1- Serviço de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa
- 24th Annual Meeting, Sociedade Portuguesa de Genética Humana, virtual meeting, 20 de Novembro. Sob a forma de comunicação oral
Introduction: Mowat-Wilson syndrome (MWS) (OMIM # 235730) is a rare cause of intellectual disability (ID) (moderate/severe) with speech impairment but comprehension preserved and typical facial features. Other congenital anomalies commonly associated are seizures, microcephaly, genitourinary abnormalities, congenital heart defects, Hirschsprung disease or chronic constipation, and growth restriction. In most cases, MWS results of de novo heterozygous truncating ZEB2 variants or deletions encompassing the gene which are responsible for the characteristic phenotype. However, in less than 5% of reported cases, atypical or milder forms of MWS spectrum are the result of missense, splice site or in-frame variants. In these cases, milder degrees of ID and some suggestive features can be present, with or without other associated congenital malformations.
Case report: A5-year-oldmale presented with development delay, dyspraxia, facial dysmorphisms (synophrys, open-mouth expression, uplifted earlobes and prominent chin), hypospadias and history of constipation, stature and weight above 95th percentile and head circumference between 50-75th percentile. EEG showed parietal epileptiform focus activity without seizures, so far. Karyotype, FRAXA and array-CGHwere normal. NGS panel for ID presented a missense variant in ZEB2 c.3141G>C (p.(Arg1047Ser)), initially classified as of uncertain significance. Analysis concluded that it is a deleterious variant and parental segregation confirmed it is de novo. The reclassification of this missense variant as likely pathogenic established the diagnosis of MWS with an atypical phenotype (including macrosomia, not previously described).
Conclusion: MWS has a characteristic phenotype, distinct facial features and it is genetically homogeneous. Rarer missense variants result in atypical/milder phenotypes and data from these patients can help understand the range of this syndrome. This case continues to expand the spectrum of MWS and highlights that it can be a less obvious diagnosis. From a practical standpoint, it provided an appropriate genetic counseling and better surveillance to this patient and family.
Palavras Chave: atypical phenotype, intellectual disability, missense variants, Mowat-Wilson syndrome, ZEB2 gene