Mowat-Wilson syndrome (MWS) is a rare genetic condition that affects multiple body systems, causing physical, developmental, and intellectual challenges. First described in 1998, the disorder is characterized by a distinctive facial appearance, intellectual disability, and various congenital malformations. MWS requires comprehensive, multidisciplinary care tailored to the specific needs of each individual. Its estimated prevalence is approximately 1 in 50,000 to 70,000 live births, suggesting the condition is often under-recognized.
Genetic Origin and Cause
Mowat-Wilson syndrome is an autosomal dominant disorder caused by a change in the ZEB2 gene, located on chromosome 2. The ZEB2 gene provides instructions for making a protein, called Smad Interacting Protein 1 (SIP1), that acts as a transcriptional corepressor, helping to turn off the expression of other genes. This protein is highly active in various tissues during embryonic development, including the brain, heart, and neural crest cells.
The genetic alteration is typically a loss-of-function mutation, such as a nonsense mutation, a frameshift mutation, or a whole or partial deletion. These changes result in haploinsufficiency, where one functional copy of the ZEB2 gene is insufficient for normal development. Over 90% of identified defects are due to these severe mutations.
Most MWS cases arise from a de novo mutation, meaning the genetic change is a spontaneous event in the affected person and was not inherited from either parent. Because the mutation is spontaneous, the recurrence risk for unaffected parents is generally very low. The disorder affects males and females equally across all ethnic groups.
Distinct Clinical Characteristics
Individuals with MWS share a recognizable set of physical features and medical issues affecting multiple organ systems, though the specific combination varies among patients. The facial appearance is often the most noticeable feature, including a high forehead, widely spaced eyes (hypertelorism), and broad, upward-flaring eyebrows. Other common traits are uplifted earlobes with a central depression, a prominent and pointed chin, and a characteristic open-mouth expression.
A significant medical concern is the high incidence of Hirschsprung disease (HSD), a congenital condition affecting the large intestine present in 40% to 50% of people with MWS. HSD occurs when nerve cells fail to develop in the wall of the colon, leading to severe constipation and intestinal blockage. This defect is a hallmark feature of the syndrome, and chronic constipation is frequent even without a formal HSD diagnosis.
Neurological and developmental impairment affects nearly all individuals with MWS. Affected people experience moderate to severe intellectual disability and significant developmental delays. Speech is severely impaired or absent in most people older than one year, though receptive language skills are often relatively better preserved.
Beyond gastrointestinal and neurodevelopmental issues, many patients have structural defects, particularly involving the heart and genitourinary system. Congenital heart defects are common, often involving abnormalities of the pulmonary arteries or valves. Genitourinary anomalies, such as hypospadias in males, are frequently observed.
Brain structure abnormalities are also often present, including hypogenesis or agenesis of the corpus callosum. Seizures and microcephaly are frequently reported clinical features.
Diagnosis and Confirmation
The initial identification of Mowat-Wilson syndrome begins with clinical suspicion based on the characteristic pattern of features. MWS should be considered when a child presents with developmental delay or intellectual disability alongside the specific facial appearance and one or more congenital anomalies, such as Hirschsprung disease or a heart defect. The distinctive facial features are important for guiding the initial evaluation, even if intestinal issues are absent.
A definitive diagnosis is established through molecular genetic testing that analyzes the ZEB2 gene. Gene-targeted testing, such as sequence analysis, is performed to identify pathogenic variants. This testing detects various types of mutations, including nonsense and frameshift changes, which account for the majority of cases.
If sequencing does not identify a mutation, the evaluation may include testing for large deletions or duplications of the gene, which account for about 15% of the pathogenic variants. Comprehensive genomic testing, such as exome sequencing, may also be employed, particularly in individuals presenting with intellectual disability and multiple congenital anomalies. Genetic confirmation is helpful in ruling out other syndromes that share overlapping features.
Comprehensive Care and Management
Since MWS is a genetic condition without a cure, the management strategy is symptomatic and requires a coordinated, multidisciplinary approach. Early intervention is paramount, focusing on addressing structural and developmental issues as they are identified. Comprehensive care includes managing the surgical and medical needs arising from congenital malformations.
Structural defects often necessitate surgical management early in life. For individuals with Hirschsprung disease, the affected segment of the colon must be surgically removed to restore normal intestinal function. Congenital heart defects, especially those involving the pulmonary arteries or valves, frequently require assessment and possible surgical correction by a pediatric cardiologist. Genitourinary anomalies, such as hypospadias, may also require surgical intervention.
Therapeutic support is a continuous component of long-term care to maximize the individual’s developmental potential. Early intervention services are essential, including physical therapy to assist with delayed motor skill development and walking. Occupational therapy helps develop fine motor skills and adaptive techniques for daily living, while speech therapy addresses profound communication limitations.
Long-term monitoring by specialists is required due to the multi-system nature of the syndrome. Regular follow-up with a neurologist is needed to manage seizures, and an ophthalmologist should monitor for potential eye issues. Routine developmental assessments are used to refine educational plans and therapeutic interventions as the individual grows, ensuring that care evolves with changing needs.