Mowat-Wilson syndrome due to a ZEB2 point mutation

Mowat-Wilson syndrome (MWS) due to a ZEB2 point mutation is a rare genetic neurodevelopmental disorder caused by heterozygous point mutations (missense, nonsense, or splice-site) in the ZEB2 gene (also known as SIP1 or ZFHX1B) located on chromosome 2q22. ZEB2 encodes a zinc finger E-box binding homeobox 2 transcription factor that plays a critical role in embryonic development, particularly in the formation of the nervous system, neural crest derivatives, and the enteric nervous system. This specific subtype is distinguished from cases caused by larger deletions encompassing the ZEB2 locus, though the clinical presentation is broadly similar. Mowat-Wilson syndrome affects multiple body systems. The hallmark features include a distinctive facial appearance (characterized by widely spaced eyes, broad nasal bridge, prominent rounded nasal tip, open mouth, and uplifted earlobes), moderate to severe intellectual disability, delayed motor development, and speech impairment that is often severe with limited or absent expressive language. Hirschsprung disease (aganglionosis of the colon, ICD-10: Q43.1) is a major associated feature, occurring in approximately 50-60% of affected individuals, and may present with neonatal bowel obstruction requiring surgical intervention. Epilepsy is very common, typically developing in early childhood, and may include various seizure types. Congenital heart defects (such as patent ductus arteriosus, ventricular septal defects, and pulmonary artery anomalies) occur in approximately 50% of patients. Other features may include urogenital anomalies (hypospadias, cryptorchidism, renal malformations), eye abnormalities, corpus callosum agenesis or hypoplasia, and short stature. There is currently no cure or disease-specific therapy for Mowat-Wilson syndrome. Management is supportive and multidisciplinary, addressing individual symptoms as they arise. This includes surgical correction of Hirschsprung disease, antiepileptic medications for seizure control, cardiac surgery when indicated, and early intervention programs including speech therapy, physical therapy, and occupational therapy. Regular monitoring by a team of specialists — including neurologists, gastroenterologists, cardiologists, and developmental pediatricians — is recommended to optimize outcomes and quality of life.

Common questions about Mowat-Wilson syndrome due to a ZEB2 point mutation