Mowat-Wilson Syndrome (MWS) is a rare, congenital genetic disorder that affects development across multiple body systems. It is characterized by a distinct combination of physical anomalies, developmental delays, and intellectual disability. First described in 1998, MWS is considered rare, with prevalence estimated between 1 in 50,000 and 1 in 70,000 live births. The syndrome results from a disruption in early embryonic development.
The Underlying Genetic Cause
Mowat-Wilson Syndrome is caused by a heterozygous change in the ZEB2 gene, located on chromosome 2 at position 2q22.3. The ZEB2 gene provides instructions for creating a protein that functions as a transcription factor.
This protein regulates the activity of other genes during embryonic formation. It is involved in the development and migration of neural crest cells, which form tissues like the nervous system, digestive tract, and facial structures. The condition results from haploinsufficiency, meaning one functional copy of the gene is insufficient for normal development.
The genetic change is typically a de novo mutation, occurring spontaneously and not inherited from either parent. About 84% of MWS cases are caused by a pathogenic variant within the ZEB2 gene, such as a nonsense or frameshift mutation. The remaining 15% result from a larger heterozygous deletion encompassing the entire gene on 2q22.3.
Characteristic Clinical Features
MWS presents with a distinctive set of features affecting multiple organ systems.
Dysmorphic Features
Dysmorphic facial features become more pronounced as the child ages. These often include widely spaced eyes (hypertelorism), a prominent and pointed chin, a saddle nose with a rounded tip, and a broad nasal bridge. Large, uplifted earlobes with a central depression are also common.
Neurological and Developmental Delays
MWS involves moderate to severe intellectual disability and significant developmental delay. Motor skills, such as sitting and walking, are delayed, and speech is often severely limited or absent. Receptive language skills are frequently better preserved, indicating a greater ability to understand communication.
Epilepsy is a common neurological component. Many affected individuals exhibit a cheerful and sociable personality, often described as having a happy demeanor with frequent smiling.
Organ System Involvement
Gastrointestinal issues are a major concern, particularly Hirschsprung disease (HSCR), present in over half of individuals with MWS. HSCR is caused by the absence of ganglion nerve cells in a segment of the large intestine. This lack of nerve cells prevents normal bowel movement, leading to chronic constipation and intestinal obstruction.
Other common findings include:
- Congenital heart defects, occurring in almost 60% of people, such as ventricular or atrial septal defects and patent ductus arteriosus.
- Structural abnormalities in the brain, including the hypogenesis or absence (agenesis) of the corpus callosum.
- Genitourinary defects, particularly hypospadias in males, where the urethral opening is not at the tip of the penis.
Confirming a Diagnosis
Diagnosis typically begins with clinical suspicion based on characteristic features. Clinicians often suspect MWS when a patient presents with intellectual disability, dysmorphic facial features, and Hirschsprung disease. A thorough physical examination and medical history establish this initial suspicion.
Definitive confirmation relies on molecular genetic testing to identify changes in the ZEB2 gene. The standard approach involves sequencing the ZEB2 gene to detect small pathogenic variants, such as point mutations. If sequencing is negative, gene-targeted deletion/duplication analysis is used to detect larger deletions encompassing the ZEB2 gene on 2q22.3.
Diagnosis also involves a differential analysis to exclude other genetic conditions that share overlapping symptoms, such as Angelman syndrome or Pitt-Hopkins syndrome.
Multidisciplinary Care and Support
Management focuses on treating specific symptoms and providing lifelong support, as there is no cure for MWS. A coordinated multidisciplinary team approach is necessary, typically including a developmental pediatrician, neurologist, cardiologist, and surgeon or gastroenterologist.
Surgical intervention is often required early in life to correct congenital malformations, such as repairing heart defects. For Hirschsprung disease (HSCR), the segment of the bowel lacking nerve cells must be surgically removed to restore normal intestinal function.
Early intervention programs incorporate physical, occupational, and speech therapies to maximize developmental potential. Since expressive speech is commonly severely impaired, alternative communication methods are introduced, such as sign language or augmented communication systems like picture exchange cards. Regular surveillance is maintained throughout life to monitor for complications like seizures or eye anomalies.