Rare nasal cleft in a patient with holoprosencephaly due to a mutation in the ZIC2 gene.

BACKGROUND: Holoprosencephaly (HPE) is a spectrum of midline malformations of the prosencephalon generally reflected in a continuum of midline facial anomalies. Patients with mutation in the ZIC2 gene usually present a normal or mildly dysmorphic face associated with a severe brain malformation. Here we present a rare unilateral nasal cleft (Tessier cleft n. 1) with holoprosencephaly in a patient with a ZIC2 mutation. CASE: The male newborn presented with alobar HPE, microcephaly, ocular hypertelorism, upslanting palpebral fissures, a bulky nose with a left paramedian alar cleft. Mutational screening for HPE genes revealed the occurrence of a frameshift mutation in the ZIC2 gene. The mutation was inherited from the father who presented only mild ocular hypotelorism but had an affected child with HPE from his first marriage. CONCLUSION: The occurrence of oral clefts is common in patients with HPE, but unusual in patients with mutation in the ZIC2 gene. To our knowledge, clefts of the nasal alae have been reported only once or twice in patients with ZIC2 mutations. In documented patients from the literature, only 2% of individuals with described pathogenic mutations in the ZIC2 gene (3/171) presented facial clefts, one of them a nasal cleft, while common oral clefts were observed in 27% of individuals (7/26) described with nonpathogenic ZIC2 mutations or presenting a concomitant mutation in another HPE gene. When compared with the general population, nasal clefts are common in ZIC2 mutations and these mutations must be searched for in undiagnosed cases.

Molecular analysis of holoprosencephaly in South America.

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.

New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly.

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.