Nevus vascularis mixtus (cutaneous vascular twin

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(1) Nevus vascularis mixtus (vascular twin nevi): purely cutaneous trait [co-occurrence of paired: (a) Nevus telangiectaticus; and (b) nevus anemicus].
CLINICAL REPORT

Nevus Vascularis Mixtus (Cutaneous Vascular Twin Nevi) Associated with Intracranial Vascular Malformation of the Dyke–Davidoff–Masson Type in Two Patients Martino Ruggieri,1,2* Pietro Milone,3 Piero Pavone,4 Raffaele Falsaperla,4 Agata Polizzi,5 Rosario Caltabiano,6 Marco Fichera,7,8 Anna Lia Gabriele,9 Angela Distefano,10 Rocco De Pasquale,11 Vincenzo Salpietro,12 Giuseppe Micali,13 and Lorenzo Pavone3 1

Chair of Pediatrics, Department of Educational Sciences, University of Catania, Catania, Italy Unit of Clinical Neurosurgery, University of Catania, Catania, Italy

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Institute of Radiology, University of Catania, Catania, Italy

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Unit of Pediatrics, University Hospital ‘‘Vittorio Emanuele’’, Catania, Italy National Centre for Rare Diseases, Istituto Superiore di Sanita, Rome, Italy

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Department ‘‘G.F. Ingrassia’’, Section of Anatomic Pathology, University of Catania, Catania, Italy

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Laboratories of Diagnostic and Molecular Genetics, IRCCS Oasi Maria Santissima, Troina, Italy

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Chair of Medical Genetics, Regional Centre for the Diagnosis and Therapy of Genetic Diseases, University of Catania, Catania, Italy Unit of Molecular Genetics, Institutes for Mediterranean Agriculture and Forest Systems (ISAFOM), National Research Council (CNR), Renda (CS), Italy 9

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Unit of Nuclear Medicine, Institute of Neurological Science, National Research Council, Catania, Italy Institute of Dermatology, University of Catania, Catania, Italy

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Unit of Genetics and Pediatric Immunology, Department of Pediatrics, University of Messina, Italy

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Chair of Dermatology, Institute of Dermatology, University of Catania, Catania, Italy

Manuscript Received: 23 March 2010; Manuscript Accepted: 12 December 2011

The term twin spotting refers to phenotypes characterized by the spatial and temporal co-occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra-cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so-called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28-year-old man and a 15-year-old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke–Davidoff–Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large

Ó 2012 Wiley Periodicals, Inc.

How to Cite this Article: Ruggieri M, Milone P, Pavone P, Falsaperla R, Polizzi A, Caltabiano R, Fichera M, Gabriele AL, Distefano A, De Pasquale R, Salpietro V, Micali G, Pavone L. 2012. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke–Davidoff–Masson type in two patients. Am J Med Genet Part A.

*Correspondence to: Martino Ruggieri, BA, MD, PhD, Department of Educational Sciences, University of Catania, Via Casa Nutrizione s.n., 95124 Catania, Italy. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2012 DOI 10.1002/ajmg.a.35221

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hepatic cavernous vascular malformation, and left Legg-CalvePerthes disease (LCPD) [LCPD-like presentation]. Array-CGH analysis and mutation analysis of the RASA1 gene were normal in both patients. Ó 2012 Wiley Periodicals, Inc.

Key words: twin spotting; phacomatosis; vascular twin nevi; brain malformation; telangiectatic nevus; nevus anemicus; Dyke–Davidoff–Masson syndrome

INTRODUCTION Congenital pigmentary and/or vascular disturbances arranged in a patchy, linear, or otherwise mosaic forms are often associated with extracutaneous anomalies consistent with underlying genetic mosaicism [Happle, 1999, 2002; Torrelo et al., 2005; Ruggieri et al., 2008b]. The term twin spotting has been used for some of these human phenotypes, characterized by the spatial and temporal co-occurrence of two (or more) different nevi arranged in variable

cutaneous patterns that do not necessarily adhere to Blaschko’s lines [Happle, 1999, 2002; Torrelo et al., 2005; Ruiz-Maldonado et al., 2008]. From experiments performed in plants and animals, it is known that twin spotting may arise from either allelic or non-allelic mutations [Vig, 1973; Harrison and Carpenter, 1977; Molho-Pessach and Schaffer, 2011]. Analogously, there are several human phenotypes suggesting the presence of either allelic or nonallelic genetic variants in twin spotting [Happle, 1999, 2002; Ruggieri et al., 2008b; Molho-Pessach and Schaffer, 2011]. Thus far, some obvious examples of allelic and non-allelic twin spotting have been delineated in humans [Happle, 1999, 2006; Ruggieri et al., 2008b] (Table I). We report on two patients, a 28-year-old man and a 15-year-old girl with a previously unrecorded association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) [Hamm and Happle, 1986; Happle, 1999] distributed over the face (in both patients) and over the entire body (in the man) along with other systemic and neurologic anomalies, including a brain malformation of the Dyke–Davidoff–Masson type [Atalar et al., 2007].

TABLE I. Examples of Allelic and Non-Allelic Twin Spotting in Humans Clinical phenotypes Allelic twin spotting (1) Nevus vascularis mixtus (vascular twin nevi): purely cutaneous trait [co-occurrence of paired: (a) Nevus telangiectaticus; and (b) nevus anemicus] (2) Cutis tricolor: combination of congenital hyper- and hypo- pigmented skin lesions in close proximity to each other in a background of normal complexion (a) purely cutaneous trait (b) complex malformation syndrome in association with facial dysmorphism, neurologic defects, behavioral anomalies, skeletal and eye defects [Ruggieri–Happle syndrome] (c) distinct type: Cutis tricolor parvimaculata (d) association with other (e.g., vascular) skin disturbances (3) Lesions of overgrowth [Proteus syndrome] and deficient growth [Elattoproteus syndrome] (4) Epidermolytic hyperkeratosis of Brocq paired patches of excessive or absent involvement Non-allelic twin spotting (1) Phacomatosis pigmentovascularis (PPV): Different types according to the variable combination of: (a) nevus flammeus (capillary malformation); (b) epidermal nevus; (c) Mongolian spots; (d) nevus anemicus; (e) nevus spilus; (f) cutis marmorata telangiectatica congenita [Type I ¼ a þ b; Type II ¼ a þ c with or without d; Type III ¼ a þ e with or without d; Type IV ¼ a þ c þ e with or without d; Type V ¼ c þ f] plus two subtypes [A, with oculocutaneous involvement; B, with extra-oculocutaneous involvement] [Phacomatosis cesioflammea ¼ a þ c (see type IIa, IIb); Phacomatosis spilorosea ¼ a þ e (see type IIIa, IIIb); Phacomatosis cesiomarmorata ¼ c þ f (see type V)] (2) Phacomatosis pigmentokeratotica: simultaneous occurrence of speckled lentiginous nevus of a popular type and epidermal nevus of a non-epidermolytic, organoid type

References Happle [1999]; Hamm and Happle [1986] Baba et al. [2003]; Boente Mdel et al. [2008, 2011]; Happle et al. [1997]; Khumalo et al. [2001]; Larralde and Happle [2005]; Lionetti et al. [2010]; Nicita et al. [2012]; Ruggieri [2000]; Ruggieri et al. [2003, 2009, 2011]

Happle [1999]; Cohen et al. [2002] Happle and K€onig [1999]

Hasegawa and Yasuhara [1985]

Happle [2002, 2005] Boente and Happle [2008]

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CLINICAL REPORTS Patient 1 The patient was the fourth born to healthy, consanguineous (5th degree) Italian parents. He has two healthy sisters and one healthy brother. Prior to the first live born child, the mother had two spontaneous miscarriages and two further miscarriages after the proband was born. The family history was otherwise unremarkable. This 28-year-old man was born by spontaneous delivery at 37 weeks gestation after a pregnancy complicated by threatened abortion recorded in the 2nd month of gestation. His birth weight was 2,250 g [25th centile], his length was 49 cm [50th centile], and his head circumference was 35 cm [50th centile]. His parents recalled multiple, patched, erythematous, and port-wine stains on the entire trunk, face, and limbs since birth. Early developmental milestones were normal. At 12 months of age, he had two episodes of febrile seizures. The second episode was complicated by a near-death episode of cardiopulmonary arrest. At that time, the ECG cardiac and abdominal ultrasounds, EEG, and routine blood and urinalysis were within normal limits; clinically there were no sequaele. At 2 years of age, he was diagnosed with insulin-dependent diabetes mellitus (IDDM) that was well controlled. At 2 years and 6 months of age, he required hospitalization for complex febrile seizures and he experienced recurrent episodes of crossed right- and left-sided, simple partial seizures involving the right upper extremity, right aspect of the face, and left lower extremity. Subsequently, he had left limb hemiplegia, speech difficulties, and mild cognitive disturbances. At that time, ECG, cardiac and abdominal ultrasounds, a full ophthalmologic examination, and routine blood tests and urinalysis were normal. Brain computed tomography (CT) and magnetic resonance imaging (MRI) studies showed asymmetry of the cerebral hemispheres with right hemisphere atrophy, ipsilateral osseous hypertrophy, hyperpneumatization of the paranasal sinuses and mastoid cells, and contralateral cerebral hypertrophy. A single photon emission computerized tomography (SPECT) study of the brain showed reduced blood perfusion in the atrophic right brain hemisphere with normal flow in the middle portion of the frontal and occipital lobes. At that time, a presumptive diagnosis of ‘‘atypical SturgeWeber syndrome’’ or ‘‘cutis marmorata telangiectatica congenita’’ with ‘‘hemimegalencephaly’’ was entertained. Treatment with phenobarbital led to good seizure control. At 5 years of age, he experienced left oculo-facio-brachial hemiparesis that remitted over 2 weeks. During late infancy and puberty, the diabetes was under poor control as were the seizures. Anti-epileptic drugs including topiramate and lamotrigine, led to good control of seizures around 11 years of age. At 11 years and 7 months of age, he manifested diabetic neuropathy, and he was shown to have an increased TSH with a normal T4 and positive antimicrosomal thyroid antibody titers (1:6400 UI; n.v. ¼ 1:200). Thyroid ultrasound examination showed diffuse non-homogeneous parenchymal echogenicity. The diagnosis of autoimmune thyroiditis was established and he was treated with L-thyroxin. When he was first brought to our attention, he was 12 years of age. At school he was under the special educational needs program

3 (‘‘action’’) at first level of support: his school performances scored at above the average level. Intellectual testing by WISC-R, at that time, was scored as 78 with no discrepancies between verbal and performance scores. He was a sociable boy. On physical examination, his weight was 75th percentile, height was 30th percentile, and head circumference was 50th percentile. Examination of his skin (Figs. 1–3) showed a nevus anemicus and a telangiectatic vascular nevus involving the child’s right, and to a lesser extent, left cheeks, and the posterior and lateral aspects of the left (and to a lesser extent the right) thigh. There were streaks of reticular patterns originating from the admixture of the two different vascular nevi distributed along the lateral and posterior aspects of the left arm and the anterior, lateral, and posterior aspects of the middle third of the left leg (Fig. 3). In addition, multiple, large, patches of varying sizes and shapes distinctly paler in the inner areas surrounded by dotted erythematous adjacent skin and smaller satellite paler macules were present on the face, trunk, and limbs (Figs. 1–2). Enhancement of the paler inner-dotted areas and satellite macules was demonstrated upon stroking (or applying heat or cold) to the involved and adjacent skin, which became erythematous. Histological analysis of a punch biopsy taken from an affected area in the right shoulder showed wider capillaries’ lumens lined with flat endothelial cells, without an increase in melanin pigmentation. The latter skin anomaly was diagnosed as a nevus anemicus. He had dysmorphic features consisting of (Fig. 1) a rounded and coarse face with synophris, hypertelorism, a large and bulbous nose, a large philtrum with thin lips, and short neck. His teeth were irregularly shaped and malpositioned. On neurologic examination, there was muscular hypotrophy in the left quadriceps, with a deficit of abduction of the left ankle. A full ophthalmologic examination was unrevealing. An ECG, cardiac ultrasound, and EEG were normal. A thyroid ultrasound examination showed mildly diffuse parenchymal echogenicity; an abdominal ultrasound examination showed a vascular malformation (3  2 cm2) in the hepatic parenchyma (Fig. 4A). Skeletal X-rays showed deviation to the left and elevation of the right iliac crests (0.3 cm) with fragmentation of the left epiphysis (Fig. 4B) consistent with a diagnosis of Legg–Calve–Perthes disease (or likely with a Legg–Calve–Perthes disease-like presentation). There was a partial cleft of the posterior arches at the levels of the 5th lumbar to 3rd sacral vertebral bodies. Intellectual testing by WISC-R was scored as 80. CT and MRI studies of the brain were similar to previous studies with an additional finding of hypoplasia of the right anterior, middle and posterior cerebral arteries demonstrated at magnetic resonance angiography (MRA) studies (Fig. 5). Since 12 years of age, he experienced two to three bouts per year of brief episodes of left hemiparesis with normal interictal EEG recordings. He was maintained on carbamazepine, and low-dose aspirin therapy was started. His mental status was unchanged with school performance at the average level. According to the laboratory testing, his diabetes was fairly-to-poorly controlled, he had nonprogressive peripheral neuropathy and there were no ocular or other systemic complications of the diabetes. He was still under treatment with L-thyroxin. At 28 years of age, his skin abnormalities were unchanged. He continued to experience two-to-three brief bouts per year of left hemiparesis with normal EEG recordings and full recovery

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FIG. 1. Patient 1 at 12 years of age. A: The telangiectatic nevus is in close proximity to the nevus anemicus in a background of normal complexion. Note that the nevus anemicus is distinctly paler in the inner area, which is surrounded by dotted erythematous adjacent skin and smaller satellite paler areas seen in the right cheek; (B and C) similar lesions are seen in the right and left shoulders and the buttocks.

FIG. 2. Patient 1 at 12 years of age. A and B: Note the telangiectatic nevus in close proximity to the nevus anemicus scattered throughout the entire body.

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FIG. 3. Ideogram of Patient 1 showing the distribution of the paired vascular nevi.

FIG. 4. A: Ultrasound examination of the internal organs showing a large, rounded vascular malformation localized in the hepatic parenchyma; (B) anteroposterior X-ray films of the pelvis and lower limbs show deviation to the left and elevation of the right iliac crests (0.3 cm across) with fragmentation of the left epiphysis, which is consistent with a diagnosis of Legg–Calve–Perthes disease.

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FIG. 5. Coronal (A) and axial (B) magnetic resonance angiography (MRA) and axial magnetic resonance imaging (MRI) of the brain obtained at 12 years of age in Patient 1 show hypoplasia of the right A1–A2 segments of the anterior cerebral artery (A and B; labeled as A1 and A2), of the right middle cerebral artery (A and B; black arrow) and of the right posterior cerebral artery (A and B; arrow head); note the asymmetry of cerebral hemispheres (C–E) with right hemisphere atrophy (C–E), ipsilateral osseous hypertrophy and hyperpneumatization of the frontal sinus (C; asterisk) and contralateral cerebral hypertrophy (C–E).

after each episode. There were no changes from prior imaging studies.

Patient 2 This 15-year-old girl was the first born of nonconsanguineous, healthy Italian parents. The child was born by spontaneous delivery at 39 weeks gestation after a normal pregnancy. Her birth weight was 3,200 g [50th centile], length was 51 cm [50th centile], and head circumference was 35 cm [50th centile]. The perinatal period was uneventful. Her early developmental milestones were normal. Since birth, multiple, patched, erythematous, and port-wine stains were noted on the left hemi-face. At 3 years (Fig. 6A) of age, she was referred to a dermatology laser clinic for treatment of the vascular malformations. She underwent laser treatment with partial and temporary improvement of the left facial vascular abnormalities. At 12 years of age, after a sudden episode of right tinnitus, she underwent an audiometric examination and auditory evoked potentials, which showed a moderate-to-severe (