EEG and sleep-EEGs usually show normal or transient epileptic discharges. Basal ganglia hyperperfusion occurs contralaterally to the side of attacks (PKD and PNKD) or anterior cingulate gyrus (PHD) on SPECT.

Therapeutic Principles PKD: Anticonvulsants, carbamazepine as first choice but also levetiracetam, oxcarbazepine, phenytoin, topiramate, barbiturates or acetazolamide. PNKD: Triggering factors should be avoided. The response to antiepileptics is less dramatic than in PKD. Benzodiazepines, sodium valproate, haloperidol, gabapentin or acetazolamide are used. PED: Gabapentin, clonazepam. PHD: Carbamazepine, phenytoin and acetazolamide.

References 1. Demirkiran M, Jankovic J (1995) Ann Neurol 38:571–579 2. Bhatia KP (1999) J Neurol 246:149–155 3. Lee HY, Xu Y, Huang Y et al. (2004) Hum Mol Genet 13:3161–3170 4. di Corcia G, Blasetti A, De Simone M, Verrotti A, Chiarelli F (2005) Eur J Paediatr Neurol 9:59–66

Paroxysmal Dystonic Choreoathetosis ▶Paroxysmal Dyskinesias

Patent Ductus Arteriosus

Paroxysmal Supraventricular Tachycardia

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Partial Persistent Truncus Arteriosus ▶Aortopulmonary Septal Defects

▶Tachycardia, Supraventricular

Partial Tetrasomy 15(pter-q13) Pars Planitis ▶Inv Dup (15) ▶Uveitis

Partial 11q Monosomy Syndrome ▶Jacobsen Syndrome

Partial Tetrasomy or Trisomy (22pter-22q11) ▶Cat Eye Syndrome

Patau Syndrome Partial Albinism ▶Trisomy 13 ▶Piebaldism

Patent Ductus Arteriosus Partial Androgen Insensitivity Syndrome ▶Androgen Insensitivity Syndrome

A DRIANA C. G ITTENBERGER- DE G ROOT, R EGINA B O¨ KENKAMP, M ARCO C. D E RUITER Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands

Synonyms Persistent ductus arteriosus; PDA

Partial Epilepsies of Childhood ▶Epilepsy, Benign Childhood with Centrotemporal Spikes and other Idiopathic Partial Epilepsies of Childhood

Definition and Characteristics Normal ductal closure after birth consists of physiological contraction followed by irreversible anatomical closure. When this closing process is absent or delayed, we talk about patent ductus arteriosus (PDA). If still present in a full-term infant beyond the age of 3 months,

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Patent Ductus Arteriosus

it is referred to as persistent ductus arteriosus. There is no strict use of the terms clinically. The PDA is histologically characterized by the close adherence between the endothelium and a subendothelial elastic lamina. Under pathological circumstances, this is an additional lamina on top of the intimal cushion, whereas in premature infants without cushion formation and delayed closure this is the regular internal elastic lamina [1,2].

Prevalence PDA occurs in 13.5% of all heart defects at birth. Data on the prevalence of PDA in full-term infants beyond the age of 3 months are not available. PDA can be found as an isolated anomaly and accompanying various congenital cardiac malformations.

Genes PDA in full-term infants is believed to be multifactorial. Familial recurrence and syndromic forms have been reported. Autosomal-recessive PDA could be linked to chromosome 12q24 [3]. In the autosomal-dominant trait of Char syndrome, the TFAP2B gene has been mapped to the critical region 6p12–21, encoding a neural crest-related transcription factor [4]. In a strain of beagles, PDA is a dominant inherited anomaly with histopathological abnormalities of the elastin deposition similar to the human PDA cases. Mutations in the human MYH11 (myosin heavy chain) genes are demonstrated to cause thoracic aortic aneurysms and/or aortic dissection (TAAD) and PDA [5].

Molecular and Systemic Pathophysiology The PDA is a vascular shunt between the systemic circulation and the pulmonary circulation. The pathophysiological consequences of these malformations vary with the size of the ductus and additional cardiac anomalies. In small- to moderate-sized isolated PDA (Fig. 1a), the continuous left-to-right shunt leads to

volume overload of the left side of the heart. The pulmonary vascular bed is not damaged by this restrictive ductus, and pulmonary pressure remains low. In large PDA (Fig. 1b) with low pulmonary vascular resistance, pulmonary congestion and medically untractable heart failure can develop. As a reaction, pulmonary arteriolar damage occurs, pulmonary vascular resistance increases, and the shunt can disappear. When the pulmonary vascular resistance exceeds the systemic vascular resistance, the ductal shunt can reverse, leading to cyanosis. Right ventricular failure due to irreversible pulmonary hypertension will develop as a final complication of PDA.

Diagnostic Principles Beyond the neonatal period, clinical diagnosis of uncomplicated PDA is suspected in presence of the pathognomonic “machinery” murmur. ECG changes reflect the pathophysiological conditions and show left ventricular hypertrophy in small- to moderate-sized PDA and biventricular hypertrophy in large PDA and right ventricular hypertrophy in patients after shunt reversal. X-ray shows the combination of cardiomegaly and pulmonary engorgement with large leftto-right shunt and the typical dilated central pulmonary arteries and rarefied peripheral pulmonary arteries with a normal-sized heart in PDA with shunt reversal. The combination of two-dimensional and Dopplerechocardiography including color-flow-mapping is conclusive in the vast majority of patients with PDA. During cardiac catheterization, oxygen step-up in the pulmonary artery, angiographic visualization of the PDA, and direct catheterization of the ductus document the presence of PDA.

Therapeutic Principles Most of uncomplicated PDA are amenable to transcatheter closure with endovascular devices. Surgical closure

Patent Ductus Arteriosus. Figure 1 Angiocardiograms of the persistent ductus arteriosus (PDA). Arrows indicate a small PDA in (a) and a large PDA in (b) connecting the pulmonary trunk to the aortic arch (AoA).

Patent Omphalomesenteric Duct

of isolated PDA is indicated in symptomatic small infants after full-term birth and if medical therapy using the prostaglandin synthesis inhibitors, indomethacin and ciboprofen, is contraindicated or has failed in premature infants [2]. In complicated PDA with irreversible pulmonary hypertension ductal closure is contraindicated. In case of ductus-dependent anomalies, PDA is medically maintained by prostaglandin treatment that inhibits ductal contraction.

References 1. Gittenberger-De Groot AC (1977) Persistent ductus arteriosus: most probably a primary congenital malformation. Br Heart J 6:610–618 2. Gittenberger-De Groot AC et al. (1980) The ductus arteriosus in the preterm infant: Histologic and clinical observations. J Pediatr 96:88–93 3. Mani A et al. (2002) Finding genetic contributions of sporadic disease: a recessive at 12q24 commonly contributes to patent ductus arteriosus. Proc Natl Acad Sci USA 99:15054–15059 4. Satoda M et al. (2000) Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet 25:42–46 5. Zhu L et al. (2006) Mutations in myosin heavy chain 11 cause a syndrome associating aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38:343–349

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Definition and Characteristics A patent omphalomesenteric duct typically presents with an umbilical discharge which is often feculent, but may also be bilious or serous (Fig. 1) [1]. Less commonly, it presents with an umbilical mass. If the patent omphalomesenteric duct is large enough, prolapse or intussusception of the small bowel may occur [2]. This may necessitate urgent surgical intervention to prevent infarction of the bowel [2]. Other complications include bleeding from the umbilical mucosa, umbilical infection, and the potential for malignancy [2].

Prevalence Anomalies of the omphalomesenteric duct occur in approximately 2% of the population. Patent omphalomesenteric duct accounts for about 2% of the omphalomesenteric duct anomalies. The sex distribution is equal.

Genes Plastin 1 (also known as Fimbrin) is a distinct plastin isoform which is specifically expressed at high levels in the small intestine [3]. It has been hypothesized that plastin 1 (PLS1) is a candidate gene for the persistence of omphalomesenteric duct.

Molecular and Systemic Pathophysiology

Patent Foramen Ovale ▶Intra-cardiac Shunts ▶Pentalogy of Fallot

Patent Omphalomesenteric Duct A LEXANDER K. C. L EUNG 1 , A NDREW L. WONG 2 1

Department of Pediatrics, Alberta Children’s Hospital, The University of Calgary, Calgary, AB, Canada 2 Department of Surgery, Alberta Children’s Hospital, The University of Calgary, Calgary, AB, Canada

In fetal life, the omphalomesenteric duct connects the primitive mid-gut to the yolk sac of the embryo through the umbilical cord. The duct forms a conduit for nourishment until the placenta is formed. The omphalomesenteric duct contains the omphalomesenteric arteries which nourish the yolk sac and the omphalomesenteric veins which drain into the sinus venosus. As the placental circulation increases, the omphalomesenteric duct involutes and disappears by the 7th–9th week of fetal life [1]. One murine study suggests that absence of inhibitory mesodermal interactions during development might result in a patent omphalomesenteric duct [4]. Its persistence may result in a completely patent omphalomesenteric duct (umbilical enteric fistula); a partially patent omphalomesenteric duct (an umbilical sinus will result if the peripheral portion is involved; a vitelline cyst, if the intermediate portion is involved; and a Meckel diverticulum, if the enteric portion is involved); a mucosal remnant at the umbilicus (umbilical polyp); and a congenital band (obliterated omphalomesenteric duct).

Diagnostic Principles Synonyms Patent vitelline duct; Enteroumbilical fistula; Umbilical enteric fistula

Umbilical discharge may be due to a patent omphalomesenteric duct, a patent urachus, or an umbilical granuloma. The nature of the discharge can often give

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Patent Vitelline Duct

Patent Omphalomesenteric Duct. Figure 1 A newborn infant with a patent omphalomesenteric duct, presenting with fecal discharge from the umbilicus.

clue to the diagnosis. A patent omphalomesenteric duct should be suspected if an “umbilical granuloma” fails to respond to cauterization with silver nitrate or the presence of a non-vascular lumen in a transected umbilical cord. If the diagnosis is in doubt, a contrast study via the stoma or ultrasonography can be used to delineate the nature of the lesion.

Therapeutic Principles A patent omphalomesenteric duct should be ligated and excised. Perioperative intravenous antibiotics should be given. Full exploration and identification of all umbilical structures should be performed [5].

References 1. Leung AK, Kao CP (1999) Consultant 39:2833–2848 2. Fleming F, Ishtiaq A, O’Connor J (2001) Ir Med J 94:182 3. Zweier C, Guth S, Schulte-Mattler U et al. (2005) Eur J Med Genet 48:360–362 4. Bossard P, Zaret KS (2000) Development 127:4915–4923 5. Cilley RE (2006) In: Grosfeld JL, O’Neill JA Coran Jr, AG (eds) Pediatric surgery, 6th edn. Mosby Elsevier, Philadelphia, PA, pp 1143–1156

Patent Vitelline Duct ▶Patent Omphalomesenteric Duct

Pathological Gambling U NDINE E. L ANG Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Berlin, Germany

Synonyms Impulse control disorders; Addiction

Definition and Characteristics Pathological gambling is classified in the DSM-IV as a disorder of impulse control with the essential feature being recurrent and maladaptive gambling behavior. Pathological gambling is a male dominated chronic progressive disease characterized by the overwhelming wish to gamble, with harmful consequences, thus sharing typical features with other impulse control disorders like trichotillomania, kleptomania or pyromania [1].

Prevalence With rates of about 0.2–3.4%, pathological gambling is a prevalent and highly disabling impulse control disorder, which also represents a form of nonpharmacological addiction. Gambling is strongly connected with antisocial personality disorder and substance abuse disorder but associations exist with depression, cyclothymia, bipolar disorder, alcohol, tobacco and attention deficit hyperactivity and with obsessive-compulsive, antisocial, narcissistic and borderline personality disorders.

Pathological Gambling

Genes As with most other behavioral syndromes, pathological gambling is a multifactorial, polygenic disorder. Male pathological gamblers in particular have up to 20% of pathological gamblers in their first-degree relatives and twin studies also indicate that genetic factors play a role in pathological gambling [1,2]. In accordance with therapeutic efforts and several neurochemical findings in gamblers, defects in a number of neurotransmitters have been implicated including dopamine, norepinephrine, serotonin and endorphins. Several specific genes have been implicated as risk factors, including the DRD2, DRD1, DRD4, DAT1, TPH, ADRA2C, NMDA1 and PS1 genes [2–4].

Molecular and Systemic Pathophysiology Increased impulsiveness and behavioral disinhibition is a key feature of several pathological states, i.e., attention deficit hyperactivity disorder, drug addiction, pathological gambling and frontal lobe syndrome. A pathological modulation of frontal lobe function was presumably involved in all of these conditions. In fact, there is evidence that an interplay between several competing decision making networks, which is involved in impulsive decisions exists in the brain. While economical planning is mediated by lateral prefrontal and parietal areas, immediate rewards seem to recruit paralimbic areas associated with midbrain dopamine neurons, including the nucleus accumbens, medial orbitofrontal cortex and medial prefrontal cortex. Common “timeless” decisions might be modulated by the prefrontal cortex and posterior parietal cortex, whereas general impatience craving for an immediate reward might be generated in limbic areas. There is ample evidence that the modulation of dopamine levels as well as dopaminergic areas in the brain affect impulsive choice behavior. Several studies found that systemic administration of D2 antagonists, but not D1 antagonists increased impulsive choice behavior and there is increasing awareness that pathological gambling can occur as a complication of Parkinson’s disease in up to 10% of patients mostly those receiving dopamine agonists. Lesions of the main serotonergic source in the brain, the rat raphe nucleus result in preference for immediate rewards and correspondingly, selective 5-HT reuptake inhibitors and 5-HT agonists decrease impulsive behavior in pigeons and rats [3].

Diagnostic Principles DSM-IV diagnostic criteria of persistent and recurrent maladaptive gambling behavior are indicated by at least five of the following [5]: 1. Is preoccupied with gambling (e.g., preoccupied with reliving past gambling experiences, handicapping

2. 3. 4. 5.

6. 7. 8.

9.

10.

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or planning the next venture or thinking of ways to get money with which to gamble). Needs to gamble with increasing amounts of money in order to achieve the desired excitement. Has repeated unsuccessful efforts to control, cut back or stop gambling. Is restless or irritable when attempting to cut down or stop gambling. Gambles as a way of escaping from problems or of relieving a dysphoric mood (feelings of helplessness, guilt, anxiety, depression). After losing money gambling, often returns another day in order to get even (“chasing” one’s losses). Lies to family members, therapist or others to conceal the extent of involvement with gambling. Has committed illegal acts, such as forgery, fraud, theft or embezzlement, in order to finance gambling. Has jeopardized or lost a significant relationship, job or educational or career opportunity because of gambling. Relies on others to provide money to relieve a desperate financial situation caused by gambling [5].

Therapeutic Principles Several outcome studies have shown cognitivebehavioral therapy to be effective in the treatment of pathological gambling. Pharmacological treatment has been proven to be effective partly depending on the main psychopathological background of the gambling. Based on this clinical concept, gamblers have been divided into three subgroups, the obsessivecompulsive subtype, the impulsive subtype and the addictive subtype. The obsessive-compulsive subtype, typically also displaying depressive and compulsive symptoms, might primarily respond to serotonin reuptake inhibitors and venlafaxine treatment. In the addictive subtype, opioid antagonists such as naltrexone or nalmefene might serve as first line agents, while impulsive subtype patients might respond best to mood stabilizers or bupropion [1].

References 1. Dannon PN, Lowengrub K, Gonopolski Y, Musin E, Kotler M (2006) Pathological gambling: a review of phenomenological models and treatment modalities for an underrecognized psychiatric disorder. Prim Care Companion J Clin Psychiatry 8:334–339 2. Eisen SA, Lin N, Lyons MJ et al. (1997) Familial influences on problem gambling: an analysis of 3,359 twin pairs. Am J Med Gen 74:657–658 3. Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Chen C, Koh P, Farwell K, Blake H, Dietz G, MacMurray JP, Lesieur HR, Rugle LJ, Rosenthal RJ (2001) The additive effect of neurotransmitter genes in pathological gambling. Clin Genet 60:107–116

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Pauci-immune Glomerulonephritis

4. Ibanez A, Blanco C, de Castro IP, Fernandez-Piqueras J, Saiz-Ruiz J (2003) Genetics of pathological gambling. J Gambl Stud Spring 19:11–22 5. American Psychiatric Association (2000) DSM-IV-TR: Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Arlington

Pauci-immune Glomerulonephritis ▶Glomerulonephritis, Crescentic

PCD ▶Siewert Syndrome ▶Immotile Cilia Syndrome

PCD Deficiency ▶Tetrahydrobiopterin Deficiencies

PA-VSD ▶Pulmonary Atresia

PCLD ▶Polycystic Liver Disease

PBC ▶Biliary Cirrhosis, Primary

PCNSL PBGD Deficiency

▶Lymphomas, Primary Central Nervous System

▶Porphyria, Acute Intermittent

PCNV PC Deficiency ▶Nausea and Vomiting ▶Pyruvate Carboxylase Deficiency

PC-II ▶Pachyonychia Congenita

PcP ▶Pneumocystis Pneumonia

Pectus Carinatum

PCP ▶Pneumocystis Pneumonia

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Pectus Carinatum A LEXANDER K. C. L EUNG Department of Pediatrics, Alberta Children’s Hospital, The University of Calgary, Calgary, AB, Canada

PCT ▶Porphyria Cutanea Tarda

PDA ▶Patent Ductus Arteriosus

PDC ▶Paroxysmal Dyskinesias

PDCD ▶Corneal Dystrophy, Pre-Descemet

PDD ▶Autism Spectrum Disorders

Synonyms Pigeon chest; Pigeon breast; Chicken breast

Definition and Characteristics Pectus carinatum is characterized by anterior protrusion of the chest wall and sternum, which is often accentuated by lateral depression of the costal cartilage (Harrison’s groves) (Fig. 1). When the protrusion is in the sternal manubrium, it is called a chondomanubrial deformity or “pigeon breast” [1]. On the other hand, when the protrusion occurs in the body of the sternum, it is called a chondrogladiolar deformity or “chicken breast” [1]. The deformity can be unilateral or bilateral. The latter can be symmetrical or asymmetrical. Torsion and angulation of the sternum is seen in 10% of cases. The deformity is usually mild but can be severe. In contrast to pectus excavatum which is usually noted at birth, pectus carinatum usually becomes apparent at about 3–4 years of age and progressively increases as the child grows. The deformity becomes much more severe during the period of most rapid growth in adolescence. Most patients are asymptomatic; occasional patients may have bone pain or tenderness at the site of protrusion. Unlike pectus excavatum, pectus carinatum does not appear to be associated with significant abnormalities of cardiovascular or respiratory function [2]. Pectus excavation is often an isolated malformation but can be a component manifestation in various genetic syndromes such as trisomy 18, Ehlers-Danlos syndrome, and Marfan syndrome [2]. Associated anomalies include scoliosis, kyphosis, coarctation of the aorta, and mitral valve disease.

Prevalence The overall prevalence is 1 in 1,700. The male to female ratio is 4:1 [1].

Genes

Pearson Syndrome ▶Mitochondrial Disorders

A genetic component is suggested by the fact that approximately 25 to 30% of patients have a family history of chest wall defect [1]. It has been postulated that pectus carinatum might be due, at least in part, to defects in connective tissue genes such as fibrillin, collagen, and transforming growth factor ß [3]. Mutations in different homeobox (HOX) genes (e.g. HOXA11,

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Pectus Excavatum

3. Creswick HA, Stacey MW, Kelly RE Jr et al. (2006) J Pediatr Surg 41:1699–1703 4. Yue Y, Farcas R, Thiel G et al. (2007) Eur J Hum Genet 15:570–577 5. Poncet P, Kravarusic D, Richart T et al. (2007) J Pediatr Surg 42:898–903

Pectus Excavatum Pectus Carinatum. Figure 1 A 2-year-old child with pectus carinatum.

HOXA13, HOXD10, and HOXD13) and balanced translocations affecting regulatory elements around the HOXD gene cluster might result in pectus carinatum [4].

Molecular and Systemic Pathophysiology Pectus carinatum results from overgrowth of the adjacent costal cartilage which push the sternum into an exaggerated anterior position. It may also result from sternal growth plate damage. The condition is usually congenital. Pectus carinatum may result from stenotomy, following treatment for pectus excavatum.

Diagnostic Principles The diagnosis is mainly clinical. X-ray and computed tomography may be used to determine the extent of the chest wall deformity. Torso models from optical imaging offer 3-D images of the chest wall deformity with no radiation exposure as an index of pectus deformities [5]. A preliminary study showed promising results for the use of torso surface measurements [5].

Therapeutic Principles The condition is often asymptomatic and treatment is usually not necessary. Orthotic bracing or surgery might be considered for cosmetic or psychological reasons [2]. Compliance is critical to the success of bracing [2]. Surgical treatment consists of costochondral resection of the deformed costal cartilages and sternal osteotomy [1,2]. Complications of surgical repair such as pneumothorax, excessive scarring, and acquired Jeune’s syndrome are uncommon.

A LEXANDER K. C. L EUNG Department of Pediatrics, Alberta Children’s Hospital, The University of Calgary, Calgary, AB, Canada

Synonyms Funnel chest; Trichterbrust; Thorax en entonnoir

Definition and Characteristics Funnel chest is a depression deformity of the anterior chest wall and sternum (Fig. 1) [1]. The deformity may be mild, moderate or severe. Funnel chest is most commonly noted in infancy and usually progresses slowly as the child grows. Rapid progression of the deformity may occur during puberty. Most patients are tall and have an aesthetic habitus [2]. Deep inspiration commonly accentuates the severity of the deformity [2]. Funnel chest is often an isolated malformation but can be a component manifestation in various genetic syndromes (e.g. Marfan syndrome, Noonan syndrome, Ehlers-Danlos syndrome, Pierre Robin syndrome, Poland syndrome, Aarskog syndrome). Individuals with pectus excavatum may have reduced exercise tolerance and diminished cardiac index [3]. The depth and extent of the depression determine the degree of compromise of cardiac and pulmonary function. The deformity may be cosmetically unsightly and affected patients might have a poor self-esteem. Approximately 10% affected individuals have associated scoliosis.

Prevalence The incidence is between 1 in 400 and 1,000 live births [2,4]. The male to female ratio is 4:1 [4]. The condition is rare in blacks and Latinos [2].

Genes References 1. Goretsky MJ, Kelly RE Jr, Croitoru D et al. (2004) Adolesc Med 15:455–471 2. Kravarusic D, Dicken BJ, Dewar R et al. (2006) J Pediatr Surg 41:923–926

It has been postulated that pectus excavation might be due, at least in part, to defects in connective tissue genes such as fibrillin, collagen, and transforming growth factor β [4]. Mutations in different homeobox (HOX) genes (e.g. HOXA11, HOXA13, HOXD10, and HOXD13) and balanced translocations affecting

Pellagra

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3. Rowland T, Moriarty K, Banever G (2005) Arch Pediatr Adolesc Med 159:1069–1073 4. Creswick HA, Stacey MW, Kelly RE Jr et al. (2006) J Pediatr Surg 41:1699–1703 5. Yue Y, Farcas R, Thiel G et al. (2007) Eur J Hum Genet 15:570–577

Pelizaeus-Merzbacher Disease Pectus Excavatum. Figure 1 A 15-year-old boy with pectus excavatum.

▶Leukodystrophy

regulatory elements around the HOXD gene cluster might result in pectus excavatum [5].

Molecular and Systemic Pathophysiology Funnel chest can be congenital or acquired. The latter may be secondary to chronic upper airway obstruction such as enlarged adenoids and tonsils, laryngomalacia, rickets, abnormalities of the diaphragm producing posterior traction on the sternum, or external pressure applied for long periods against the anterior surface of the chest [1]. Congenital funnel chest is often sporadic and might result from intrauterine pressure. Majority of familial cases have a multifactorial mode of inheritance although an autosomal dominant trait has been described [1]. Biochemical studies have shown abnormalities in the structure of type 2 collagen in costal cartilage, abnormal levels of zinc, magnesium, and calcium, and a disturbance in collagen synthesis [4].

Diagnostic Principles The diagnosis is mainly a clinical one and no laboratory test is usually necessary.

Therapeutic Principles The condition is usually benign and no treatment is necessary. Surgical correction may be considered for cosmetic reason or when cardiopulmonary function is compromised. Pulmonary function tests, chest radiograph, electrocardiogram, echocardiogram and computed tomography of the chest are useful to determine the need for surgical correction. The minimally invasive Nuss technique has gained wide acceptance by the surgical community.

Pellagra M UA M M E R S EYH A N Department of Dermatology, Inonu University, Malatya, Turkey

Synonyms Niacin deficiency; Alpine scurvy; Mayidism; Maidism; Mal de la rosa; Mal rosso; Saint Ignatus’ itch

Definition and Characteristics The term pellagra is derived from the Italian “pelle”, and “agra”, meaning “skin” and “rough”, respectively (thickened rough skin) [1,2]. Pellagra can be either primary or secondary. The primary form results from inadequate dietary niacin and/or its precursor, tryptophan [3]. In the secondary form, other diseases/conditions interfere with its absorption and/or processing despite adequate quantities in the diet [1,2]. Pellagra is characterized by four classic symptoms, traditionally remembered as the mnemonic of the 4D: dermatitis, diarrhea, dementia, and, when untreated, although very seldom, death [1–3]. Full symptoms occur in only 22%, dermatitis alone in 33% [4]. The clinical characteristics are shown in Table 1. Untreated pellagra gradually progresses to death within 4–5 years, due to multiorgan failure. If it is treated appropriately, the prognosis is excellent [1].

References

Prevalence

1. Leung AK, Hoo JJ (1987) Am J Med Genet 26:887–890 2. Fonkalsrud EW (2003) World J Surg 27:502–508

The current incidence is unknown; epidemics are no longer evident [1]. It is still endemic in areas of

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Pellagra

Pellagra. Table 1 Clinical characteristics findings of pellagra The classical findings: 4D Early symptoms Skin findings

Mucosal manifestations

Gastrointestinal manifestations

Neuropsychiatric manifestations (late stage findings)

Dermatitis, diarrhea, and dementia, when untreated, death Weakness, loss of appetite, abdominal pain, diarrhea, photosensitivity, and psychiatric or emotional distress Early lesions • Symmetrical, erythematous, photosensitive pruritic rash on the dorsa of the hands, face, neck and chest • “Butterfly” eruption on the face, looks like lupus erythematosus • “Casal’s necklace” on the front of the neck and • Anterior continuation, also known as “cravat” • A dull erythema of the bridge of the nose, with fine, yellow, powdery scales: “sulfur flakes” • Sometimes vesicles and bullae develop: “wet pellagra” • Symmetrical and clearly demarcated dermatosis of the hands forms the “glove” or “gauntlet” • Eruption of the feet, between malleoli and toes forms a “boot” Late lesions • Erythema fades with dusky, brown-red coloration • Hard, rough, scaly, hyperkeratotic, cracked and brittle dermatosis: “rough skin” or “goose skin” • Parchment-like appearance develops • Follicular hyperkeratosis on the face • Painful fissures in the palms, soles and digits • Cheilitis • Angular stomatitis • Glossitis: tongue is erythematous and hypertrophic with pseudo-membranous furrows, erosions, or ulcers, later atrophy and loss of papillae occurs • Painful fissures, ulceration, and atrophy on buccal mucosa and vagina • Scrotal, vaginal and perineal erythema, erosions • Poor appetite, nausea, vomiting, abdominal pain • Diarrhea, gastritis, and achlorhydria; stools are typically watery but occasionally can be bloody and mucoid • Headache, fatigue, poor concentration, anxiety, insomnia, delusions, hallucinations, stupor, apathy, tremor, ataxia, spastic paresis, depression, confusion, dementia, and psychosis • Occasionally peripheral neuritis and myelitis • Coma may develop in the later stages

South Africa and Asia (particularly India) where major dietary intake is maize (low in tryptophan) and millet (interferes with tryptophan metabolism due to its high leucin content) [2,3]. In developed countries, it occurs sporadically among chronic alcoholics, food faddists, and patients with malabsorption. Other possible causes are carcinoid tumors, which divert tryptophan to serotonin, and Hartnup disease, which has impaired tryptophan absorption [1,3]. Some medications may induce pellagra by interfering with the niacin biosynthesis, such as isoniasid, azathioprine, 5-fluorouracil, chloramphenicol, antiepileptics and pyrazinamide [1,3,4].

Molecular and Systemic Pathophysiology Generic terms of niacin are nicotinic acid, nicotinamide or niacinamide [1,2]. Niacin can be obtained directly

from the diet or synthesized from dietary tryptophan [1]. It is required for adequate cellular function and metabolism of essential component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) [2]. These compounds are important coenzymes for numerous oxido-reductases involved in glycolysis, protein, amino-acid, fatty acid and pyruvate metabolism, pentose biosynthesis, generation of high-energy phosphate bonds, glycerol metabolism, tissue respiration, and detoxification [1,2]. It has been theorized that manifestations of pellagra result from the inadequacy of NAD and NADP levels to maintain cellular energy transfer reactions. Hence, tissues with high-energy requirements such as brain or those with high turn-over rates such as skin or gut are particularly affected [2].

Pemphigoid

It has been postulated that photosensitivity reaction occurs due to urocanic acid deficiency, which protects the skin from ultraviolet (UV) rays by absorbing light in the UVB range. Moreover, kynurenic acid, a metabolic by-product of the tryptophan–kynurenine–nictonic pathway, accumulates in pellagra as a result of nicotinamide deficiency. Kynurenic acid induces phototoxic changes when subjected to UV radiation. Atrophy of sebaceous glands and decrease in wax esters in sebum probably leads to dry skin [1,2]. Histopathological changes in the skin are relatively nonspecific. Vesicles, if present, may arise sub- or intraepidermally, as a result of vacuolar degeneration of the basal layer, or of intense spongiosis, respectively. There is also perivascular lymphocytic infiltrate of the superficial vascular plexus. Older lesions may have epidermal hyperkeratosis and parakeratosis, with variable acanthosis. Eventually, there may be epidermal atrophy overlying dermal fibrosis and sebaceous gland atrophy [1]. Mucosal inflammation and atrophy involves most of the gastrointestinal (GI) tract. Pathological changes in the nervous system can be found in the brain, spinal cord, and peripheral nerves. The posterior and lateral columns are demyelinated due to prolonged niacin deficiency. Peripheral neuritis and myelitis are occasionally encountered [1,4].

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management. Underlying pathology of secondary pellagra should also be treated [1]. Prevention of pellagra is possible with 8 mg niacin in the daily diet of infants and 9–20 mg/day for older children [4]. Food sources of niacin, and/or tryptophan include nutritional yeast, eggs, liver, lean pork, bran, peanuts, red meat, poultry, fish, whole-grain cereals, rice and milk [2–4]. In recent times, niacin has been investigated as a potential AIDS prevention factor, because HIV infection induces niacin depletion [1,2].

References 1. Hegyi J, Schwartz RA, Hegyi V (2004) Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol 43(1):1–5 2. Karthikeyan K, Thappa DM (2002) Pellagra and skin. Int J Dermatol 41(8):476–481 3. James WD, Berger TG, Elston DM (2000) Andrews’ diseases of the skin. Clinical dermatology. Saunders Elsevier, UK/USA pp 479–486 4. Lucky AW, Powel J (2003) In: Schachner LA, Hansen RC (eds) Cutaneous manifestations of endocrine, metabolic, and nutritional disorders. Pediatric dermatology. Edinburg, Mosby p 940

Diagnostic Principles The diagnosis of pellagra should focus on the presence of the “3 D’s,” localization, and seasonal appearance. Low serum niacin, tryptophan, NAD and NADP levels can confirm the diagnosis. A combined excretion of Nmethylnicotinamide, a normal metabolite of niacin, and pyridone of less than 1.5 mg in 24 h indicates niacin deficiency [1,2,4]. Response to therapy is a partial diagnostic criterion [1].

Pellagrosis P ▶Niacin Deficiency ▶Pellagra

Therapeutic Principles Administration of niacin or nicotinamide cures the syndrome; the latter, causing no vasomotor disturbance, is preferred. The adult and childhood dose is 100–300 mg/day, and 10–50 mg/day orally in three separate doses for several days, respectively, followed by the oral administration of 50 mg every 8–12 h until all skin lesions heal. Mental changes disappear within 24–48 h but skin lesions may take 3–4 weeks. If the symptoms are severe or GI absorption is poor, 1g niacin 3–4 times daily should be provided, initially by the parenteral route [1–3]. Bed rest, avoiding alcohol intake and sun exposure is necessary in acute cases. Dehydration due to diarrhea, severe glossitis and dry skin requires symptomatic

PEM ▶Malnutrition

Pemphigoid ▶Bullous Pemphigoid

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Pemphigoid Gestationis

Pemphigoid Gestationis S ILKE H OFMANN , L EENA B RUCKNER-T UDERMAN

dermoepidermal junction in direct immunofluorescence and deposition of circulating IgG at the epidermal side of saline-separated human skin. Autoantibodies to the NC16a-domain of collagen XVII can be detected in the majority of patients by ELISA [3].

Department of Dermatology, University Medical Center, Freiburg, Germany

Therapeutic Principles Synonyms Gestational pemphigoid; Herpes gestationis

Definition and Characteristics Pemphigoid gestationis (PG) is a peculiar variant of bullous pemphigoid with tissue-bound and circulating autoantibodies against collagen XVII/BP180, a transmembrane protein of hemidesmosomes. Being a self-limited disease, it is characterized by a pruritic papulovesicular eruption on the abdomen during pregnancy, with or without recurrences in subsequent gestations [1].

Prevalence Not known. The estimated incidence is 1:10,000– 1:40,000 pregnancies.

Genes

Topical corticosteroids in combination with antihistamines or low dose systemic corticosteroids are mostly sufficient. Immunoapheresis or rituximab represent treatment options in severe cases. The therapy should be monitored in collaboration with obstetricians.

References 1. Yancey KB, Egan CA (2000) Pemphigoids: clinical, histologic, immunopathologic, and therapeutic considerations. JAMA 284:350–356 2. Giudice GJ, Emery DJ, Zelickson BS et al. (1993) Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immunol 151:5742–5750 3. Powell AM et al. (2005) Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol 141:705–710

Association with HLA class II alleles DRB1* 0301, DQA1* 0501, DQB1* 0201 and DQB1* 0401/0407 has been observed.

Pemphigus Foliaceus Molecular and Systemic Pathophysiology Hemidesmosomes are multiprotein complexes which mediate attachment of basal keratinocytes to the underlying basement membrane zone. Collagen XVII is a type II transmembrane protein extending from the cytoplasm of the basal keratinocyte to the extracellular matrix. Autoantibodies in PG specifically recognize the membrane-adjacent NC16a domain of the collagen XVII ectodomain [2]. The observation of infants developing transient skin lesions due to transplacental passage of maternal autoantibodies suggests that these autoantibodies are pathogenic. Similar to bullous pemphigoid, deposition of IgG1 antibodies in the dermoepidermal junction activates complement which generates an inflammatory infiltrate with increased protease activity leading to blister formation. Hormonal factors certainly play a role in the pathogenesis of PG and exacerbations have been observed during subsequent pregnancies, but also due to hormone producing tumors and oral contraceptives.

Diagnostic Principles The diagnosis is based on subepidermal blister formation in histology, linear C3 deposits at the

S ILKE H OFMANN , L EENA B RUCKNER-T UDERMAN Department of Dermatology, University Medical Center, Freiburg, Germany

Definition and Characteristics Pemphigus foliaceus (PF) and the endemic Brazilian pemphigus (fogo selvagem) are autoimmune bullous dermatoses characterized by autoantibodies against desmoglein 1, a surface protein of keratinocytes. Impaired cell-cell adhesion leads to fragile, superficial blisters which result in scaly, crusted erosions on the skin. Mucosal involvement is usually absent.

Prevalence The incidence of pemphigus is estimated to range from 1 to 5 new cases per million per year. Except in Tunisia and Brazil, PF has a lower incidence than pemphigus vulgaris. The endemic fogo selvagem affects young adults and has a prevalence of up to 3.4% in some rural areas of Brazil [1].

Pemphigus Vulgaris

Genes Association with HLA class II alleles DRB1*0402, DRB1*1401 and DQB1*0302 in caucasians and DRB1*14 and DQB1*0503 in Japanese has been reported.

Molecular and Systemic Pathophysiology PF sera specifically bind to the 160 kDa-transmembrane glycoprotein desmoglein 1, which is predominantly expressed in the superficial layers of the epidermis and only minimally expressed in mucous membranes. Therefore, anti- desmoglein 1 antibodies induce loss of cell-cell adhesion (acantholysis) in the upper epidermis, while desmoglein 3 compensates for the loss of functional desmoglein 1 in the oral epithelium (desmoglein compensation theory). The pathogenicity of antibodies against desmogleins has been demonstrated by various mouse models. Peritoneal injection of patients’ autoantibodies against desmoglein 1 or desmoglein 3 in newborn mice has been shown to reproduce the typical clinical features of pemphigus [2]. In contrast to the pathogenesis of bullous pemphigoid, complement activation is dispensable in the development of pemphigus lesions. Mechanisms for acantholysis in pemphigus include steric hindrance by binding of autoantibodies to their epitopes, proteinase activation, and down-regulation of adhesion by cellular signaling events [3].

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Pemphigus Vulgaris S ILKE H OFMANN , L EENA B RUCKNER-T UDERMAN Department of Dermatology, University Medical Center, Freiburg, Germany

Definition and Characteristics Potentially life-threatening autoimmune blistering dermatosis associated with autoantibodies against intercellular adhesion proteins of keratinocytes. In pemphigus vulgaris (PV), autoantibodies are predominantly directed against desmoglein 3 leading to intraepidermal, suprabasal blisters. Clinical hallmarks are painful erosions of the oral mucosa with or without flaccid cutaneous blisters and erosions.

Prevalence The prevalence of pemphigus is not known; the incidence is estimated to range from 1 to 5 new cases per million per year. The disease is found all over the world, it affects women and men equally and typically manifests between 30 and 60 years of age. People of Jewish ancestry have a higher incidence of pemphigus.

Diagnostic Principles

Genes

The diagnosis is made on the basis of subcorneal acantholysis in histology and intercellular IgG and C3-deposits in the upper epidermis by direct immunofluorescence. Circulating autoantibodies against desmoglein 1 can be detected by indirect immunofluorescence or ELISA with recombinant desmogleins.

Association with HLA class II alleles DRB1*0402, DRB1*1401 and DQB1*0302 in caucasians and DRB1*14 and DQB1*0503 in Japanese has been reported.

Therapeutic Principles Severe forms of PF are treated with oral corticosteroids alone or in combination with immunosuppressive agents similar to the treatment of pemphigus vulgaris. In localized forms of PF, superpotent topical steroids or topical calcineurin inhibitors may be sufficient to obtain clinical remission.

References 1. Empinotti JC et al. (2006) Clinical and serological follow-up studies of endemic pemphigus foliaceus (fogo selvagem) in Western Parana, Brazil (2001–2002). Br J Dermatol 155:446–450 2. Hashimoto T (2003) Recent advances in the study of the pathophysiology of pemphigus. Arch Dermatol Res 295: S2–S11 3. Waschke J et al. (2006) Inhibition of Rho A activity causes pemphigus skin blistering. J Cell Biol 175:721–727

Molecular and Systemic Pathophysiology The antigenic target in PV, desmoglein 3, is a transmembrane glycoprotein of desmosomes (Fig. 1). By anchorage of the cytokeratin filaments, desmosomes mediate strong intercellular adhesion between keratinocytes [1]. As demonstrated by an active mouse model anti-desmoglein 3 antibodies interfere with the function of desmogleins leading to loss of keratinocyte cell adhesion (known as acantholysis) and subsequent blister formation in the epidermis [2]. The pemphigus vulgaris antigen, 130 kD desmoglein 3, and the pemphigus foliaceus antigen, 160 kD desmoglein 1, belong to the cadherin supergene family and compensate for each other functionally, when expressed in the same cell (Fig. 2). However, in PV anti-desmoglein 3 antibodies impair the function of desmoglein 3 and lead to erosions in mucous membranes, where desmoglein 1 cannot compensate for the loss of function of desmoglein 3 [3].

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Pendred Syndrome

Pemphigus Vulgaris. Figure 1 Structure of the desmosome. Desmosomes contain two types of transmembrane proteins, desmogleins and desmocollins, which are always expressed as a pair and bind to plakoglobin (PG). The desmosomal cytoplasmic constituents plakoglobin (PG) and plakophilin (PP) associate with desmoplakin (DP) which itself interacts with the keratin filaments.

References

Pemphigus Vulgaris. Figure 2 Distribution of desmoglein 1 and desmoglein 3 in skin and mucous membranes. The distribution of desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) varies between skin and mucous membranes. While desmoglein 1 is significantly expressed throughout the epidermis, desmoglein 3 is restricted to the basal layers. In contrast, desmoglein 3 is expressed at a higher level in mucous membranes than desmoglein 1. When coexpressed in the same cell, desmoglein 1 and desmoglein 3 can compensate for each other explaining the clinical features of the different pemphigus variants (desmoglein compensation theory).

1. Amagai M (2003) Desmoglein as a target in autoimmunity and infection. J Am Acad Dermatol 48:244–252 2. Shimizu A et al. (2004) IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model. J Invest Dermatol 122:1145–1153 3. Stanley JR (2001) Pathophysiology and therapy of pemphigus in the 21st century. J Dermatol 28:645–646

Pendred Syndrome ▶Pendred’s Syndrome

Diagnostic Principles Histology shows suprabasal acantholysis and direct immunofluorescence intercellular IgG and C3 deposits in the lower epidermis. Circulating autoantibodies react with human skin or monkey esophagus by indirect immunofluorescence. The molecular specificity of the antibodies is determined by ELISA with recombinant desmogleins.

Therapeutic Principles Oral prednisone alone or combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, dapsone, cyclophosphamide, methotrexate) are the mainstay of therapy for PV. In recalcitrant PV, the antiCD20-antibody rituximab, protein A-immunoadsorption or high-dose intravenous immunoglobulins may help to achieve a clinical and serological remission.

Pendred’s Syndrome P ETER KOPP 1 , D OUGLAS F ORREST 2 1

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 2 National Institutes of Health, NIDDK, Bethesda, MD, USA

Definition and Characteristics Pendred’s syndrome (OMIM 274600) is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification.

Pendred’s Syndrome

Deafness is often prelingual, but it may be progressive and become apparent only later in childhood; it is associated with enlargement of the endolymphatic system. The thyroid enlargement is variable and may be influenced by nutritional iodide intake. Hypothyroidism occurs in some, but not all patients and it is not causally involved in the development of hearing impairment.

Prevalence Estimations in the United Kingdom predicted a frequency of about 0.000,075. The true prevalence may be higher because of unrecognized allelic variants.

Genes The disorder is caused by mutations in the PDS/ SLC26A4 gene located on chromosome 7q31, and is thought to be genetically homogenous. Expression of the thyroid phenotype is influenced by the amount of nutritional iodine intake. Mutations in SLC26A4 identified in patients with Pendred syndrome or with non-syndromic deafness display allelic heterogeneity. More than 150 mutations are known including a large number of missense mutations and a small number of nonsense and intronic mutations. The loss-of-function of some of these mutations is in part due to retention of the mutated protein in intracellular compartments. Allelic variants without thyroid phenotype: Nonsyndromic (familial) enlarged vestibular aqueduct, non-syndromic autosomal recessive deafness DFNB4.

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bicarbonate, hydroxide and formate in oocyte and mammalian cell systems. Based on the typical enlargement of the endolymphatic system in patients with Pendred’s syndrome and the Pds null mouse [1], pendrin is assumed to be involved in anion and fluid transport in the inner ear. The exact role remains to be defined but Pds−/− mice have progressive degeneration of the stria vascularis, acidification of the endolymph and an associated loss of the endocochlear potential [2]. In thyroid follicular cells, pendrin is inserted into the apical membrane and, together with other, unidentified channels, it is involved in iodide transport into the follicular lumen. There is no overt renal phenotype, possibly because of the existence of other transporters with redundant function. PDS gene mutations display significant allelic heterogeneity and include numerous inactivating missense, nonsense and splice site mutations (Fig. 1).

Diagnostic Principles In its classic presentation, the combination of congenital sensorineural deafness and goiter, the diagnosis of Pendred’s syndrome can be confirmed by a positive perchlorate test in most patients [3]. If the phenotype is limited to deafness with an enlarged endolymphatic system documented by imaging of the inner ear, mutational analysis of the PDS gene is essential for making a definite diagnosis [4].

Therapeutic Principles Molecular and Systemic Pathophysiology Pendrin is predominantly expressed in the inner ear, the thyroid and the kidney. Functionally, pendrin has been shown to transport chloride and iodide, and to exchange

Early diagnosis is essential in order to avoid further progression in children with hearing impairment since cochlear implants have been useful in acquiring normal language development in a small number of patients.

Pendred’s Syndrome. Figure 1 PDS/SLC 26A4 gene and secondary protein structure.

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Pentalogy of Fallot

In case of hypothyroidism, patients with Pendred’s syndrome are treated with levothyroxine. Large goiters may occasionally need surgical correction.

References 1. Everett LA, Belyantseva IA, Noben-Trauth K, Cantos R, Chen A, Thakkar SI, Hoogstraten-Miller SL, Kachar B, Wu DK, Green ED (2001) Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet 10:153–161 2. Wangemann P, Nakaya K, Wu T, Magnatic RJ, Itza EM, Sanneman JD, Harbridge DE, Billings S, Marcus DC (2007) “Loss of cochlear HCo−3 secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model”. Am J Physiol Renal Physiol 292:F1345–F1353 3. Kopp P (2000) Pendred’s syndrome and genetic defects in thyroid hormone synthesis. Rev Endocr Metabol Dis 1/2:109–121 4. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nature Genet 17:411–422

clinical picture and prognosis is most affected by the degree of pulmonary stenosis. It is more severe when the pulmonary valve is atretic. 3. Right ventricular hypertrophy is not an anatomical pathology and develops secondary to pulmonary stenosis. 4. Overriding of the aorta over the septal defect, due to a malalignment type of VSD. Part of the aorta exits from the right ventricle [1,2]. 5. When ASD or PFO accompany the four components mentioned above it is called Pentalogy of Fallot [3] (Fig. 1).

Prevalence Data on the incidence of the pentalogy of Fallot are not consistent. In addition to reports where it was found rarely in patients with heart disease, some report an incidence as of concurrent TOF and ASD or PFO as high as 83% [1]. This may be due to the frequent

Pentalogy of Fallot E MINE D IBEK M ISIRLIOG˘ LU 1 , N URSEL A LPAN 2 1

Department of Pediatrics, Kırıkkale University Faculty of Medicine, Kırıkkale, Turkey 2 Department of Cardiology, Ministry of Health, Ankara Diskapi Children’s Diseases Training and Research Hospital, Ankara, Turkey

Synonyms Tetralogy of Fallot (TOF) with atrial septal defect (ASD) or patent foramen ovale (PFO)

Definition and Characteristics Pentalogy of Fallot is a congenital heart defect with five anatomical components: 1. Ventricular septal defect (VSD) consists of an unrestricted large anterior, subaortic perimembranous malalignment. It leads to equalization of right and left ventricular pressures. 2. Right ventricular outflow tract obstruction (pulmonary stenosis, PS); infundibular (subvalvular) stenosis is found in all patients and may be accompanied by valvular and supravalvular stenosis. The patient’s

Pentalogy of Fallot. Figure 1 Anatomic abnormalities in pentalogy of Fallot. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; PA, pulmonary artery; AO, overrriding aorta; ASD, atrial septal defect; VSD, ventricular septal defect.

Pentalogy of Fallot

occurrence of ASD as a congenital cardiac anomaly, and its evaluation is coincidental in TOF cases and not as a component of the pentalogy.

Genes Pentalogy of Fallot can be associated with a syndrome or patients may have chromosomal anomalies as reported in the literature. There have been case reports of pentalogy of fallot associated with Down’s syndrome, Steinfeld syndrome, Holt-Oram syndrome, and incomplete trisomy 22 (22q13) [3,4]. Microdeletion of 22q11 is the most frequent chromosomal anomaly associated with conotruncal defects. Concurrence of TOF and atrioventricular septal defect may be seen especially in Down’s syndrome [1,3].

Molecular and Systemic Pathophysiology Embryonic Development: Tetralogy of Fallot is a result of abnormal conotruncal development that consists of incomplete rotation and faulty partitioning of the conotruncus during septation. The deviation of the conal septum is the reason for the VSD and the overriding aorta. The subpulmonic obstruction is believed to be created by abnormal anterior septation of the conotruncus by the bulbotruncal ridges but this remains uncertain. The degree and nature of the anterior and cephalad deviation of conal spectrum determine the severity of subpulmonic obstruction [1]. Atrial septal defects are classified according to their location relative to the fossa ovalis, their proposed embryogenesis, and their size. The foramen ovale represents a normal interatrial communication that is present throughout fetal life. Functional closure of the foramen ovale occurs postnatally, and fibrous adhesion may develop during the first year of life. Patent foramen ovale may develop if anatomical closure does not occur. Secundum ASD is the result of excessive resorption of septum primum and the inability of septum secundum to close ostium secundum [1]. Molecular Pathophysiology: Although there are no data on the molecular pathophysiology of the pentalogy of Fallot, conotruncal heart defects such as TOF are due to alterations in migration of a specific neural crest cell population called cardiac neural crest (NC). It is possible that cardiac NC may influence the myocardial Ca2+ channels development and the expression of the proteins involved. This cellular and molecular interaction can be assigned not only to the structural characteristics of the congenital heart defect but also to the embryonic development of the heart defect. Conotruncal defects have been shown to be associated with an increase in intracellular Ca reserves in cardiac neural cells. Sarcoplasmic reticulum Ca ATPase (SERCA) is a membrane protein and catalyzes the

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ATP-dependent transport of Ca from the cytosol to the sarcoplasmic reticulum (Ca2+ re-uptake into the sarcoplasmic reticulum (SR) through the SR Ca2+/ATPase pump (SERCA)). Its activity is inhibited by phospholamban (PLN) and sarcolipin (SLN). PLN and SLN have been shown to be low in TOF patients [5]. Systemic Pathophysiology: The pathophysiology varies depending on the degree of right ventricular outflow obstruction. The pulmonary infundibulum is hypertrophic and the right ventricular outlet narrows. In addition, the pulmonary valve annulus, main pulmonary artery, and pulmonary artery branches may be narrow. The lungs therefore receive less blood than normal. The right ventricular pressure is equal to or higher than the left ventricular pressure due to PS. Part of the blood arriving at the right atrium and right ventricle from the systemic veins goes into the systemic circulation by the way of overriding aorta and by the route of VSD because PS causes shifting of blood from pulmonary artery [1,2]. If the PS is very severe, the right-to-left shunt increases and the clinical findings become more marked. Pulmonary perfusion for maintaining life can only take place if PDA or aortopulmonary collaterals develop. With mild PS, the lungs receive adequate blood, there may be a two-way shunt through the VSD and there is no cyanosis. Mild PS patients have mild clinical findings and occasionally presents in adulthood. Cases with uncorrected pentalogy of Falloto living until the seventh decade have been reported.

Diagnostic Principles The clinical manifestations reflect the variable severity of right ventricular outflow obstruction. Newborns and infants may present either with cyanosis or systolic murmur. A worsening clinical picture is seen in newborns with critical right ventricular outflow obstruction after closure of the ductus arteriosus due to decreased pulmonary perfusion [1,2]. Hypercyanotic episodes are characterized by a severe and prolonged decrease in arterial saturation and most often seen at the ages of 2 to 4. There is substantial increase in right-to-left shunting due to a change in the ratio of pulmonary and systemic vascular impedance. Episodes usually develop in the morning following crying, feeding, and defecating. They are characterized by severe cyanosis and often associated with hyperpnea. If prolonged and severe, lethargy and death may result. Children may assume a knee-chest position. Squatting is another sign and seen following exercise. During exercise sytemic vascular resistance decreases. This causes decrease in left ventricular pressure. As a result right-to-left shunt increases so the lungs receive less blood. Decreased lung perfusion cause increase in hypoxia and cyanosis. The patient can no longer walk and squats.

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Pentalogy of Fallot

At physical examination, cyanosis is the most prominent finding and may not be present at birth if the PS is mild. There is marked cyanosis from birth in patients with pulmonary valve atresia. The right ventricle pressure increases as the infundibular stenosis increases, the blood supply to the lung decreases, and right-to-left shunt starts, with cyanosis occurring later in the first year of life. Clubbing of nailbeds can be present in longstanding cases. A systolic murmur is located at the left upper sternal border as expected with valvular PS. The intensity of the murmur inversely related to the degree of pulmonary obstruction. The severity of the murmur decreases as the PS increases. There is no murmur in case of pulmonary valve atresia or there may be a mild PDA or aortopulmonary collateral continuous murmur in some patients. An accentuated right ventricular impulse will be found. Growth and development may be delayed in the untreated patient with severe disease. Clubbing of nailbeds can be present in longstanding cases. Polycythemia and relative iron deficiency are usually seen in laboratory tests. The polycythemia is due to the hypoxia and the resultant production of erythropoietin. In radiography, the heart size is normal and the cardiac apex turned upward (right ventricular hypertrophy), the pulmonary conus is collapsed (hypoplasic pulmonary artery), and lung vascularity is decreased (hypoplasic pulmonary artery branches due to PS). This creates a cardiac silhouette that resembles a boot-shaped heart or coeur en sabot (wooden shoe). Electrocardiography reveals right axis and right ventricular hypertrophy. Arrhythmias are uncommon in young patients, but ventricular ectopy and other arrhythmias may appear in untreated older children. Two-dimensional echocardiography provides noninvasive diagnosis of all anatomical findings. Doppler echocardiography analysis provides further data regarding hemodynamic characteristics. The degree of PS may be determined with Doppler. The indications for diagnostic catheterization have diminished substantially with advances in noninvasive technology. Invasive studies are helpful when deciding on surgical or medical management strategies. Right ventricular angiography will usually provide reliable imaging of the infundibular and pulmonary artery anatomy. Left ventricular angiography will usually define left ventricular function, VSD, the degree of aortic override, and the presence of ASD.

Therapeutic Principles The definitive treatment for pentalogy of Fallot is surgical. Primary repair is performed electively at 6–12 months of age in well grown infants with less severe cyanosis and without hypercyanotic spells. Early

complete repair may be performed safely and prevents development of complications from additional palliative procedures, long-standing cyanosis, and other serious comorbidities (systemic arterial emboli, cerebrovascular complications). Prevention or prompt treatment of dehydration is important to avoid hemoconcentration and possible thrombotic episodes [1,2]. Medical treatment is used for newborns with critical right ventricular outflow obstruction and for hypercyanotic spells. Neonates who have ductal-dependent pulmonary blood flow should be given prostaglandin E1 (0.05– 0.20 μg/kg/min) but this situation does not develop frequently. Hypercyanotic spells require medical treatment including oxygen, volume expansion, sedation with morphine or ketamine, and, if needed, vasopressors such as phenylephrine. Although it is currently accepted that hypercyanotic spells provide an important rationale for earlier palliative surgical intervention, propranolol (1 mg/kg every 6 hr) has been suggested for minimizing or eliminating these events. Iron treatment may decrease the frequency of spells. Interventional catheterization procedures are performed to relieve of various levels of pulmonary obstruction and to embolize accessory and duplicated sources of pulmonary blood flow. The frequency and indications for catheter-based intervention are determined to a large degree by the preferences of the clinician and institution. Surgical intervention is required for resection of hypertrophic muscular trabeculations that narrow the right ventricular outlet. The patient’s pulmonary valve remains competent. A pulmonary valvotomy is performed if the pulmonary valve is stenotic, and a valvectomy may be performed if the pulmonary valve annulus is small or the valve is extremely thickened. The VSD and ASD are completely closed. A small patent foramen ovale may be left as a possible source for right to left atrial decompression in the postoperative period [1,2]. The surgical risk of total correction is less than 5% [2]. Shunt surgery should be carried out urgently if severe cyanosis or frequent spells are seen within the first year of life. Palliative systemic-to-pulmonary artery shunt is performed to increase pulmonary artery blood flow and decrease the amount of hypoxia to augment the growth of the branch pulmonary arteries. Corrective surgery is performed later [1]. An anastomosis between the right or left pulmonary artery and right or left subclavian artery (modified Blalock-Taussig Shunt) provides a communication using a vascular graft between the pulmonary artery and the subclavian artery (modified Blalock-Taussing Shunt). A Waterston-Cooley Shunt anastomoses the ascending aorta to right pulmonary artery, a Pott’s Shunt provides

Peptic Ulcer

an anastomosis of the descending aorta to left pulmonary artery, and Central shunts generate an anastomosis between the main pulmonary artery and ascending aorta using a vascular graft [1,2]. The overall survival of patients who have had operative repair is excellent, provided the VSD has been closed and the right ventricular outflow tract obstruction has been relieved. All Pentalogy of Fallot patients should have regular cardiology follow-up by a cardiologist. The patients are still at risk if endocarditis after complete repair and prophylaxis is recommended [1]. Death may occur from endocarditis or congestive heart failure.

References 1. Siwik ES, Patel CR, Zahka KG, Goldmuntz E (2001) Tetralogy of Fallot. In: Allen HD, Gutgesell HP, Clark EB, Driscoll DJ (eds) Moss and Adams’ heart disease in infants, children, and adolescents: including the fetus and young adult, 6th edn. Lippincott Williams & Wilkins, Philadelphia, pp 880–902 2. Bernstein D (2004) Tetralogy of Fallot. In: Behrman RE, Kliegman RM, Jenson HB (eds) Nelson textbook of pediatrics, 17th edn. Saunders company, Philadelphia, pp 1524–1528 3. Misirlioglu ED, Aliefendioğlu D, Dogru MT, Sanli C (2006) Pentalogy of fallot in a patient with Down syndrome. Anadolu Kardiyol Derg 6(4):397 4. Nöthen MM, Knöpfle G, Födisch HJ, Zerres K (1993) Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet 46(4):467–470 5. Simona Vittorini S, Storti S, Parri MS, Cerillo AG, Clerico A (2007) SERCA2a, phospholamban, sarcolipin, and ryanodine receptors gene expression in children with congenital heart defects. Mol Med 13(1–2):105–111

Pentasomy X ▶X Polysomies, in Females

1605

PEPCK Deficiency ▶Phosphoenolpyruvate Carboxykinase Deficiency

Peptic Ulcer M ARK O ETTE Clinic for Gastroenterology, Hepatology, and Infectious Diseases, University Clinic Duesseldorf, Duesseldorf, Germany

Synonyms Gastric ulcer; Duodenal ulcer

Definition and Characteristics An ulcer of the mucosa is defined by disruption of the surface integrity leading to a local defect >5 mm in size with excavation to the submucosa due to inflammation [1]. The disease may affect all parts of the gastrointestinal tract, but the predominant manifestation is ulcering of the lower part of the stomach and the upper part of the duodenum (duodenal bulb). More than 80% of duodenal ulcers and 60% of gastric ulcers are induced by Helicobacter pylori infection. Majority of other cases are associated with the use of nonsteroidal anti-inflammatory drugs (NSAID). Rarely the cause is Zollinger-Ellison syndrome. Clinical symptoms of peptic ulcer consist of upper abdominal discomfort, pain, nausea, and weight loss. The pain pattern of gastric ulcer is aggravation during food intake; patients with duodenal ulcer complain of pain in fasting condition, especially at night. However, the predictive value of pain for the presence of ulcers is low. Complications of ulcer disease are penetration or perforation of the affected site, gastrointestinal bleeding, and, rarely, gastric outlet obstruction.

Prevalence

PEO ▶Progressive External Ophthalmoplegia

It is estimated that the lifetime incidence of duodenal ulcers is 6–10% in the western population. Gastric ulcer tends to occur later in life in comparison with duodenal ulcers and affects more males than females. Autopsy studies suggest a similar incidence of gastric and duodenal ulcers [1]. As a result of widespread application of eradication therapy of H. pylori infection, the prevalence of peptic ulcer is declining since the 1980s.

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Peptic Ulcer

However, there is evidence that peptic ulcer not induced by H. pylori or NSAID use is rising [2].

Molecular and Systemic Pathophysiology The mucosal surface is constantly challenged by a large number of different noxious agents, e.g., acid, pepsin, pancreatic and biliary secretions, drugs, alcohol, or infectious organisms. The epithelial defense and repair system consists of three major elements. The preepithelial part is a mucous-bicarbonate layer containing mucin, fatty acids, and phospholipids, serving as a physicochemical barrier. The middle layer is represented by the cellular wall. The third element of defense is represented by the submucosal microvascular system. It provides bicarbonate to neutralize the secretion of HCl and supplies the mucosa with micronutrients and oxygen while removing metabolic end-products. The cellular release of mucus and bicarbonate is regulated by prostaglandins, which occur in high concentrations in the gastric mucosa. Further tasks of the prostaglandins are the inhibition of acid production, the regulation of mucosal blood flow, and epithelial cell restitution. HCl (produced by parietal cells) and pepsinogen (produced by chief cells) are the major secretory products that induce mucosal damage. Continuous submucosal blood perfusion and an alkaline environment are required for effective mucosal repair. Epithelial regeneration is modulated by prostaglandins, epidermal growth factor (EGF), and transforming growth factor (TGF) α. Restitution of smaller defects is induced by EGF, TGF-α, and basic fibroblast factor (FGF). FGF and vascular endothelial growth factor (VEGF) stimulate angiogenesis. H. pylori infection of the gastric mucosa is the major etiology of peptic ulcer [3]. However, less than 15% of affected patients develop peptic ulcers. Important virulence factors are CagA, a signaling protein, VacA, a cytotoxin, and BabA, an adhesin, all secreted by the bacterium [3]. CagA induces a proinflammatory response and cell proliferation in the host, VacA results in cell surface perforation and induction of apotosis, BabA facilitates adhesion to the cell surface. Furthermore, phospholipases and proteases produced by the bacterium breakdown the glycoprotein lipid complex of the surface mucus. Genetic polymorphisms leading to enhanced secretion of the proinflammatory cytokine interleukin 1β are host factors with increased risk of hypochlorhydria induced by H. pylori. Although patients with blood group O have an increased risk of ulcer development, no genetic predisposition of ulcer disease has been established. Smoking is an important environmental factor associated with ulcer disease. No dietary factors have been identified as causative agents. In cases with gastric ulcer, a diffuse colonization pattern of H. pylori with pangastritis in histology

examination is regularly found. Gastric adenocarcinoma and lymphoma are associated with this manifestation. Basal and stimulated acid output is normal or diminished. Duodenal ulcer is associated with antralpredominant colonization of H. pylori. This constellation leads to increased gastrin secretion mediated by H. pylori-induced reduction of somatostatin-producing cells. The increased acid secretion results in protective gastric metaplasia of the duodenal bulb. This epithelial compartment is infected by H. pylori with the consequence of inflammation and ulceration. The use of NSAID leads to peptic ulcer by inhibition of prostaglandin production, reduction of epithelial blood perfusion, direct toxicity by intracellular trapping of ionized drug forms, and disturbed healing of lesions.

Diagnostic Principles The diagnosis of gastrointestinal ulcer is established by endoscopy (see Figs. 1 and 2). A further use of endoscopy is differentiating inflammatory bowel disease, non-ulcer dyspepsia, malignant disorders, and others. Other techniques like radiographic examination or ultrasound do not play a significant role in the diagnosis of gastrointestinal ulcers. Testing for H. pylori may be applied during endoscopy using the urease test of a biopsy or histology of gastric mucosa. In cases with recurrence of disease after eradication therapy, a biopsy specimen can be used for culture and resistance testing. Non-invasive tests with inferior sensitivity and specificity are serology, 13C urea breath test, and stool antigen test.

Therapeutic Principles The leading therapeutic principle in the treatment of peptic ulcer is inhibition of acid secretion. Antacids, H2receptor antagonists, or cytoprotective agents may be used. The best efficacy is documented for proton pump inhibitors. These inhibit the H+, K+-ATPase of the gastric

Peptic Ulcer. Figure 1 Gastric ulcer.

Pericarditis, Acute

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Pericardial Constriction ▶Pericarditis, Constrictive

Pericarditis, Acute M ASSIMO I MAZIO Cardiology Department, Maria Vittoria Hospital, Torino, Italy Peptic Ulcer. Figure 2 Duodenal ulcer.

Definition and Characteristics mucosa irreversibly. Standard doses of proton pump inhibitors in combination with either amoxicillin/ clarithromycin or metronidazol/clarithromycin over 1 week are used for eradication therapy of H. pylori infection [4]. Nowadays, surgery is needed only for complications.

References 1. Del Valle J (2006) In: Kasper DL, Braunwald E, Fauci A, Hauser SL, Longo DL, Jameson JL (eds) Harrison’s principles of Internal Medicine, 16th edn. McGraw-Hill, New York, Chicago, San Francisco, and others, pp 1746–1762 2. Chow DKL, Sung JJY (2007) Nat Clin Pract Gastroenterol Hepatol 4:176–177 3. Kusters JG, van Vliet AHM, Kuipers EJ (2006) Clin Microbiol Rev 19:449–490 4. Ford AC, Delaney BC, Forman D, Moayyedi P (2006) Cochrane Database Syst Rev 2:CD003840

PFO ▶Patent Foramen Orale

Perheentupa Syndrome ▶Mulibrey Nanism

Acquired acute inflammatory disease of the pericardium.

Prevalence The incidence of pericarditis in postmortem studies ranges from 1 to 6%. It is diagnosed antemortem in only 0.1% of hospitalized patients and in 5% of presentations to emergency departments for nonacute myocardial infarction chest pain [1,2]. In a prospective study on 274 consecutive cases of pericarditis from an urban area, the incidence of new cases of acute pericarditis was 27.7 cases per 10,000 population/year [3].

Genes Additional research is in progress on the possible link between recurrent pericarditis and autoinflammatory diseases. The autoinflammatory diseases comprise both hereditary (familial Mediterranean fever, FMF; mevalonate kinase deficiency, MKD; TNF receptor associated periodic syndrome, TRAPS; cryopyrin associated periodic syndrome, CAPS; Blau syndrome; Pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, PAPA; chronic recurrent multifocal osteomyelitis, CRMO) and multifactorial (Crohn’s and Behçet’s diseases) disorders. Mutations responsible for FMF, TRAPS, CAPS, PAPA include proteins involved in the modulation of inflammation and apoptosis [4]. Recurrent attacks of pericarditis are a feature of the FMF, nevertheless mutations related to FMF were not found in Caucasian patients with sporadic cases of recurrent idiopathic pericarditis [5].

Molecular and Systemic Pathophysiology Pericarditis is an inflammatory disease of the pericardium characterized by both pericardial inflammatory infiltrate and exudate, usually consisting of fibrin and

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Pericarditis, Acute

inflammatory cells [6,7]. The type of inflammatory cells and pericardial fluid depend on the cause of pericarditis (Table 1). Histological findings include granulocyte or lymphocytic-mononuclear infiltration of the pericardium, and sometimes of the subepicardium. Lymphocytes dominate in viral infections, whereas polymorphonuclear cells are predominant in bacterial infections. Pericardial fluid is hypercellular and purulent in bacterial infections, mainly hemorrhagic in tuberculous and neoplastic pericarditis, and serofibrinous in viral and autoreactive forms. Higher titers of antimyolemmal and antisarcolemmal antibodies are found in viral and autoreactive forms. Some cytokines such as IL6 and IL8 are significantly increased in pericardial effusion compared to the serum and are markers of the local inflammatory response. Elevation

of biomarkers has been reported in acute pericarditis. Persistent cTnI elevations suggest myopericarditis. The rise in cTnI in acute pericarditis is roughly related to the extent of myocardial inflammation, but unlike acute coronary syndromes, is not a negative prognostic marker [3,8].

Diagnostic Principles The typical clinical manifestations of acute pericarditis consist of chest pain (usually pleuritic), a pericardial friction rub, and widespread ST segment elevation on the electrocardiogram, and the possible appearance of pericardial effusion. At least two of these four features should usually be present for the diagnosis [9]. In all cases elevation of inflammatory markers (ie. C-reactive

Pericarditis, Acute. Table 1 Etiology of acute pericarditis Etiology

Frequence*

Idiopathic

Up to 85%

Infectious Viral (common: Coxsackie, Echovirus, Adenovirus, Influenza, CMV, EBV) Bacterial (Tbc, other rare: Staphylococcus aureus, Klebsiella pneumoniae, Pneumococcus, Meningococcus, Hemophilus, Coxiella burnetii, etc.) Fungal (rare: Candida, Histoplasma) Parasitary (rare) Autoimmune Systemic autoimmune diseases Pericardial injury syndromes Autoreactive pericarditis Neoplastic Primary tumors (rare) Secondary tumors (common: lung, breast carcinoma, and lymphoma) Metabolic Uremia (frequent) Myxedema (common) Other (rare) Pericarditis in disease of surrounding organs Acute myocardial infarction, Aortic aneurysm, Lung infarction, pneumonia, Paraneoplastic pericarditis Traumatic

>60%

Pathogenesis Generally a viral infection, sometimes autoimmune and postinfectious pathogenesis Spread and multiplication of the infectious agent with serofibrinous (viral), hemorrhagic (bacterial, viral, tuberculous), or purulent inflammation (bacterial)

Up to 15%

Cardiac involvement of the basic disease or secondary disease after infectious pericarditis or invasive procedures

Up to 10%

Infiltration of malignant cells with generally hemorrhagic effusion

5 min after birth 3. Neonatal encephalopathy (e.g., seizures, coma, hypotonia) 4. Multiple organ involvement (kidney, lungs, liver, heart, intestines) Hypoxic ischemic encephalopathy (HIE) is one of the major causes of neonatal mortality, morbidity and long term neurodevelopmental sequelae. HIE is classified into mild, moderate and severe types depending on the degree of central nervous system (CNS) and systemic involvement. In severe HIE, mortality is 50– 89% and the majority of the deaths occur in the newborn period due to multiorgan failure. Among survivors the sequelae include mental retardation,

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Perinatal Asphyxia

epilepsy and cerebral palsy (either hemiplegia, paraplegia, or quadriplegia). In moderate HIE, severe disability occurs in 30–50% and 10–20% have minor deficits. Infants with mild HIE are free from serious complications. In the absence of obvious neurodeficits during infancy, 15–20% patients develop significant learning difficulties. Surrogate markers of fetal distress are present in the majority of patients during the perinatal period. However, early recognition and intervention of fetal distress by monitoring technologies does not eradicate the problem.

Prevalence In developed countries prevalence of severe HIE is 2–4/1,000 live births and in developing countries it is 5–10/1,000 live births. According to the World health organization, world wide one million children die with diagnosis of asphyxia and nearly the same number of children survive with significant handicap.

Molecular and Systemic Pathophysiology The initiating mechanisms of perinatal asphyxia include hypoxia, ischemia, hemorrhage, perinatal infection, inflammation, metabolic disturbances etc. and in a neonate either single or multiple factors may initiate the chain of events triggering HIE. Significant hypoxia depresses myocardium, reduces cerebral perfusion leading to ischemia. Cerebral autoregulation in sick neonates is impaired. The range of systemic blood pressure over which cerebral autoregulation is functional is 40 mm Hg in adults as opposed to 10–20 mm Hg in neonates which narrows further with HIE. There is increased expression of nitric oxide synthase including both, inducible and neuronal, forms (iNOS and nNOS) in the newborn period which also narrow the autoregulatory window. Further cerebral vasoconstriction secondary to systemic hypertension does not occur because of down regulation of prostaglandin receptors in the newborn period due to high prostaglandin levels. Therefore, cerebral blood flow becomes pressure passive in patients with perinatal asphyxia. With drop in systemic blood pressure, cerebral blood flow (CBF) falls below critical levels causing ischemia and reduced delivery of energy substrates (glucose and oxygen) to brain tissue leading to primary energy failure, cytotoxic edema and neuronal death. Encephalopathic neonates with evidence of cerebral damage on amplitude integrated electroencephalography (a EEG) display impaired cerebral autoregulation. Utilization of metabolites like glucose, ketones and lactate (normally) increases during the perinatal period and the pattern of injury after HIE can be explained on the basis of this high metabolic demand in subcortical area’s. Anaerobic metabolism that ensues following asphyxia rapidly depletes stores of high energy phosphate (ATP and phosphocreatinine)

in the brain resulting in accumulation of lactate and inorganic phosphate. Ischemia followed by reperfusion exacerbates neuronal injury secondary to generation of oxygen free radicals and delivery of therapeutic agents. Although there is some recovery of high energy phosphates with reperfusion, 6–24 h later delayed or secondary energy failure ensues. The extent of depletion of high energy phosphates and accumulation of lactate correlates with the severity of HIE. This phase which lasts for 48–72 h is characterized by edema, apoptosis and secondary neuronal death. The biochemical events that lead to secondary energy failure, necrosis apoptosis and secondary neuronal death include following: Excitotoxicity: Hypoxic ischemic encephalopathy (HIE) manifests as seizures and burst suppression on electroencephalography suggesting a prominent role for neuronal excitability and excitotoxicity. Excitotoxicity refers to excessive glutamatergic neurotransmission which leads to cell death. Glutamate is the main excitatory neurotransmitter and its release, uptake and resynthesis is tightly coupled to cerebral glucose oxidation as shown by magnetic resonance spectroscopy. Elevated glutamate has been documented by proton magnetic spectroscopy in cerebrospinal fluid (CSF) of patients who have suffered HIE and CSF levels of excitatory amino acids are directly proportional to the severity of HIE. After stimulating its receptors (NMDA, AMPA or Kaninate), glutamate is removed from the synapse by glutamate transporters on glial cells. The glia convert glutamate to glutamine which is then transported out of glial cells in to neurons which convert it back to glutamate [1]. The process requires energy and is disrupted by secondary energy failure. Overactivation of NMDA receptor is the commonest mechanism of neuronal injury in HIE. The receptor is composed of four heteromeric subunits, the combinations of which create different functional modules. The receptor has multiple functional sites including a cation selective ion channel which transports Na+, K+ and Ca+. The NMDA receptor is overexpressed in neonatal brain which allows synaptogenesis and plasticity. However, uninhibited stimulation of receptor as occurs in HIE leads to massive influx of Na+, and water with associated cellular swelling and necrosis, elevated intracellular Ca+ concentration and associated mitochondrial dysfunction, energy failure and apoptosis [2]. Neuronal death that occurs depends on the developmental expression and function of these receptors. Adenosine receptors are also expressed by excitatory neurons and levels of adenosine increase exponentially during ischemia stimulating these receptors. This excessive adenosine receptor activation inhibits axonal growth and white matter formation. Non specific adenosine receptor antagonists, which are beneficial

Perinatal Asphyxia

in preventing renal and tubular damage due to perinatal asphyxia when given early could potentially have a role in limiting neuronal injury in HIE. Oxidative Stress: Increased production of reactive oxygen radicals also contributes to the pathogenesis of neonatal HIE. Under physiological conditions, more than 80% of oxygen in the cell is reduced to adenosine triphosphate (ATP) by cytochrome oxidase and the rest is converted to superoxide and hydrogen peroxide. Superoxide and hydrogen peroxide are scavenged enzymatically by superoxide dismutase, catalase, and glutathione peroxidase and non-enzymatically by reaction with alphatocopherol and ascorbic acid. Damage to mitochondria during asphyxia results in accumulation of superoxide and immaturity of antioxidant defenses will result in conversion of superoxide to hydroxyl radicals. With reperfusion after ischemia these free radicals directly damage DNA, proteins and membrane lipids, cause lipid peroxidation, initiate apoptosis and react with nitric oxide to produce peroxynitrile radicals. All these are implicated in the secondary neuronal death. Neonatal brain is particularly vulnerable to free radical attack and lipid peroxidation because of three factors; (i) Polyunsaturated fatty acid content of brain is high. There is a basal level of lipid peroxidation that is high at term. Lipid peroxidation

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causes phospholipase activation that increases free radical production which in turn increase lipid peroxidation and a vicious cycle occurs in brain. (ii) Antioxidant enzymes like superoxide dismutase, catalase, and glutathione peroxidase are immature in neonates. (iii) There is increased free iron relative to the adults. The damaging potential of free iron and immaturity of enzymatic oxidant defenses are interrelated. Free iron catalyses the production of various reactive oxygen species. Increased free iron is detectable in the plasma and CSF of asphyxiated newborns. Nitric Oxide: Nitric oxide (NO) functions both physiologically and pathologically. Its production by enzymes of endothelial cells, astrocytes and neurons is stimulated by intracellular calcium. NO thus produced has a role in pulmonary, systemic and cerebral vasodilatation and exerts a compensatory vascular effect after ischemia during reperfusion. NO is also produced by inducible NO synthase (iNOS) in response to stress which modifies the NMDA receptor facilitating calcium entry and enhancing cytotoxicity. Nitric oxide and nitric oxide synthase are also implicated in the programmed cell death that results from HIE [3]. The combined effect of all these pathways leading to secondary neuronal death is shown in Fig. 1.

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Perinatal Asphyxia. Figure 1 Mechanism of secondary neuronal death in perinatal asphyxia.

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Perinatal Asphyxia

Inflammation: Cytokines are the final common mediators of brain injury that is initiated by hypoxicischemia, reperfusion and infection. In neonates CSF concentrations of IL-ß, IL-6 and IL-8 increase after perinatal asphyxia in comparison to controls and increased magnitude correlates with severity of encephalopathy. Also other mediators like platelet activating factor, arachidonic acid and their metabolites like prostaglandins, leukotrienes, thromboxanes and cyclooxygenase are involved in the inflammatory response during evolution of brain injury after ischemia and reperfusion. Genetic Effects: Same type of injury manifests differently in different neonates with regards to clinical presentation, imaging studies and neurodevelopmental outcome. Such variability appears to be genetically based. However, susceptibility factors for neonatal brain injury have not been identified clearly. Study of very preterm infants showed an association of singlenucleotide polymorphisms such as endothelial nitric oxide synthase A (922) G, factor VII (Arg353Gln) and del (−323)10 bp-ins, and lymphotoxin a (Thr26Asn) with spastic cerebral palsy. Such type of associations increases the assumption that certain polymorphisms may increase the susceptibility to perinatal asphyxia.

2.

3.

4.

5.

6.

serum creatinine, creatinine clearance and BUN estimation should be done during initial few days. Study of liver function tests and cardiac enzymes (Tropoin 1, Tropoin T, & CK – MB) should be done to look for the involvement of these organs. Echocardiography for myocardial contractility is needed if ionotropic support is required. Ultrasound of the head is easy and can be performed at bedside. It shows presence of cerebral edema, intracerebral or intraventricular hemorrhage. However posterior fossa hemorrhage cannot be visualized. CT scan of the head is important to confirm cerebral edema (obliteration of ventricles, flattening of gyri) and any hemorrhage seen on ultrasound. Areas of reduced density on CT scan are compatible with evolving infarcts. Also CT is important in ruling out posterior fossa hemorrhage. MRI brain is very helpful in moderate to severe HIE during early stages and follow-up. It may show grey-white matter injury, developmental defects and status of myelination. Diffusion weighted MRI is more accurate to identify areas of edema early in the course of the disease. Amplitude electroencephalography helps in the early identification of patients with poor outcome.

Diagnostic Principles Diagnosis of HIE is based on history and neurological examination. Fetal distress or surrogate markers of fetal distress are present in the majority of the patients in the perinatal period. There is a history of resuscitation at birth and umbilical arterial blood shows acidosis or increase in base deficit. The involvement of the central nervous system depends on the severity of HIE. In mild HIE, there is transient irritability, increase in sympathetic activity and muscle tone which improves over 3–4 days. In moderate HIE, there is hypotonia, increased parasympathetic activity and weak neonatal reflexes. Seizures occur in 80%. All features normalize in 1–2 weeks with only 20–30% patients developing long term disability. In severe HIE, patients are comatose, hypotonic with absent neonatal reflexes. Seizures occur initially, are resistant to treatment and subsequently frequency decreases due to extensive neuronal injury. Electroencephalogram shows burst suppression or is isoelectric which portends poor prognosis. Involvement of other systems like kidneys, lungs, gastrointestinal tract and cardiovascular system also occur in severe HIE. Laboratory and imaging studies help to know the extent of involvement of CNS and other systems: 1. Electrolytes and renal function tests should be done daily till improvement occurs. Serum sodium, potassium and chloride determinations are important to rule out SIADH and other complications. Also

Therapeutic Principles 1. Maintain adequate ventilation and perfusion. Mechanical ventilation may be required in severe cases. 2. Fluid and electrolyte status should be maintained to prevent SIADH and other complications. Two third fluids should be given if there is hyponatremia and weight gain in initial few days. Subsequently fluid intake is individualized depending upon urine output, weight gain and renal parameters. Avoid hypoglycemia, hypocalcaemia or hyperglycemia as all exacerbate neuronal injury. 3. Avoid acidosis, hypoxia, hypercarbia and hypocarbia. All, especially the last, exacerbate brain injury. Maintain PaO2 between 60 and 80 mm Hg, PaCO2 between 35 and 40 mmHg and pH between 7.35 and 7.45. 4. Maintain mean blood pressure at 45–50 mmHg in term babies. Inotropic support may be needed to maintain mean blood pressure in the desired range. 5. Seizures should be controlled early and effectively. Phenobarbitone may be used initially. If needed phenytoin may be added in resistant seizures. Continuous EEG monitoring should be done as clinically asymptomatic seizures have been shown to increase neuronal injury. 6. Brain cooling due to whole body hypothermia has been shown to be very effective in the management of HIE. It has a therapeutic window of 6 h

Periodic Catatonia

and brain is cooled for 48–72 h after which slow rewarming is done. The possible mechanisms of action include: (i) reduced metabolic rate and energy depletion; (ii) decreased excitatory transmitter release; (iii) reduced alterations in ion flux; (iv) reduced apoptosis due to HIE; and (v) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions. In a recent study on whole body hypothermia by Shankaran et al. [4], death or disability occurred in 44% of patients in hypothermic group vs. 62% in the control group (RR 0.72, C.I.0.54–0.95). Hypothermia not only decreases the incidence of cerebral palsy at 18 months of age but also improves outcome in the neonatal period. 7. Renal and tubular damage in perinatal asphyxia is caused by adenosine. Theophylline, a non specific adenosine receptor antagonist has protective effect if given within 1 h of birth [5].

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Definition and Characteristics Periodic catatonia is a bipolar disorder in the schizophrenic spectrum with prominence of qualitative psychomotor changes. Two psychotic poles, psychomotor excitement and inhibition, involve parakinesia, grimacing or mask-like facies, iterations and posture stereotypies, as well as distorted stiff movements or akinetic negativism. In most cases, acute psychotic episodes are accompanied by hallucinations and delusions, but in remission there remains a distinct mild to severe catatonic residual state with psychomotor weakness and diminished incentive [1].

Prevalence 1:10,000 in periodic catatonia; the morbidity risk is 27% for first-degree relatives; penetrance of the disorder is estimated to be 40% [2,4].

Genes References 1. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497 2. Mishra OP, Delivoria-Papadopoulos M (1999) Cellular mechanisms of hypoxic injury in the developing brain. Brain Res Bull 48:233–248 3. Roland EH, Poskitt K, Rodriguez E, Lupton BA, Hill A (1998) Perinatal hypoxic–ischemic thalamic injury: clinical features and neuroimaging. Ann Neurol 44:161–166 4. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. (2005) Whole-body hypothermia for neonates with hypoxic-ischemicencephalopathy. N Engl J Med 353:1574–1584 5. Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH (2006) Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr 149:180–184

Periodic Catatonia G ERALD S TO¨ BER 1 , A NDRE´ R EIS 2 1

Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany 2 Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

Synonyms Catatonic schizophrenia; Catatonia; Kahlbaum’s syndrome, periodic catatonia

Periodic catatonia is the first sub-phenotype of the schizophrenic psychoses with confirmed linkage despite considerable genetic heterogeneity in two independent genome-wide linkage scans (GS) on twelve and four extended multiplex pedigrees [3,4]. Major disease loci, supported by independent pedigrees, were observed at chromosome 15q15 and 22q13, with further putative loci on chromosomes 1, 6, 11, 13, 16 and 20. Parametric, non-parametric and haplotype analyses were consistent with an autosomal dominant transmission with reduced penetrance. Chromosome 15q15: In GS I, non-parametric analyses found the most significant allele sharing between affected individuals on chromosome 15q15 at position 35.3 cM ( p = 2.6 × 10−5, maximum nonparametric lod score 3.57), replicated by GS II with the main peak on chromosome 15q at position 32.3 cM ( p = 0.003). Linkage and haplotype analyses in three exceptionally large pedigrees linked to chromosome 15q15 disclosed a critical region between markers D15S1042 and D15S659, which could be further refined to a 7.49 Mb interval, containing 123 known genes (unpublished results). The current positional cloning project involves a systematic mutation scan of all genes from the critical region in search of diseaseassociated haplotypes and/or mutations in linked pedigrees and a cohort of 250 index cases. Chromosome 22q13: Mainly supported by a single four-generation pedigree, a second locus was identified on chromosome 22q13 with a maximum multipoint LOD score of 2.59 (θ = 0.0) under an autosomal dominant model. Previously, a sequence variant in the gene MLC1 (coding for autosomal recessively inherited megaloencephalic leukoencephalopathy with subcortical cysts; MLC) had been proposed to cause periodic catatonia

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Periodic Dystonia

and recently a small sample of cases produced a weak association to a two-locus haplotype in the promoter region. However, a systematic mutation scan of MLC1 had earlier produced compelling evidence that MLC1variants are not associated with periodic catatonia in sample of 140 cases [5].

Molecular and Systemic Pathophysiology In catatonia, systemic pathophysiology and the involved neuro-anatomical structures remain undetermined, but basal ganglia and thalamo-cortical loops seem to be involved. Using broadly defined criteria for catatonia, imaging techniques revealed a decreased blood flow in right lower and middle prefrontal and parietal cortex during acute akinesia; motor activation was reduced in the contralateral motor cortex and in a single case study, acute akinesia caused a reversible complex dysregulation of glucose metabolism in large brain areas. Animal models of catatonia unfortunately reduce disturbed human psychomotor behavior, i.e., expressive and reactive movements, excessively to animal immobility or antipsychotic drug-induced catalepsy.

Diagnostic Principles Diagnosis is made by clinical observation; diagnostic laboratory and specific neuro-imaging abnormalities are missing. In the framework of international classification systems, catatonia is recognized as a cluster of gross, non-specific psychomotor traits and mostly identifies a state of extreme motor inhibition. In view of K. Leonhard’s nosological differentiation, psychomotor disturbances are complex, and as a basic point quantitative hyperkinetic or akinetic changes (motility psychoses with phasic remitting course) have to be discriminated from qualitative changes, true “catatonic” signs (periodic and systematic catatonia. Psychomotor disorders: catatonia phenotypes, and etiological aspects Motility psychosis: . Subphenotype of the cycloid psychoses . Bipolar phasic with quantitative psychomotor disturbances . Low genetic loading according to family and twin studies . Multifactorial etiology (environmental factors, modifying genes?) Systematic catatonias: . Distinct subtypes; involvement of discrete functional psychic units . Chronic progressive without remission . Low genetic loading according to family and twin studies . Multifactorial etiology, early noxious events (gestational infections)

Periodic catatonia: . Subphenotype of the unsystematic schizophrenias . Bipolar with residual syndrome and qualitative psychomotor disturbances . Genetically mapped in two independent genome scans . Autosomal dominant transmission with reduced penetrance . Major gene locus on chromosome 15q15, and genetic heterogeneity Gjessing’s concept of periodic catatonia pooled bipolar psychomotor disorders with phasic course and those with episodes of worsening.

Therapeutic Principles In catatonia, specific therapies are not available. Acute hyperkinetic attacks respond well to first- and second-generation antipsychotic drugs, benzodiazepines reduce affective tensions. Electroconvulsive therapy should be applied in cases with severe stupor or excessive psychomotor agitation, combined with dysregulation of autonomic status. Patients with periodic catatonia seem to benefit from modern low dose antipsychotic maintenance therapy, but still develop the characteristic catatonic residual syndrome.

References 1. Leonhard K (1999) Classification of endogenous psychoses and their differentiated etiology, 2nd rev. and enlarged edn. Springer, Wien 2. Beckmann H, Franzek E, Stöber G (1996) Genetic heterogeneity in catatonic schizophrenia: a family study. Am J Med Genet (Neuropsychiatric Genet) 67:289–300 3. Stöber G, Saar K, Rüschendorf F, Meyer J, Nürnberg G, Jatzke S, Franzek E, Reis A, Lesch KP, Wienker TF, Beckmann H (2000) Splitting schizophrenia: periodic catatonia susceptibility locus on chromosome 15q15. Am J Hum Genet 67:1201–1207 4. Stöber G, Seelow D, Rüschendorf F, Ekici A, Beckmann H, Reis A (2002) Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity. Hum Genet 111:323–330 5. Rubie C, Lichtner P, Gärtner J, Siekiera M, Uziel G, Kohlmann B, Kohlschütter A, Meitinger T, Stöber G, Bettecken T (2003) Sequence diversity of KIAA0027/ MLC1: are schizophrenia and megalencephalic leukoencephalopathy allelic disorders? Hum Mutation 21:45–52

Periodic Dystonia ▶Paroxysmal Dyskinesias

Periodic Paralyses, Familial

Periodic Movements in Sleep ▶Periodic Limb Movement

Periodic Leg Movements ▶Periodic Limb Movement

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with L-Dopa and dopamine agonists relieving symptoms and dopamine blockers worsening the symptoms [3].

Diagnostic Principles Diagnosis is based on (i) complaints of insomnia and/or excessive daytime sleepiness, (ii) repetitive stereotypic extremity movements, (iii) polysomnographic demonstration of the movements and subsequent arousal reactions, (iv) no other medical illness or medication accounting for the PLMs, and (v) other sleep disorders may be present but should not contribute to the PLMs. Polysomnography can document the PLMs and can lead to the diagnosis of other, accompanying sleep disorders [1].

Therapeutic Principles

Periodic Limb Movement J AN R E´ MI , S OHEYL N OACHTAR Section of Sleep, Department of Neurology, University of Munich, Munich, Germany

Synonyms Periodic leg movements; Leg jerks; Periodic movements in sleep, PLMs

Definition and Characteristics Periodic limb movements (PLMs) are repetitive, stereotypic movements of the extremities preferably during sleep. PLMs can be a part of the Restless-LegSyndrome (RLS). In this case, also unpleasant sensations of the urge to move and paresthesias are part of the syndrome. However, PLMs also represent a separate nosological entity. Typically the big toe is extended and ankle, knee and hip can be flexed to a small extent. The patients can be aware of the leg jerks and complain of bad sleep, or sometimes they are unaware of the sleep events and will complain about excessive daytime sleepiness alone. Next to RLS, PLMs can accompany other sleep disorders like narcolepsy and sleep apnea and may disappear upon successful treatment of the primary sleep disorder [1].

Prevalence The prevalence increases with age. It is very low under the age of 30 and can reach 34% in patients over the age of 60 [2].

Molecular and Systemic Pathophysiology As in restless-legs-syndrome, the dopamine transmitter system plays a role in the pathophysiology of PLMs,

The treatment of PLMs is similar to the treatment of the restless legs syndrome, consisting mainly of dopaminergic medication, namely L-Dopa or dopamine agonists [3].

References 1. American Academy of Sleep Medicine (2001) International classification of sleep disorders, revised: Diagnostic and coding manual. American Academy of Sleep Medicine, Chicago, Illinois 2. Trenkwalder C, Walters AS, Hening W (1996) Neurol Clin 14:629–650 3. Guilleminaut C, Mondini S, Montplaisir J, Mancuso J, Cobasko D, Dement WC (1987) Sleep 10:393–397

P Periodic Paralyses, Familial K ARIN J URKAT-R OTT, F RANK L EHMANN -H ORN Applied Physiology, Ulm University, Ulm, Germany

Synonyms Hyperkalemic periodic paralysis; HyperPP; Hypokalemic periodic paralysis; HypoPP; Andersen syndrome (AS)

Definition and Characteristics Two dominant episodic types of weakness with or without myotonia, HyperPP and HypoPP, are distinguished by the serum K+ level during attacks. Intakes of K+ and glucose have opposite effects in the two disorders; while K+ triggers attacks and glucose is a remedy in HyperPP, glucose-induced hypokalemia provokes attacks in HypoPP, which are ameliorated by K+ intake. Due to additional release of K+ from

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Periodic Paralyses, Familial

muscle in HyperPP and uptake of K+ by muscle in HypoPP, the resulting dyskalemia can be so severe that cardiac complications arise. During an attack, death can also occur due to respiratory insufficiency. Independently of the severity and frequency of the paralytic episodes, many patients develop a chronic progressive myopathy in the forties, an age at which the attacks of weakness decrease. An additional form of familial PP is the Andersen syndrome, which is also dominantly inherited and affects not only the skeletal but also the cardiac muscle. It may show hyper-, normoor hypo-kalemia during paralytic attacks. Another type of dyskalemic periodic paralysis has been reported by Abbott et al. (2001) but questioned, since the prevalence of the underlying genetic variant is the same in patients and controls and no paralytic attacks could be provoked in the carriers [1].

Prevalence 1:200,000 in HyperPP, 1:100,000 in HypoPP and 1:1,000,000 in AS.

Genes HyperPP: Point mutations in SCNA4 (17q23) encoding Nav1.4, the voltage-gated sodium channel of skeletal muscle [2].

HypoPP: Point mutations in SCNA4 (HypoPP-2) (2) or CACNA1S (1q23) encoding Cav1.1, the L-type calcium channel of skeletal muscle (HypoPP-1) [3]; all amino acid changes are situated in voltage sensors. AS: Mutations in KCNJ2 (17q23) encoding Kir2.1, the inward rectifier potassium channel of skeletal and cardiac muscle [4].

Molecular and Systemic Pathophysiology HyperPP is caused by mutations in the voltage-gated sodium channel Nav1.4 that is essential for the generation of muscle fiber action potentials. Most Nav1.4 mutations are situated at inner parts of transmembrane segments or in intracellular loops and affect structures that may form the three-dimensional docking site for the fast inactivation particle. Any malformation may reduce the affinity between the “latch bar and the catch” (Fig. 1). The α subunit consists of four highly homologous domains I-IV with six transmembrane segments each (S1–S6). The S5–S6 loops and the transmembrane segments S6 form the ion selective pore, and the S4 segments contain positively charged residues every third amino acid, conferring voltage dependence to the protein. The S4 segments are thought to move outward upon depolarization thereby inducing channel opening. When inserted in the membrane, the four

Periodic Paralyses, Familial. Figure 1 Scheme of the voltage-gated Na+ channel.

Periodic Paralyses, Familial

repeats of the protein fold to generate a central pore as schematically indicated on the right bottom of the figure (see insert). The repeats are connected by intracellular loops. One of them, the III-IV linker, contains the inactivation particle (amino acids IFM close to the shown G to E/A/V) which potentialdependently binds to its docking site. The mutations associated with HyperPP and HypoPP-2 and other muscle sodium channelopathies (see ▶Myotonia and paramyotonia), are indicated in the one-letter code for amino acids. The mutant channels avoid the inactivated state and, in contrast to normal Na+ channels, reopen from the inactivated to the open state, corresponding to a gainof-function defect. As a result, sodium influx is increased as shown in vitro and in vivo. This inward current is associated with a sustained membrane depolarization that increases the electrical driving force for potassium, and potassium released from muscle elevates its serum concentration. Sodium influx into muscle fibers is accompanied by water, causing hemoconcentration and further increase in serum potassium. This is a vicious cycle that spreads out and affects the surrounding muscle fibers. In contrast to the gain-of-function changes in HyperPP, HypoPP is associated with a loss-of-function defect of Nav1.4 or Cav1.1, the main subunit of the voltage-gated L-type Ca2+ channel complex (dihydropyridine receptor) located in the t-tubular system. HypoPP-1 and 2 are clinically similar, and in both channel types, the mutations are located exclusively in the voltage-sensing S4 segments; those of Nav1.4 are located in domain 2 and those of Cav1.1 in domains 2 or 4. Functionally, the inactivated state is stabilized in the Na+ channel mutants, while the channel availability is reduced for the Ca2+ channel mutants. It is still unclear how the loss-of-function mutations of these two cation channels can produce the long-lasting and pronounced membrane depolarization that inactivates the sodium channels and thereby leads to the fiber inexcitability. AS has mutations affecting the Kir2.1 channels, which are essential for maintaining the highly negative resting membrane potential of muscle fibers and accelerating the repolarization phase of the cardiac action potential. The mutations mediate loss of channel function by haploinsufficiency or by dominant-negative effects on the wild type allele and lead to long-lasting depolarization and membrane inexcitability.

Diagnostic Principles In the past, provocative tests have been carried out for diagnostic reasons. As they have harbored the risk of inducing a severe attack they had to be performed by an experienced physician and a standby anesthesiologist; the serum potassium and glucose levels and the ECG had to be closely monitored.

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Nowadays, provocative tests should be restricted to patients in whom molecular genetics fail to identify the underlying mutation. Since histological alterations are not specific, a muscle biopsy should only be performed in patients with atypical features or for documentation of a vacuolar myopathy.

Therapeutic Principles HyperPP: During an attack of weakness, serum potassium levels should be reduced by stimulation of the sodium-potassium pump, e.g. by continuous mild exercise or carbohydrate ingestion or salbutamol inhalation. Permanent stabilization of serum potassium at a low level should be achieved by thiazide diuretics. Alternatively, carbonic anhydrase inhibitors are the second choice and may be effective via myoplasmic acidification. HypoPP: All substances which decrease serum potassium levels either by shifting potassium into the cells or by excretion by the kidney should be avoided including high carbohydrate/sodium meals, bicarbonate and potassium-lowering diuretics, a sedentary lifestyle or strenuous physical exercise. Attacks should be treated orally with potassium chloride. Carbonic anhydrase inhibitors are the prophylactic medication of choice. Potassium-sparing diuretics, such as triamterene, amiloride, and spironolactone may be administered in addition. AS: The most important task is to find out whether the cardiac arrhythmia is potentially fatal or not. Drugs or provocative tests that induce hypokalemia can provoke ventricular tachycardia and must be avoided. Patients with former syncopes or bursts of ventricular tachycardia in the resting or Holter ECG recordings are at high risk. Such symptoms and signs may demand the implantation of a defibrillator or a pacemaker.

References 1. Jurkat-Rott K, Lehmann-Horn F (2005) J Clin Invest 115: 2000–2009 2. Rojas CV, Wang J, Schwartz L, Hoffman EP, Powell BR, Brown Jr RH (1991) Nature 354:387–389 3. Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers P, Lapie P, Vale-Santos JE, Weissenbach J, Fontaine B (1994) Hum Mol Gen 3:1415–1419 4. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, AL Fish FA, Hahn A, Nitu A, Özdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ (2001) Cell 105:511–519 5. Jurkat-Rott K, Mitrovic N, Hang C, Kuzmenkin A, Iaizzo P, Herzog J, Lerche H, Nicole N, Vale-Santos J, Chauveau D, Fontaine B, Lehmann-Horn F (2000) Proc Natl Acad Sci USA 97:9549–9554

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Periodic Vestibulocerebellar Ataxia

Periodic Vestibulocerebellar Ataxia ▶Episodic Ataxia Type 1 and Type 2

Periodontal Diseases MARINELLA HOLZHAUSEN, N ATHALIE V ERGNOLLE Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB, Canada

Synonyms Gum disease; Periodontopathia; Gingivitis; Periodontitis

Definition and Characteristics The human periodontal diseases encompass a group of oral disorders characterized by infection and inflammation that affect the surrounding and supporting tissues of the teeth, including gingival tissue, periodontal ligament, cementum, and alveolar bone. The two major forms of periodontal diseases are gingivitis and periodontitis, but they can be subclassified as gingival diseases (plaque-induced and non-plaque induced), chronic periodontitis, aggressive periodontitis, periodontitis as a manifestation of systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, periodontitis associated with endodontic lesions and developmental or acquired deformities and conditions [1]. Gingivitis is gingival inflammation, characterized by redness, swelling, and tendency to bleed, without clinical attachment loss or with non-progressing attachment loss. Periodontitis is inflammation that reaches both gingival tissues and adjacent attachment apparatus, and is characterized by progressive loss of connective tissue attachment and alveolar bone. Periodontitis is an insidious destructive condition, which, if left untreated can lead to tooth mobility and potential exfoliation of teeth.

Prevalence Periodontal diseases constitute the most common oral infections in humans and the major cause of tooth loss in adults. It is estimated that the prevalence of severe periodontal destruction is remarkably consistent in different populations affecting around 10% of the population in the world.

Molecular and Systemic Pathophysiology The presence of a bacterial biofilm is a sine qua non condition for the initiation and progression of most of the periodontal diseases [2]. The subgingival growth of certain species of primary Gram-negative anaerobic bacteria has been implicated in the complex bacterial etiology of the disease. Interestingly, the presence of periodontal bacteria solely is not sufficient to explain periodontal disease episodes. In fact, in periodontal healthy individuals, the saliva, the gingival crevicular fluid (a serum exudate), the epithelial surface, and the initial stages of inflammatory response are able to maintain an ecological balance with the bacteria. Protective response of the host involves the recruitment of neutrophils, production of antibodies, and the possible production of anti-inflammatory mediators including transforming growth factor-β (TGF- β), interleukin-4 (IL-4), IL-10, and IL-12. It is believed that periodontal tissue breakdown occurs as a result of alterations in the number or in the pathogenicity of certain microorganisms, mainly porphyromonas gingivalis, bacteroides forsythus, and actinobacillus actinomycetemcomitans. In addition, modifications in the host susceptibility may accentuate the activation of destructive host immuno-inflammatory responses. Host tissues and immune cells may respond to bacterial infection by producing pro-inflammatory mediators such as arachidonic acid metabolite prostaglandin E2, matrix metalloproteinases (connective tissue degrading enzymes) and the cytokines IL-1, IL-6 and tumor necrosis factor-α (TNF- α), which are potent periodontal tissue degrading agents responsible for connective tissue and alveolar bone destruction. Environmental, acquired and genetic risk factors, such as cigarette smoking, stress, diabetes and IL-1 gene polymorphisms, may exacerbate the host response and, therefore, increase the susceptibility to periodontal diseases.

Diagnostic Principles The diagnosis of periodontal disease relies on traditional clinical and radiographic assessments, and it is based on the patient’s medical and dental histories, on the amount of observable plaque and calculus, and presence of clinical signs of inflammation (e.g., bleeding following probing), periodontal probing attachment levels, and radiographic analysis of the alveolar bone height [3]. The use of culture DNA probes or assessment of specific cell surface antigenic profiles, and enzymatic activity may identify the presence of periodontal pathogens. In addition, the host response can be assessed by gingival crevicular fluid detection of host-derived enzymes, tissue breakdown products or inflammatory mediators. Furthermore, a genetic test for polymorphisms in the IL-1 gene cluster identifies individuals that

Peripheral Artery Disease

may have an increased secretion of IL-1β in response to inflammation-induced stimuli.

Therapeutic Principles The aim of periodontal therapy is to minimize or eliminate inflammation and to stop the progression of periodontal attachment loss [4]. In many patients, personal plaque control measurements, and professional plaque and calculus removal (scaling and root planning) are essential for controlling inflammatory periodontal diseases. However, in some advanced and aggressive forms of periodontal disease, or in medically compromised patients, supplemental therapeutic approaches may be required, such as the use of systemic antibiotics, subgingival delivery of antibiotics/antimicrobials, and host modulatory therapies. The surgical periodontal treatment has to be considered in those cases in which elimination/reduction of excessive probing depths is necessary to facilitate the patient’s personal periodontal maintenance. There are also surgical procedures that attempt the regeneration of lost periodontal tissues or improvement of esthetics in exposed root surfaces.

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Peripheral Arterial Occlusive Disease ▶Peripheral Artery Disease

Peripheral Artery Disease M ARTIN S CHILLINGER Division of Angiology, Department of Internal Medicine II, University of Vienna, Medical School, Vienna, Austria

Synonyms PAD; Peripheral arterial occlusive disease; Atherosclerosis

Definition and Characteristics References 1. Armitage GC (1999) Development of a classification system for periodontal diseases and conditions. Ann Periodontol 4:1–6 2. Offenbacher S (1996) Periodontal diseases: pathogenesis. Ann Periodontol 1:821–878 3. Armitage GC (2003) Diagnosis of periodontal diseases. J Periodontol 74:1237–1247 4. The American Academy of Periodontology (2001) Treatment of plaque-induced gingivitis, chronic periodontitis, and other clinical conditions (position paper). J Periodontol 72:1790–1800

PAD is defined by atherosclerotic obstruction of lower limb arteries and may affect all vascular segments, i.e. the aorta, the pelvic arteries, the femoropopliteal segment and the tibioperoneal arteries. Conventional risk factors for atherosclerosis account for only about 50% of the cases [1].

Prevalence The prevalence of PAD clearly increases with age, and the disease affects approximately 9% of the population above the age of 50 years and 15% of the population above 65 years. More than two thirds of the patients remain asymptomatic.

Genes

Periodontitis ▶Periodontal Diseases

Periodontopathia ▶Periodontal Diseases

Accumulating evidence suggests that PAD has an important hereditary component [2]. Among the panel of novel risk factors various genetic abnormalities potentially play a relevant role. Identification of target genes responsible for an increased risk of PAD, however, has been a slow and difficult process [3]. Polymorphisms in many different genes have been attributed to convey an increased risk for atherosclerosis and PAD. Single nucleotide polymorphisms (SNP) are the most frequently described changes in the DNA sequence which are thought to exert a pathogenetic effect in PAD. Insertion and deletion polymorphisms and variable number of tandem repeats (VNTR) also have been reported to be functionally relevant in this context. Interpreting the numerous publications in this field of research it seems important to consider

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Peripheral Artery Disease

the following issues: First, most studies on genes and PAD are cross-sectional association studies investigating specific genotypes in patients and controls. These studies are mostly underpowered and prone to publication bias, as positive studies are far more likely to be published than negative ones. E.g., for evaluation of a single polymorphism with a frequency of 10% within the target population a sample size above 400 participants is needed to detect a clinically relevant effect size of a doubled risk, the number of participants of course increases when multiple polymorphisms are investigated. Second, studies infrequently report a functional relevance of the investigated polymorphisms in the respective study populations. An ideal study reports on the genetic variant, changes in expression pattern on the level of the RNA, changes in the levels of the gene product (enzyme, protein) – the so called intermediate phenotype – and changes of the clinical phenotype (presence of disease or disease severity). This pathophysiologic chain of evidence hardly has been demonstrated for any polymorphism presumably involved in the pathogenesis of PAD. Third, PAD is a multifactorial and polygenetic disease. “Multifactorial” indicates that the interaction of multiple risk factors determines the individual’s risk, in particular, geneenvironment interactions seem relevant. “Polygenetic” indicates that gene–gene interactions likely contribute to the initiation and progression of atherosclerosis. Genetic polymorphisms, investigated in the context of peripheral artery disease are involved in the pathogenesis of traditional cardiovascular risk factors (dyslipidemia, hypertension, diabetes and insulin resistance), inflammation, anti-oxidant effects. Endothelial dysfunction, coagulation and thrombosis, and platelet dysfunction, as amplified below.

Molecular and Systemic Pathophysiology Dyslipidemia: More than 230 mutations in the gene encoding for the LDL-receptor are known (http:/www. ucl.ac.uk/fh), which account for homozygous or heterozygous familial hypercholesterolemia. Another less severe cause for familial hypercholesterolemia is the Arg3500Gln (or exceptionally, Arg3531Cys) mutation of apolipoprotein B, the molecule that acts as a ligand for LDL receptors. Apolipoprotein E binds VLDL and IDL and occurs in three main versions: apo-E3, the natural isoform, apo-E2 and apo-E4, which are caused by SNPs at positions 158 and 112, respectively. Apo-E4 seems to exert a deleterious effect on atherosclerosis as shown in the 4S-trial whereas apo-E2 seems to be beneficial. Rarely, familial dysbetalipoproteinemia affects patients with the apoE2 allele causing a complete deficiency of apo-E. The serum concentration of lipoprotein (a) is determined by >90% by genetic causes, elevated levels

above 30 mg/dL and particularly a coincidence with the apo-E4 allele have been demonstrated to exert particularly unfavorable effects with respect to atherosclerosis development. With respect to PAD, however, one study demonstrated that genetic variability of apo-B contributes to atherosclerosis risk, but not specifically to PAD, and another study investigated the apolipoprotein AI-CIII-IV gene cluster and found no association with the disease. For HDL mutations a specific association with PAD has not been demonstrated unequivocally as yet, although states of low HDL and respective polymorphism like in the lecithin-cholesterol acyl transferase (LCAT) seem to promote PAD. Several other polymorphisms in the cholesterol ester transfer protein (CETP) have also only been investigated with respect to coronary atherosclerosis. The gene of the lipoprotein lipase is particularly prone to mutations (www.ncbi.nlm.gov/omin) which lead to increased triglyceride levels. The role of these genetic variants with respect to PAD remains to be investigated. A rare Mendelial disease – Tangier’s disease is characterized by premature atherosclerosis including PAD – is due to a mutation in the ABC1 transporter gene, which forms a channel for cholesterol egress through cell membranes. Recently, a SNP in the plasma PAF-acetylhydrolase (PAF-AH) at position 994G > T in exon 9 has been described to be associated with PAD and seemed to interact with hypercholesterolemia in a Japanese population. Focusing on gene-drug interactions, the LEADER trial found no modulating effect of three polymorphisms in the peroxisome proliferators activated receptor alpha gene, two apolipoprotein CIII polymorphisms and one beta fibrinogen polymorphism with respect to treatment effects of bezafibrate. Hypertension: Molecular variants of the genes encoding for the renin-angiotensin-aldosterone and sympatho-adrenergic system are related to hypertension development and thus may promote PAD development. Particularly the insertion/deletion polymorphism of the ACE gene clearly has functional relevance as it influences plasma ACE activity and was investigated with respect to atherosclerosis development and progression. In the context of PAD, the relation of the ACE polymorphism with restenosis after percutaneous interventions, insulin resistance and hypertension may be relevant, although an implication of this polymorphism in PAD remains debatable due to divergent findings. Polymorphism of the angiotensin II receptor, chymase A and aldosterone synthase have only been studied in the context of cardiac atherosclerosis. Insulin Resistance and Diabetes: Several mutations causing rare forms of insulin resistance have been described involving the insulin receptor and the insulin receptor substrate (IRS). In particular, the G972R polymorphism of the IRS-1 gene, which can be found

Peripheral Artery Disease

in 6–7% of the population is clearly associated with insulin resistance and premature atherosclerosis. Inflammation: Atherosclerosis is considered a chronic inflammatory disease and several genes encoding for mediators of inflammation have been studied in the context of PAD. These include ICAM-1, interleukin 6 polymorphisms (G/C -174), interleukin 1 (including its receptor antagonist) and IL-5 polymorphisms revealing partly positive associations, but no convincing evidence as these findings were not confirmed in independent cohorts. Furthermore, genetic variability in the CRP gene has been discussed potentially relevant for atherosclerosis development and variability of the E-selectin Ser128-Arg polymorphism was analyzed with respect to restenosis after endovascular treatment of PAD patients. Various chemokines are thought to be associated with atherosclerosis. In this context the homozygous Delta 32 mutation of the gene of the chemokine receptor CCR5 was suggested to differentiate PAD from aneurismal disease. Anti-oxidant Effects: Various anti-oxidants are thought to play a role in the development of atherosclerosis. In patient with peripheral artery disease, a GT length polymorphism in the heme oxygenase-1 (HO-1) gene promoter has been demonstrated to be associated with future cardiovascular adverse events and restenosis after endovascular treatment, however, an association with development of PAD has not been shown as yet. Another enzyme potentially relevant for anti-oxidant defense in the vascular wall particularly in diabetic subjects is glutathione peroxidase-1 (GPx-1). Four polymorphisms in GPx-1 were identified and associated with increased intima media thickness and risk for peripheral artery disease. The haptoglobin 2–2 genotype also was shown to be associated with PAD in one study. Endothelial Dysfunction: Polymorphisms in the NADH/NADPH oxidase, NO-synthase and methylene tetrahydrofolate reductase (MTHFR) seem to be associated with endothelial dysfunction. However, for the p22 phox gene polymorphism (C242T), a component of the NADH/NADPH oxidase system, negative findings were reported with respect to an association with PAD. The C677T polymorphism of MTHFR, which causes a less efficient catabolism of homocysteine into methionine and thus increases homocysteine by 25% in states of folate deficiency, presumably increases the risk for PAD particularly in diabetic subjects. This polymorphism has to be separated from rare causes of severe hypercysteinemias capable of producing homocysteinuria like homozygous CBS deficiency, an exceptional Mendelian disease. A SNP in the human paroxonase-1 (PON-1) gene (Q192R) which may reduce LDL oxidation has been demonstrated to show a direct relation with brachial flow mediated vasodilation in PAD patients.

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Coagulation and Thrombosis: Fibrinogen levels partly depend on the genotype and several polymorphisms particularly in the beta-chain of fibrinogen have been described in PAD patients, and an association with PAD was demonstrated for the -455GG genotype of fibrinogen. Polymorphisms of factors VII and XIII were discussed to have protective effects against coronary artery disease, polymorphisms in factors VIII and IX or vWF were also suggested to be involved in coronary artery disease. However, for PAD, negative results exist for factor VII (R/Q353) and XIII (V34L) polymorphism. Other genetic variants involved in coagulation and venous thrombosis like factor V Leiden and MTHFR C677T showed no associations with chronic limb ischemia, discrepant data exist for prothrombin mutation G20210A. An increase in plasma PAI-1 levels is considered an important prothrombotic and proatherogenic factor. This protein is under control of the 4G/5G polymorphism in the promoter zone. Carriers of the 4G allele were thought to have a higher risk for atherosclerosis and PAD, although negative results were found in the Edinburgh Artery Study. Platelet Dysfunction: Polymorphisms modifying platelet function are found in genes encoding for the Glycoprotein IIb/IIIa receptor for fibrinogen, the Glycoprotein Ib-IX V receptor for vWF (Kozak polymorphism) and the Glycoprotein Ia-IIa receptor for collagen. For PAD, however, a negative report on the PI(A) polymorphism of platelet glycoprotein IIIa, the HPA-3 polymorphism of platelet glycoprotein IIb and a VNTR polymorphism of glycoprotein IIb in subjects with diabetes was published. Addressing drugresponse, a functional polymorphism in the clopidogrel target receptor gene P2Y12 has been demonstrated to modulate the susceptibility for future cardiovascular events in patients with PAD receiving clopidogrel.

Diagnostic Principles Clinical symptoms are typical: Intermittent claudication impairs patients’ walking distance by exercise-induced pain of the muscles of the calf or thigh. Advanced stages of PAD are characterized by ischemic rest pain of the toes or foot, and ischemic tissue loss. Diagnosis is made by palpation of the pulses, measurement of anklebrachial pressure index, oscillography and by various imaging techniques like duplex ultrasound, magnetic resonance imaging angiography, computed tomography angiography and conventional intra-arterial digital subtraction angiography.

Therapeutic Principles Best medical treatment should be administered for all stages of PAD including platelet inhibitors like aspirin or clopidogrel, statins (irrespective of the cholesterol level) and control of risk factors like hypertension or

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diabetes mellitus. Furthermore, life-style modification with cessation of smoking and exercise training has to be performed, although the latter is contra-indicated for patients with critical limb ischemia. Revascularisation by endovascular or surgical techniques is optional for patients with severe claudication, but has to be performed in all patients with critical limb ischemia. Gene-therapeutic approaches are not yet available. According to animal experiments, administration or induction of VEGF and stem-cell therapy seem promising approaches.

References 1. Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR, Garside DB, Wilson PW (2003) Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA 290:891–897 2. Marenberg ME, Risch N, Berkman LF, Floderus B, De Faire U (1994) Genetic susceptibility to death from coronary heart disease in study of twins. N Engl J Med 330:1041–1046 3. Nabel EG (2003) Genomic medicine – cardiovascular disease. N Engl J Med 349:60–72

Peripheral Facial Paralysis ▶Facial Paralysis

which consists of motor and sensory neurons, nerve roots, plexus and peripheral nerves. More than 100 types of peripheral neuropathy have been identified, each with its own characteristic spectrum of symptoms, pattern of development and prognosis. Impaired function and symptoms depend on the type of nerves that are damaged, but most peripheral neuropathies affect all fiber types to some extent. The disorders can be defined by the pattern of nerve-fiber involvement; some disorders can involve single peripheral nerves (mononeuropathies), others numerous individual peripheral nerves (mononeuritis multiplex). Generalized disorders conform to a polyneuropathy syndrome, which usually implies both sensory- and motor-fiber involvement in a symmetric or asymmetric distribution and typically with a distal-to-proximal gradient of involvement consistent with a lengthdependent axonal degeneration. Furthermore, the disorders can be classified into acute neuropathies (e.g. Guillain-Barré syndrome) or chronic disorders (e.g. polyneuropathy due to diabetes mellitus). A broad spectrum of symptoms is characteristic for peripheral neuropathies; some combinations of symptoms may be recognized as specific syndromes. Sensory symptoms include sensory loss including touch, pain, thermal sensation, vibratory sense and joint position sense and burning pain, especially at night. Motor symptoms can include weakness, muscular atrophy, muscle cramps and fasciculation. Damage to autonomic nerves can cause orthostatic hypotension, hypohidrosis, gastrointestinal dysmotility, urinary bladder dysfunction and erectile dysfunction.

Prevalence

Peripheral Nerve Hyperexcitability Syndrome ▶Neuromyotonia, Autoimmune and Idiopathic

Peripheral Neuropathies, Acquired H ANS -J U¨ RGEN G DYNIA , A LBERT C. LUDOLPH Department of Neurology, University of Ulm, Ulm, Germany

Definition and Characteristics The term acquired peripheral neuropathies describes non-inherited damage of the peripheral nervous system,

Peripheral neuropathies affect 2.4% of the population [1].

Molecular and Systemic Pathophysiology There are numerous reasons for peripheral nerves to malfunction. Damage to nerves can result from one of the specific conditions associated with acquired neuropathy, including: – Physical injury to a nerve, e.g. acute or prolonged compression – Metabolic neuropathy, e.g. diabetes mellitus, renal failure, liver dysfunction – Nutritional neuropathy, e.g. Vitamin B12 deficiency, chronic alcohol abuse with thiamine deficiency – Infections, e.g. HIV, leprosy, diphtheria, syphilis, Lyme, Colorado tick fever – Immune mediated neuropathy, e.g. CIDP, GuillainBarré syndrome – Autoimmune disorders, e.g. periarteriitis nodosa, rheumatoid arthritis, SLE, Sjögren syndrome – Drugs and toxins, e.g. cisplatin, arsenic, mercury – Miscellaneous causes, e.g. ischemia

Peritonitis

The specific mechanisms by which the above-mentioned causes induce pathological changes in the nerves are individual in each disease and not completely understood. Molecular mechanisms include disruption of axonal transport, enzyme and coenzyme inhibition and protein glycosylation. Despite the diverse causes, peripheral nerves exhibit only a few distinct pathophysiological reactions due to injury: – Wallerian degeneration where the axon degenerates distal to a lesion – Axonal degeneration, often at the most distal extent of the axon – Segmental demyelination i.e. degeneration of the myelin sheath with sparing of the axon Wallerian degeneration often occurs in focal mononeuropathies, axonal degeneration and segmental demyelination can be seen in generalized polyneuropathies. Whereas axonal degeneration is the most common type of pathological reaction in polyneuropathies of “metabolic/toxic” etiology, segmental demyelinating polyneuropathies are often of inflammatory origin or immune-mediated.

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References 1. 2. 3. 4.

Hughes RAC (2002) BMJ 324:466–469 Lacomis D (2002) Muscle Nerve 26:173–188 Barohn R (1998) Semin Neurol 18:7–18 Sindrup SH, Jensen TS (2000) Neurology 55:915–920

Peripheral Neuropathies, Inherited ▶Neuropathies, Inherited Peripheral

Peripheral T-Cell Lymphoma ▶T-Cell Lymphoma, Cutaneous (other than Mycosis Fungoides)

Diagnostic Principles Despite a detailed history and neurological examination to determine the part of the peripheral nervous system that is affected, appropriate investigations are necessary: Electromyography and nerve conduction velocities are important to localize and characterize the nature and severity of the neuropathy. To screen for an underlying cause, e.g. diabetes, vitamin deficiencies or antibodies, blood tests should be performed. A lumbar puncture can be necessary when infectious agents or immune mediated or autoimmune disorders are suspected. A nerve biopsy can occasionally be performed to confirm the presence of nerve inflammation, e.g. in vasculitic neuropathy.

Peritonitis THOMAS NAMDAR, C LAUS F ERDINAND E ISENBERGER , WOLFRAM T RUDO K NOEFEL Department of General, Visceral and Pediatric Surgery, University Hospital Duesseldorf, Heinrich-HeineUniversity, Duesseldorf, Germany

Synonyms Diffuse abdominal sepsis

Definition and Characteristics Therapeutic Principles The treatment will depend on the underlying cause and the type of neuropathy, e.g. optimizing blood sugar in diabetic neuropathy, immune globulins or steroids in some immune-mediated neuropathies, surgical decompression in some cases of carpal tunnel syndrome. In patients who have neuropathy-associated pain, specific pain management should be instituted. Typically, neuropathic pain responds to a variety of drugs, including antiepileptic drugs, membrane stabilizers and tricyclic antidepressants [2,3,4]. Additionally, various strategies of physical therapy are known to be helpful, as well as ankle-foot orthosis in patients with foot drop.

Peritonitis implies an inflammatory response of the peritoneal layer (surface: about 2 m2) caused by bacteria, fungi, viruses, or chemical agents. A localized peritoneal inflammation may cause diffuse peritonitis if untreated and can result in sepsis. The mortality is still high (20–60%) and depends on factors such as age, time of intervention, and obesity. A combined treatment of surgical intervention, intensive care management, and conservative management is mandatory [1].

Prevalence Secondary peritonitis is responsible for 99% of all peritonitis cases, primary peritonitis only for one percent. Primary peritonitis occurs in 8–22% of all cases of

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Peritonitis

patients with liver cirrhoses/ascites or other underlying diseases, which may cause primary peritonitis. Diffuse peritonitis is the reason for surgery in about 7% of all laparotomies in german university hospitals. 25% of all patients in a surgical intensive care unit are diagnosed as having intraabdominal infections. Secondary peritonitis can be diagnosed in different extents and severity in all cases of patients with bowel, stomach or other perforation in the abdomen. Peritonitis occurs in about 5–20% of all patients undergoing laparotomy for different reasons (i.e.: bowel, colon, pancreas, liver).

Molecular and Systemic Pathophysiology Primary Peritonitis: Infection of the peritoneal fluid in absence of intra-abdominal focus (spontaneous bacterial peritonitis in patients with cirrhosis; hematogeneous peritoneal infection in pneumonia, i.e., streptococcus, pneumococcus, or tuberculosis); CAPD-related chronic peritonitis (sclerosing peritonitis; [2]). Secondary Peritonitis: Infection of the peritoneal cavity (stomach a bowel perforation, ischemic necrosis, penetrating injuries or abscess) and chemical peritonitis (barium peritonists). Tertiary Peritonitis: Persistent peritoneal inflammation and clinical signs of peritonism following secondary peritonitis from nosocomial pathogens.

The peritoneal function is to equilibrate the intraabdominal fluid and constitute a barrier against pathogens. The peritoneal mesothelial cells represent an ultrafiltration barrier for microorganisms. Additionally, they produce cytokines, prostaglandines, and growth factors. In case of local peritoneal inflammation, cellular (macrophages, lymphocytes, neutrophiles, etc.) and humoral defense mechanisms get activated. Untreated inflammation releases a systemic response by lymphatic and hematogeneous spreading. Interleukin (IL)-1 and tumor-necrosis-factor (TNF)alpha activate peritoneal mesothelial cells. Bradykinine and histamine cause a hyperperfusion of the infected area. Neutrophil cells are recruited by IL-6, IL-8, and prostaglandins are secreted [3]. In proinflammatory situations, peritoneal fibroblasts proliferate and synthesis of extracellular matrix increases to avoid a peritoneal infectious spreading. To facilitate the cellular migration to the abdominal cavity, the capillary permeability increases, regulated by the kallikreine-kininesystem, leukotriene, and eicosanoide. A peritoneal edema is caused, which may lead to the sequestration of several liters of fluid into the peritoneum (Figure 1). The following intra-vasal fluid loss leads to a hypovolemic situation, leading to acute renal insufficiency. The increasing pressure in the abdomen caused by the systemic inflammatory reaction and fluid sequestration may lead to an abdominal compartment syndrome,

Peritonitis. Figure 1 Peritonitis cascade caused by local peritoneal inflammation results in ACS und sepsis, if untreated.

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compromising renal and hepatic perfusion and function. The tense abdomen with high intra-abdominal pressure can result in a reduced lung function (Figure 1). The compensatory activation of the sympatho-adrenalsystem tries to resist these systemic inflammatory effects like continuous hypotonia and hypovolemia, which follow interstitial and peritoneal edema.

Diagnostic Principles The intra-abdominal pressure (IAP, normally 12 mmHg) is caused, which may result in an abdominal compartment syndrome (ACS) with IAP > 20 mmHg. The ACS affects renal function, liver function, reduces cardiac output, pulmonary ventilation, and visceral perfusion [4] (Figure 1). As an early predictive parameter for patient mortality, the blood serum level of IL-6 increases 2–4 h after inflammatory start-up. High or persisting high IL-6 levels are a prognostic sign for a severe clinical course [5]. The serum level of pro-Calcitonine (PCT) is a prognostic parameter in septic patients. A PCT elevation is a specific sign of a bacterial infection [5]. Bedside tests for IL-6 and PCT are available. Many authors tried to score peritonitis, but the APACHE Score remains the only widely used score for the evaluation of the prognosis in critically ill surgical patients in intensive care medicine.

Therapeutic Principles Primary peritonitis, usually a monomicrobial infection, is treated by systemic antibiotics. A surgical treatment is only indicated if the conservative therapy fails or if conservative therapy is associated with deterioration of organ function such as renal, cardiovascular, or respiratory disturbances [1]. In secondary peritonitis, immediate surgical eradication of the infectious focus is mandatory. Ascites should be collected and an empiric antimicrobiological therapy should be started. The antibiotic management should be changed after receiving the intra-operative microbiological results (escalation or deescalation). Therefore third-generation cephalosporins or broad-spectrum penicillins each combined with metronidazole are widely used as primary empiric therapy [1]. Antibiotic therapy should be maintained until fever or other signs of inflammation disappear. Depending on the intraoperative findings and postoperative course, a relaparotomy should be performed on demand when indicated by septic signs or by insufficient primary source control (Figure 2). A planned relaparotomy aims at mechanical cleansing and allows a control of the infected area. Other concepts like continuous abdominal lavage or instillation of antibiotic fluids in the peritoneal cavity

Peritonitis. Figure 2 Intra-operative situs of a patient with fibrinous/purulent peritonitis after perforation of the colon.

are not well established except for pancreatitis. However, regular reoperations are often necessary. To prevent an abdominal compartment it may be necessary to leave a temporary laparostomy (Figure 2). Paralytic bowel obstruction may lead to a temporary colostomy or iceostomy. To prevent ACS complications, adequate intensive care with support of respiratory function, fluid management, and circulatory support is mandatory. Nonsurgical options like gastric or rectal decompression, application of gastric and colon prokinetics, and sedation are recommended. Continuous veno-venous hemofiltration with aggressive ultrafiltration should be evaluated individually [4]. There are a variety of dressing and closure options, including vacuum dressing. For tertiary peritonitis with persistent inflammatory changes in the abdominal cavity, despite effective control of the infectious focus there is no surgical treatment because the underlying mechanism is a profound rearrangement of the inflammatory response during septic disease [1]. Clinical studies using antimediator treatment showed disappointing results [3].

References 1. Wong PF, Gilliam AD, Kumar S, Shenfine J, O′Dair GN, Leaper DJ (2005) Antibiotic regimens for secondary peritonitis of gastrointestinal origin in adults. Cochrane Database Syst Rev. (18)2:CD004539

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2. Calandra T, Cohen J (2005) The International sepsis forum consensus conference. Definiftion of Infection in the ICU. Crit Care Med 7(2):1538–1548 3. Broche F, Tellado JM (2001) Defense mechanisms of the peritoneal cavity. Curr Opin Crit Care 7(2):105–116 4. Sugrue M (2005) Abdominal compartment syndrome. Curr Opin Crit Care 11(4):333–338 5. Gogos CA (2000) Pro-versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and fututre therapeutic options. J Infect Dis. 181(1):176–180

impairment in the activity of the reliculoendothelial system, neutrophils, and macrophages dysfunction, and low levels of complement and other proteins with opsonic activity. Some characteristics of ascitic fluid are predisposing factors in developing SBP. In fact, patients with low ascites fluid levels of complement and total protein have less bactericidal and opsonic activities of ascitic fluid and are at increased risk to develop SBP.

Diagnostic Principles

Peritonitis, Spontaneous Bacterial P ERE G INE´ S , M O´ NICA G UEVARA Liver Unit, Hospital Clinic and University of Barcelona, CIBERHED, IDIBAPS, Barcelona, Spain

Synonyms SBP

Definition and Characteristics Spontaneous bacterial peritonitis (SBP) is defined as a bacterial infection of ascitic fluid without any intraabdominal surgically treatable source or infection [1].

Prevalence The prevalence of SBP in cirrhotic patients with ascites admitted to the hospital ranges between 10 and 30%. The prevalence is higher in patients with previous episodes of SBP.

Molecular and Systemic Pathophysiology The exact mechanism by which ascites fluid becomes infected in patients with cirrhosis is unknown. However, the finding of enteric organisms in the mesenteric lymph nodes of animal models with portal hypertension and SBP suggest bacterial translocation of intestinal organisms from the lumen through the intestinal wall to the ascites fluid via the lynphatics as one of the most important mechanisms. Mechanisms involved in the pathogenesis of bacterial translocation include impairment of the intestinal barrier, intestinal bacterial factors, and alterations in the local immune response. Portal hypertension may produce vascular stasis and edema of the intestinal mucosa. These features have been considered as responsible for the increased permeability of the intestinal barrier. Among bacterial factors, an intestinal bacterial overgrowth mainly due to a decreased intestinal motility may play a role. The cause of the impairment of small bowel motility in cirrhosis is unknown. Finally, in cirrhotic patients the alterations in systemic immune defense mechanisms are represented by

In some patients with SBP, signs and symptoms may be suggestive of peritoneal infection, such as abdominal pain, fever, and/or alteration in gastrointestinal motility. In other cases, the main manifestations of SBP are an impairment of liver function or renal failure. Finally, in some cases SBP may be asymptomatic [1]. A diagnostic paracentesis should be performed on hospital admission in all cirrhotic patients with ascites to investigate the presence of SBP, even in patients admitted for reasons other than ascites. The analysis of ascitic fluid should also be performed in any cirrhotic patient who develops compatible signs or symptoms of a peritoneal infection or an impairment of liver or renal function without any other causes. The diagnosis of SBP is made whenever ascites polymorphonuclear count (PMN) is greater than 250/mm3. Culture of ascites fluid identifies the responsible organism in 30–50% of ascites fluid infections. Culture should be performed in blood culture bottles at the bedside of the patient to increase the sensitivity of the method. Bacterascites is a positive ascitic fluid culture with ascites PMN count 10 g/l, lactic dehydrogenase > normal serum levels [1].

Therapeutic Principles Once an ascites PMN count >250 mm3 is detected, antibiotic therapy needs to be started. The empirical treatment of SBP should be third-generation cephalosporins i.v. [1]. The combined administration of antibiotics plus albumin has been shown to decrease the incidence of renal failure and improve survival in patients with SBP. Antibiotic treatment can be safely discontinued once ascitis PMN count decreases below 250/mm3, which occurs in a mean period of 5 days. A control paracentesis should be performed 48 h after starting therapy. It is useful in assessing antibiotic

Persistent Hyperinsulinemic Hypoglycemia

response and the need to modify the treatment. Patients who have recovered from an episode of SBP are at high risk of developing recurrence of ascites infection usually weeks or months after the first infection. Long-term prophylaxis with oral quinolones (norfloxacin 400 mg/day p.o.) at a dose of 400 mg every day is indicated in these patients.

References 1. Rimola A, Garcia-Tsao G, Navasa M et al. (2000) Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. Int Ascites Club J Hepatol 32:142–153 2. Ghassemi S, Garcia-Tsao G (2007) Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol 21(1):77–93 3. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, Vila C, Pardo A, Quintero E, Vargas V, Such J, Ginès P, Arroyo V (2007) Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. Sep; 133(3):818–824 4. Cárdenas A, Ginès P (2008) What’s new in the treatment of ascites and spontaneous bacterial peritonitis. Curr Gastroenterol Rep Feb; 10(1):7–14 5. Terg R, Fassio E, Guevara M, Cartier M, Longo C, Lucero R, Landeira C, Romero G, Dominguez N, Muñoz A, Levi D, Miguez C, Abecasis R (2008) Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study. J Hepatol May; 48(5):774–779 6. Tandon P, Garcia-Tsao G (2008) Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis Feb; 28(1):26–42

Permanent Alopecia

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Persistent Hyperinsulinemic Hypoglycemia A NTONIO L. C UESTA -M UN˜ OZ Centre for the Study of Monogenic Diseases of Pancreatic Beta-Cell, Fundación IMABIS, Carlos Haya Hospital, Málaga, Spain

Synonyms Hyperinsulinism of infancy and childhood (HI); Congenital hyperinsulinism; Familial hyperinsulinism; Pancreatic nesidioblastosis

Definition and Characteristics Inappropriate insulin release for the level of glycemia. HI is a heterogeneous disorder where the pathophysiological base is a failure of the pancreatic β-cell to suppress insulin secretion during hypoglycemia.

Prevalence Incidence in general population is about 1/50,000 births, and 1/2,500 births in countries with high rate of consanguinity.

Genes The pancreatic β-cell sulfonylurea receptor (SUR1) ABCC8, and the inward rectifying potassium channel (Kir6.2) gene KCNJ11 (ch11p15). Glucokinase (GCK) (ch7p15.3 – p15.1). Glutamate dehydrogenase GLUD 1 (ch10q23.3). Short-chain 3-hydroxyacil CoA dehydrogenase enzyme gene SCHAD (ch4p24–4q25). These genes are responsible for 50% of the cases of HI.

Molecular and Systemic Pathophysiology ▶Scarring Alopecia

Persistent Atrioventricular Ostium ▶Atrioventricular Septal Defects

Persistent Ductus Arteriosus ▶Patent Ductus Arteriosus

KATP Channels and Insulin Secretion: SUR1 and Kir6.2 are subunits of the KATP channel of the β-cell. Kir6.2 determines the K+ selectivity, rectification, and gating, and is inhibited by ATP, and SUR1 acts as a conductance regulator of Kir6.2. The KATP channels complex links the metabolic demands of pancreatic β-cell with insulin release by transducing the metabolic status of the β-cell into cell membrane electrical activity. Changes in the intracellular ATP/ADP ratio regulate the function of these channels. ATP inhibits Kir6.2 and ADP counteracts by activating SUR1 [1]. Defects in KATP channels due to mutations in SUR1 and Kir6.2 genes lead to a spontaneous depolarization of β-cell membrane (−30 mV) in the absence of glucose metabolism, causing constant activation of Ca2+ channels, unregulated entry of Ca2+, and uncontrolled release of insulin [2]. Autosomal recessive inheritance of two

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Persistent Hyperinsulinemic Hypoglycemia of Infancy

abnormal SUR-1 or Kir6.2 alleles results in diffuse HI and inheritance of an abnormal paternal SUR1 allele with somatic loss of the maternal chromosome 11p15 to focal adenomatosis. GK, GDH, SCHAD and Insulin Secretion: Glucokinase (GK) is a glycolytic enzyme that functions as a “glucose sensor” in pancreatic β-cell by controlling the rate-limiting step of β-cell glucose metabolism. GK governs glucose-stimulated insulin secretion (GSIS). Autosomal dominant gain-of-function mutation of GCK led to an activation of the GK that lowers the threshold for GSIS. The high activation of GK will increase the glucose metabolism leading to an excess of ATP production in β-cell, which in turn will lead to inappropriate closure of KATP channels, unregulated Ca2+ influx, and insulin release, thus causing hypoglycemia [3]. Glutamate dehydrogenase enzyme (GDH) catalyzes the conversion of glutamate to α-ketoglutarate in islet and liver. GDH is activated by ADP and inhibited by GTP. The amino acid leucine allosterically activates GDH and stimulates insulin secretion via increasing the rate of oxidation of glutamate in the tricarboxylic acid cycle. In liver, glutamate governs the synthesis of N-acetylglutamate, a critical activator of carbamoyl-phosphate synthetase; the oxidation of glutamate by GDH provides free ammonia as well [4]. Defects in GLUD1 gene can lead to a decrease in the sensitivity of GDH to GTP that will create an activated enzyme, which in turn will increase the mitochondrial metabolism resulting in high ATP/ADP ratio and hence the high insulin secretion. Simultaneously, the excessive activity of GDH in liver will cause excessive ammonia production. SCHAD catalyzes the conversion of L-3OH-acyl-CoA to 3-ketoacyl-CoA in the fatty acid oxidation cycle in the mitochondria of the β-cell. Gene defects in SCHAD are expected to lead to an increase in intramitochondrial L-3-hydroxybutyryl-CoA, which can inhibit carnitine palmitoyltrnasferase-1 and elevate cytosolic long-chain acyl-CoA, which has pleiotropic actions on β-cell function.

Diagnostic Principles The clinical diagnosis is based on evidence of the effects of HI, including hypoglycemia, inappropriate suppression of lipolysis and ketogenesis, and (more traditionally) positive glycemic responses after the administration of glucagon when hypoglycemic. The first clinical manifestations of HI are mainly experienced shortly after birth. Cyanosis, respiratory distress, sweating, hypothermia, irritability, poor feeding, hunger, jitteriness, lethargy, apnea, which can progress to vomiting, seizures, tachycardia, and averted neonatal death. In older children and adults, symptoms tend to be confusion, headaches, dizziness, syncope, and when

severe, loss of consciousness. The definition of a glucose requirement to maintain normoglycemia is a key indicator as well as therapeutic step in HI, and the demonstration of an increased glucose requirement is the sign of underlying HI. Diagnostic criteria for patients with severe early-onset HI are (i) a glucose requirement of >6– 8 mg kg–1 min–1 to maintain blood glucose above 2.6–3 mM; (ii) blood glucose values 600 mmol/l and a daily phenylalanine tolerance of 400 mutant alleles) explains the large interindividual variation in metabolic phenotype (PAHdb, http://www.pahdb.mcgill.ca). For >100 PAH mutations, the associated metabolic phenotypes have been ascertained [3,4].

Diagnostic Principles Systematic neonatal screening for hyperphenylalaninemia identifies all newborns with PAH deficiency. The metabolic phenotype and the inherent dietary requirements are usually determined by indirect means, for example by determining the dietary intake of phenylalanine tolerated while keeping serum phenylalanine concentrations within the desired therapeutic range (phenylalanine tolerance), or the rate of phenylalanine elimination following an oral protein challenge or an oral or intravenous dose of phenylalanine [1,2]. Responsiveness to treatment with BH4 (see below) can be assessed by measuring the plasma phenylalanine response after BH4 loading. Diagnosis by PAH mutation analysis is feasible in the vast majority of cases. Genotype usually predicts phenotype [3].

Therapeutic Principles All disease manifestations associated with PAH deficiency can be effectively prevented by the implementation of a low-phenylalanine diet in the neonatal period. The diet should be maintained for life to prevent the

Phenylalanine Hydroxylase Deficiency. Figure 1 The phenylalanine hydroxylating system.

Phenylketonuria

development of symptoms associated with “phenylalanine intoxication,” i.e., lack of power of concentration, sustained reaction time, headache, and depression. The amount of dietary phenylalanine tolerated to maintain the blood phenylalanine within the therapeutic range depends on the severity of the disorder. PAH mutation analysis provides the basis for predicting the metabolic phenotype and anticipating dietary requirements [3]. Treatment with BH4 has been reported to decrease the plasma phenylalanine concentrations in patients with milder forms of PAH deficiency [5].

References 1. Scriver CR, Kaufman S (2001) The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1667–1724 2. Güttler F (1980) Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency. Acta Paedriatr Scand Suppl 280:1–80 3. Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, Ullrich K, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63:71–79 4. Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR (1997) Human PAH mutation and hyperphenylalaninemia phenotypes: a metanalysis of genotypephenotype correlations. Am J Hum Genet 61:1309–1317 5. Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347:2122–2132

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Prevalence Prevalence varies with ethnicity: Heterozygosity ranges from less than 1% of the black race to 2% in Caucasians. The number of mutations of the phenylalanine (Phe) hydroxylase (PAH) gene is already greater than 500 and they vary in severity from mild to moderate and severe. The gene defect is located on the chromosome number 12 at the q22–q24 region. Recently the PAH gene has been crystallized, as well.

Molecular and Systemic Pathophysiology Neuropathology affects primarily the central nervous system. The competition theory on the transport of amino acids to the brain seems to be the most extensively studied. Recent research suggests that the elevated blood Phe levels interfere with the transport of large neutral amino acids (LNAA) into the brain, thus protein synthesis in the brain is compromised. Studies on the mouse brain show that protein synthesis is reduced when phenylalanine levels are increased. Since Phe has the lowest km for the transporter, this reduces the entrance of the other eight LNAA into the brain. There are many other theories; none have been proven, other than the fact that high blood and brain levels of phenylalanine lead to a cascade of events that result in white matter disease. It may well be that not only one metabolic pathway is affected that contributes to the pathology of PKU.

Diagnostic Principles Confirmation of the diagnosis of PKU during the newborn period requires a careful evaluation of the status of Phe metabolism by plasma amino acid analysis and identification of the PAH mutation. Tetrahydrobiopterin metabolic defects should be ruled out, as well as a dihydropteridine reductase disorder.

Therapeutic Principles

Phenylketonuria R ICHARD KOCH 1 , K ATHRYN M OSELEY 2 1

Department of Genetics, Children’s Hospital Los Angeles, Los Angeles, CA, USA 2 CHEAR, University of Michigan Medical School, Ann Arbor, MI, USA

Synonyms Hyperphenylalaninemia; PKU

Definition and Characteristics Autosomal recessive defect in untreated patients usually results in profound mental retardation and neurodegenerative changes.

Once the diagnosis of PKU is established, a Pherestricted diet should be initiated with the goal of establishing a blood Phe level of 2–6 mg % (120–360 μmol/l). These are the established guidelines in the United States suggested by the National Institute of Health after a worldwide review of treatment practices, however, clinics in different countries may have their own established guidelines. Infants born with two severe mutations of the PAH gene will need dietary therapy throughout their life, however guidelines vary after 10–12 years. These individuals are considered to have classic PKU. Persons with a moderate degree of hyperphenylalaninemia of 12–20 mg % (720–1,080 μmol/l) usually exhibit one severe mutation, such as R408W and one mild mutation, such as F39L still need treatment, but may follow a more relaxed diet if the guidelines permit. Persons with blood Phe levels of less than 10 mg % (600 μmol/l) usually are not treated with a

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Pheochromocytoma

Phe-restricted diet. Mental illness, especially depression, may be seen in those not adhering to the diet. Finally, women must be aware during their productive years, that blood Phe levels greater than 6 mg % (300 μmol/l) may be harmful to the development of their fetus during pregnancy.

References 1. Scriver CR, Kaufman S, Eisensmith RC et al. (1977) The hyperphenylalaninemias. In: Scriver CR, Beaud AL, Sly W et al. (Eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York pp 1015–1075 2. Guttler F, Azen C, Guldberg P et al. (1999) Relationship between genotype biochemical phenotype and cognitive performance in females with phenylalanine hydroxylase deficiency. Report from the Maternal PKU Collaborative Study. Pediatrics 104:258–262 3. Koch R, Fishler K, Azen C et al. (1977) The relationship of genotype to phenotype in Phenylalanine hydroxylase deficiency. Biochem Mol Med 60:92–101 4. Koch R, Friedman E, Azen C et al. (1999) The international collaborative study of maternal phenylketonuria status report 1998. Ment Retard Dev Disabil 5:117–121 5. Fusetti F, Erlandsen H, Flatmark T et al. (1998) Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. J Biol Chem 273:16962–16966

Pheochromocytoma G RAEME E ISENHOFER , K AREL PACAK Clinical Neurocardiology Section, NINDS, National Institutes of Health, Bethesda, MD, USA

Synonyms Intra-adrenal paraganglioma

even hypotension [1]. Headaches, excessive truncal sweating and palpitations are the most common symptoms. Others include pallor, dyspnea, nausea, constipation and episodes of anxiety or panic attacks. Signs and symptoms that occur in paroxysms reflect episodic catecholamine hypersecretion. Paroxysmal attacks may last from a few seconds to several hours, with intervals between attacks varying widely and as infrequent as once every few months.

Prevalence Pheochromocytomas are rare with an annual detection rate of 2–4 per million. Relatively high prevalences of the tumor in autopsy studies (1:2,000) suggest that many are missed during life, resulting in premature death. The actual annual incidence is therefore likely to approach 10 per million.

Genes Current estimates indicate that close to 30% of pheochromocytomas occur due to mutations of five genes [2]. Family-specific mutations of the von Hippel-Lindau (VHL) tumor suppressor gene determine the varied clinical presentation of tumors in VHL syndrome that, apart from pheochromocytomas, can include retinal and central nervous system hemangioblastomas, and tumors and cysts in the kidneys, pancreas and epididyma. Mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2 (MEN 2) result in pheochromocytoma, medullary thyroid cancer and parathyroid disease in MEN 2a and additional cutaneous and mucosal neuromas in MEN 2b. Mutations of the neurofibromatosis type 1 (NF 1) gene carry a relatively small risk of pheochromocytoma, presenting commonly as multiple fibromas on skin and mucosa and “café au lait” spots. More recently discovered mutations of succinate dehydrogenase subunits B and D (SDHB & SDHD) genes lead to familial paragangliomas. Clinical features of pheochromocytomas – such as the frequency of malignancy, adrenal and extra-adrenal locations of tumors, and types of catecholamines produced – vary according to the particular mutation (Table 1).

Definition and Characteristics Pheochromocytomas are usually defined as catecholamine-producing neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia [1]. According to the 2004 World Health Organization classification of endocrine tumors, only those tumors derived from adrenal chromaffin cells are defined as pheochromocytomas. Those derived from extra-adrenal chromaffin tissue are defined as paragangliomas. Sustained or paroxysmal hypertension is the most common clinical sign of a pheochromocytoma, although some patients present with normotension, or

Molecular and Systemic Pathophysiology The molecular mechanisms linking known gene mutations to development of pheochromocytomas have not been precisely elucidated. Recent evidence, however, suggests that hereditary tumors may develop from neural crest progenitor cells arrested during embryonic development due to failure of apoptosis [3]. Systemic pathophysiology associated with pheochromocytoma is mainly the result of the hemodynamic and metabolic actions of catecholamines produced and secreted by the tumor. Variability in pathophysiology may reflect differences in types of catecholamines produced,

Pheochromocytoma

Pheochromocytoma. Table 1

Genes and characteristics of hereditary pheochromocytoma

Gene Chromosome Exons Germ-line mutation frequencya Penetrance of tumorsa Malignant frequencya Adrenal location Extra-adrenal location Catecholamine produced

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VHL 3p25 3 8% 20% 4% +++ + NE

RET 10q11.2 21 5% 50%