RESUMO
Holoprosencephaly (HPE), the most common malformation of the human brain results from abnormal cleavage of the forebrain during the early embryonic developmental stages. The spectrum of malformations in HPE is wide, ranging from the classical cyclopia/proboscis to fairly asymptomatic forms [i.e. a single maxillary central incisor (SMCI)]. HPE may be caused by environmental or genetic factors. ZIC2 (13q32) was the second gene identified in which mutations cause HPE and recently a specific phenotype was ascribed to ZIC2-mutation HPE. Earlier, we reported a boy presenting HPE and deafness. Cytogenetic analyses were normal. Using array-comparative genomic hybridization (aCGH), we found a de novo 129 kb del(13)(q32) encompassing ZIC2 and ZIC5. There is no evidence for the involvement of ZIC5 in human diseases. We reviewed the literature for ZIC2-ZIC5 deletions and their involvement in neural tube defects (NTDs). Interestingly, we found evidence for a specific facial phenotype for ZIC2 gene deletion patients distinct from those with point mutations. In addition, based on the clinical data together with pathology, imaging and functional studies, we suggest an outline for a model explaining the genetic heterogeneity of ZIC2-ZIC5-associated NTDs and propose further studies for validation.
Assuntos
Holoprosencefalia/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Deleção Cromossômica , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA , Heterogeneidade Genética , Humanos , Masculino , Mutação , Defeitos do Tubo Neural/genética , FenótipoRESUMO
BACKGROUND: In 1967, Cross et al. [J Pediatr 1967;70:398-406] reported four siblings with intellectual disability, microcephaly, neurologic and ocular disorders, and hypopigmentation involving skin and hair. This novel entity, known as oculocerebral hypopigmentation syndrome (OCHS) or Cross syndrome (OMIM 257800), is assumed to be autosomal recessive. However, its genetic cause is still unknown. CASE REPORT: A 4-year-old girl is reported with OCHS, a history of recurrent infections and vertebral fusion of L4-L5. Central nervous system and cardiac imaging as well as metabolic screening were normal. Microscopic hair investigations did not show any melanin deposit defects. RESULTS: Using molecular cytogenetics, we detected a de novo interstitial del(3)(q27.1q29) of the paternal chromosome. To our knowledge, this is the first molecular genetics finding in a patient with OCHS. Here we discuss the genotype-phenotype correlations and suggest candidate genes for this disorder. CONCLUSION: Investigating further patients would enable fine-mapping the OCHS locus and identifying its putative gene.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 3/genética , Anormalidades Craniofaciais/genética , Transtornos da Pigmentação/genética , Pré-Escolar , Mapeamento Cromossômico , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Microcefalia/genéticaRESUMO
Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.