Classic Mowat-Wilson Syndrome

Excerpt

Clinical characteristics: Classic 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 and/or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpus 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 epilepsy 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 classic MWS is established in a proband with the typical recognizable dysmorphic facial features and developmental delay / intellectual disability and/or a heterozygous pathogenic variant in ZEB2 (most classic MWS-related ZEB2 pathogenic variants lead to predicted haploinsufficiency for the functional components of the ZEB2 protein) 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: Classic 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 gonadal mosaicism for a classic MWS-causing pathogenic variant. Individuals with classic 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 classic MWS because of the recurrence risk associated with the possibility of parental mosaicism or a balanced chromosome rearrangement.