Academic journal article Genetic Counseling

Phenotypic Variability in Micro Syndrome: Report of New Cases

Academic journal article Genetic Counseling

Phenotypic Variability in Micro Syndrome: Report of New Cases

Article excerpt

Summary: Phenotypic variability in micro syndrome: report of new cases: The authors describe seven Egyptian patients (5 males and two females) with microcephaly, mild microphthalmia, microcornea, congenital cataracts and hypogenitalism (only in males). These features (after excluding possible non-genetic causes) are consistent with the diagnosis of Micro syndrome. Clinical, neurological, ophthalmologic examinations and brain imaging and electrophysiological studies were performed in all patients. Three cases had characteristic facial features consistent with those originally described in the Micro syndrome whilst the rest of the cases had clearly different facies to that of the original patients of Micro syndrome but similar to those described in Martsolf syndrome. The patients had a variable degree of brain atrophy but hypogenesis of the corpus callosum was evident only in five patients. Abnormal gyral pattern, small cerebellum, vermian hypoplasia and delayed myelination were additional imaging findings in 3 cases. All patients had delayed visual evoked potential but normal electroretinogram. The frequently-reported parental consanguinity emphasizes the major role of the single gene inheritance. Mutation analysis for two patients showed homozygous nonsense mutation of RAB3GAP1 in one while the other showed no evidence of linkage to either RAB3GAP1 or RAB2GAP2. Based on these cases and review of the literature, RAB3GAP genes dysregulation may result in a spectrum of phenotypes that range from Micro syndrome to Martsolf syndrome.

Key-words: Micro syndrome - Microphthalmia - Hypogenesis of corpus callosum - Hypogenitalism - Microcephaly - Congenital cataract.

INTRODUCTION

The triad of microcephaly, congenital cataract and microphthalmia have a variety of different etiologies incorporating prenatal viral infection as well as many Mendelian syndromes. In 1993 Warburg et al. (22) described a new autosomal recessive disorder in a consanguineous family with 3 affected children. These authors named the disorder Micro syndrome as the children had developmental abnormalities of the eye (microphthalmia, microcornea, congenital cataracts, optic nerve atrophy), central nervous system (microcephaly, hypogenesis of the corpus callosum, abnormal gyral patterns) and hypogenitalism (micropenis and cryptorchidism) and hence the acronym Micro syndrome (22). Since this initial case report, several other case reports have confirmed the inheritance pattern and helped to further delineate other clinical features associated with this condition: polymicrogyria, hypoplastic cerebellum, congenital hip dislocation, anomalies of the kidney and joint hypermobility and skin hyperextensibility (1, 4, 6, 7, 12, 15, 17, 22, 23). Micro syndrome is an extremely rare pathology, whose true incidence is not known and most of the published reports were of Muslim origin. The diagnosis of this syndrome is a clinical one, which should be distinguished from other similar clinical disorders with microcephaly, congenital cataract and hypogenitalism i.e: Cerebro-Oculo-Facio-Skeletal (COFS), Cockayne syndrome, a syndrome of cataract, arthrogryposis, microcephaly and kyphoscoliosis (CAMAK) a syndrome of cataract, arthrogryposis, microcephaly, failure to thrive and kyphoscoliosis (CAMFAK), Smith-Lemli-Opitz syndrome (SLO), and CAHMR a syndrome of cataract, hypertrichosis, and mental retardation (21). Martsolf syndrome has many overlapping features with Warburg Micro syndrome, but the ocular and neurodevelopmental defects are less severe in Martsolf syndrome.

Micro and Martsolf syndromes are heterogenous autosomal recessive disorders. Mutations in the RAB3GAP1 have been shown to cause Micro syndrome (2) while mutaions in RAB3GAP2 have been associated with Matsolf syndrome (3). Rab3GAP is a key regulator of Rab3 pathway which is implicated in calcium mediated exocytosis of neurotransmitters and hormones. RAb3GAP is a heterodimeric enzyme and is composed of a catalytic subunit encoded for by RAB3GAP1 and a noncatalytic subunit encoded for by RAB3GAP2. …

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