Clinical characteristics: Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression), congenital heart defects with predilection for abnormalities of the pulmonary arteries and/or valves, Hirschsprung disease or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpal callosum. Most affected individuals have moderate-to-severe intellectual disability. Speech is typically limited to a few words or is absent, with relative preservation of receptive language skills. Growth restriction with microcephaly and seizure disorder are also common. Most affected people have a happy demeanor and a wide-based gait that can sometimes be confused with Angelman syndrome.
Diagnosis/testing: The diagnosis of MWS is established in a proband with classic dysmorphic facial features and developmental delay / intellectual disability and/or a heterozygous pathogenic variant in ZEB2 identified by molecular genetic testing.
Management: Treatment of manifestations: Care by the appropriate specialist for dental anomalies, seizures, ocular abnormalities, congenital heart defects, chronic constipation, Hirschsprung disease, genitourinary abnormalities, and pectus anomalies of the chest and/or foot/ankle anomalies; educational intervention and speech therapy beginning in infancy. Surveillance: Annual eye examination in childhood to monitor for strabismus and refractive errors; monitoring for otitis media; regular developmental assessments to plan/refine educational interventions; periodic reevaluation by a clinical geneticist.
Genetic counseling: MWS is an autosomal dominant disorder caused by a pathogenic variant in ZEB2, a heterozygous deletion of 2q22.3 involving ZEB2, or (rarely) a chromosome rearrangement that disrupts ZEB2. Almost all individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo genetic alteration; rarely, recurrence in a family has been reported when a parent has a low level of somatic or presumed germline mosaicism for a MWS-causing pathogenic variant. Individuals with MWS are not known to reproduce. Once the causative genetic alteration has been identified in the proband, prenatal testing may be offered to parents of a child with MWS because of the recurrence risk associated with the possibility of parental mosaicism or a balanced chromosome rearrangement.
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