Jan 22, 2004 - Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features. We describe two previously ...
Perinatal/Neonatal Case Presentation Trisomy 14 Mosaicism: A Case Report and Review of the Literature M. Fran Lynch, MD Caraciolo J. Fernandes, MD Lisa G. Shaffer, PhD Lorraine Potocki, MD
Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features. We describe two previously unreported abnormalities in this condition and delineate physical and psychomotor features and concerns for medical management. Trisomy 14 mosaicism should be suspected in individuals who have the features described herein, thus prompting cytogenetic evaluation of blood, and possibly other tissues for diagnosis. Journal of Perinatology (2004) 24, 121–123. doi:10.1038/sj.jp.7211048 Published online 22 January 2004
INTRODUCTION Although complete trisomy 14 is not compatible with postnatal life, trisomy 14 mosaicism has been diagnosed in newborns and children with multiple congenital anomalies. This chromosomal abnormality was first described in 1970 and many characteristic features have been described, with the most common being growth and psychomotor retardation, dysmorphic craniofacial features such as abnormal or low-set ears, micrognathia, cleft or highly arched palate, short neck, and congenital heart and genitourinary abnormalities (reviewed in Fujimoto et al.1 and Johnson et al.2). We present a female infant with mosaic trisomy 14 with Dandy– Walker malformation and neonatal teeth. These clinical characteristics were not previously described in association with this chromosomal abnormality and may be less common features of this disorder. The abnormal cell line was present only in this child’s blood, as cultured fibroblasts showed a normal chromosomal complement with biparental representation of chromosomes 14.
Department of Pediatrics (M.F.L., C.J.F.), Baylor College of Medicine, Houston, TX, USA; Texas Children’s Hospital (M.F.L., C.J.F., L.P.), Houston, TX, USA; Department of Molecular and Human Genetics (L.P.), Baylor College of Medicine, Houston, TX, USA; Section of Neonatology (C.J.F.), Baylor College of Medicine, Houston, TX, USA; Health Research and Education Center (L.G.S.), Washington State University, Spokane, WA, USA. Address correspondence and print requests to Lorraine Potocki, MD, FACMG, Assistant Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Clinical Care Center, 6621 Fannin, MC CC1560, Houston, TX 77030, USA.
CLINICAL REPORT This female infant was the 2900 g product of a 39-week gestation delivered by spontaneous vaginal delivery to a 28-year-old gravida 9, para 7 mother (Figure 1). A diagnosis of Dandy–Walker malformation was made by prenatal ultrasound, but amniocentesis was declined. Apgar scores were 6 at 1 minute, 6 at 5 minutes and 7 at 10 minutes after birth. She was bradycardic and was intubated in the delivery room for poor respiratory effort. Initial measurements demonstrated length less than the third percentile for age although the weight and FOC were within the normal range. The anterior fontanelle was large. There was frontal bossing, upslanted palpebral fissures, bitemporal narrowing, a short and upturned nose, long but well-developed philtrum with downturned mouth, a neonatal tooth, multiple alveolar frenula, and a notched alveolar ridge. The thorax was narrow. A grade three out of six holosystolic murmur was present. The liver was palpable 3.5 cm below the right costal margin. There were hypoplastic fingernails and a unilateral single transverse palmar crease. Brain imaging consisting of both computed tomography and magnetic resonance imaging confirmed the presence of a Dandy–Walker malformation characterized by a large posterior fossa cyst communicating with the fourth ventricle and hypoplasia of the cerebellar vermis (Figure 2). There was ventriculomegaly without evidence of hydrocephalus. An echocardiogram demonstrated a large muscular ventricular septal defect, atrial septal defect and patent ductus arteriosus (the cardiac anomalies were repaired at age 6 weeks). An abdominal ultrasound showed a normal sized liver and kidneys with normal echogenicity. Skeletal survey showed bilateral hypoplastic first ribs, right-sided fifth finger clinodactyly, and short middle phalanges of the second and fifth digits on the right hand. The patient had a prolonged admission in the neonatal intensive care unit. By age 5 weeks, the patient began developing hydrocephalus, but did not require ventriculoperitoneal shunting until age 4 and 1/2 months. She developed seizures and was treated with phenobarbital. The patient had an abnormal renal ultrasound showing increased cortical echogenicity at age 5 weeks; however, she had no vesiculoureteral reflux, proteinuria, or abnormalities of electrolytes or creatinine. A renal scan showed decreased functional mass of the right kidney without scarring. Other medical concerns diagnosed during infancy include profound sensorineural hearing loss with incomplete formation of the spiral structures of the cochlea, tracheomalacia, and poor suck and swallow with aspiration evident on formal swallow evaluation. By age 2 years, the patient had had several admissions for severe upper respiratory tract infections, pneumonia, and/or dehydration.
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She had profound growth deficiency, psychomotor retardation, and chronic pulmonary disease. She had mild elevations of her liver enzymes but normal liver function. She was fed exclusively by the gastrostomy tube and required oxygen by nasal canula because of hypoxia. Nursing care was provided in the home. On examination she had severe hypotonia and head leg. She could not fix or follow, but had a structurally normal ophthalmologic examination. She was nonverbal and could not clear her face when prone, and was unable to grasp objects. The length, weight, and head circumference were all far below the 5th percentile (B50th percentile for 8, 6, and 9 months respectively). Dysmorphic craniofacial features were again noted (Figure 3a), as well as a linear cutaneous pigmentary variation of the trunk and extremities (Figure 3b), which was not evident in infancy. She had a structurally normal ophthalmic and fundoscopic examination.
CYTOGENETIC AND MOLECULAR STUDIES
Figure 1. Patient at age 2 and 1/2 months. Note the frontal bossing, bitemporal narrowing, upslanting palpebral fissures, short and upturned nose, a long but well-developed philtrum, and micrognathia. The thorax was narrow.
Figure 2. MRI of the brain in the neonatal period confirmed the Dandy–Walker malformation which was initially detected on prenatal ultrasound. 122
Chromosome analysis of peripheral blood revealed a mosaic complement with trisomy 14 in 23% of cells (47,XX, þ 14) and a normal female complement (46,XX) in 77%. Chromosome analysis performed on cultured skin fibroblasts revealed a normal female complement. Using polymorphic markers from chromsome 14, normal biparental inheritance was seen in both blood and tissue (data not shown). Whether the extra chromosome 14 in blood was of maternal or paternal origin could not be determined.
DISCUSSION While complete trisomy 14 is uniformly lethal, trisomy 14 mosaicism has been observed in infants and children. Several characteristic features of this chromosomal abnormality have been described which may enable the clinician to suspect this diagnosis even prior to obtaining a chromosome analysis. The most common features are growth and psychomotor retardation, broad nose, abnormal or low-set ears, micrognathia, short neck, and congenital cardiovascular disease.1,2 Although these features are relatively nonspecific, they should prompt a cytogenetic examination. Several other more unusual features have been described (Table 1) but are seen in a smaller percentage of patients. The presence of these features should prompt consideration of trisomy 14 mosaicism as the specific diagnosis. One such feature is abnormal skin pigmentation, which is a common finding in individuals with mosaic chromosomal abnormalities including mosaic trisomy 14.3,4 The patient we describe did not exhibit abnormal skin pigmentation at birth, yet this was evident by age 2. Table 1 compares the major clinical features of previously reported cases of trisomy 14 mosaicism and our patient. The features most commonly seen in other patients with trisomy 14 mosaicism were present in our patient, with body asymmetry being Journal of Perinatology 2004; 24:121–123
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Table 1 Clinical Features of Mosaic Trisomy 14 Feature Developmental delay Growth retardation Seizures Microcephaly Dandy–Walker malformation Hearing impairment
Case report
Previous reports
+ + + + (postnatal onset) +
12/18 17/18 1/18 7/18
Hypertelorism Micrognathia Neonatal tooth Notched alveolar ridge Narrow thorax Body asymmetry
+ (sensorineural) + + + + +
Abnormal pigmentation
+
Congenital heart disease Genitourinary/renal anomalies
+ +
Not previously reported 2/18 (not reported in 16 cases) 9/18 17/18 Not previously reported Not previously reported Not previously reported 9/18 (not reported in five cases) 7/18 (not reported in five cases) 16/18 7/18
+: feature is present; : feature is not present.
and a notched alveolar ridge. These features may represent less common congenital anomalies in the mosaic trisomy 14 syndrome. While chromosomal mosaicism can be detected in lymphocytes obtained from peripheral blood, the clinician who suspects a chromosomal abnormality should also sample other tissues such as skin for analysis because mosaicism may be limited to these tissues.
Acknowledgements Figure 3. Patient at age 2 years. (a) There is thin and relatively sparse hair, frontal bossing, upslanting palbebral fissures, short and upturned nose, long philtrum, downturned mouth held in an open, hypotonic posture, and micrognathia. (b) Pigmentary variation in a linear pattern is evident on the trunk and right upper extremity.
a notable exception. It is important to recognize, however, that in previously reported cases, body asymmetry was never noted before 5 months of age and in one case2 was not noted until 7 years of age. Another feature reported in mosaic trisomy 14 is neonatal hepatitis.5 While our patient had mild and transient elevations of transaminases, it is unclear whether these enzymatic abnormalities were secondary to phenobarbital or part of her genetic syndrome. Our patient also exhibited features that have not previously been reported in association with trisomy 14 mosaicism. Among these were Dandy–Walker malformation, presence of a neonatal tooth, Journal of Perinatology 2004; 24:121–123
We thank the patient’s parents for their permission to use photographs of their daughter, and Christopher McCaskill for the molecular studies.
References 1. Fujimoto A, Allanson J, Crowe CA, Lipson MH, Johnson VP. Natural history of mosaic trisomy 14 syndrome. Am J Med Genet 1992;44:189–96. 2. Johnson VP, Aceto T, Likness C. Trisomy 14 mosaicism: case report and review. Am J Med Genet 1979;3:331–9. 3. Tunca Y, Wilroy RS, Kadandale JS, Martens PR, Gunther WM, Tharapel AT. Hypomelanosis of Ito and a ‘mirror image’ whole chromosome duplication resulting in trisomy 14 mosaicism. Ann Genet 2000;43:39–43. 4. Ku¨ster W, Ko¨nig A. Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism. Am J Med Genet 1999;85:346–50. 5. Iglesias A, McCurdy LD, Glass IA, et al. Mosaic trisomy 14 with hepatic involvement. Ann Genet 1997;40:104–8. 123
