Mowat-Wilson syndrome (MWS) is a rare genetic condition that impacts multiple body systems, leading to medical and developmental challenges. First described in 1998, this syndrome is characterized by a distinctive facial appearance, intellectual disability, and various congenital anomalies. While the exact incidence is unknown, estimates suggest it may occur in at least 1 in 70,000 live births, though it is likely under-diagnosed due to symptom variability.
The Genetic Origin of the Syndrome
Mowat-Wilson syndrome is caused by a change in the ZFHX1B or ZEB2 gene, located on chromosome 2. This gene provides instructions for making the ZEB2 protein, which acts as a transcriptional repressor. The ZEB2 protein plays a significant role in regulating the expression of other genes during embryonic development.
The condition typically results from a mutation or deletion in one copy of the ZEB2 gene, leading to a reduced amount of functional protein. This mechanism, called haploinsufficiency, disrupts normal developmental pathways for many organs and tissues. Over 80% of individuals diagnosed with MWS have a pathogenic variant in the gene, while the remaining cases involve a partial or complete deletion.
The majority of MWS cases arise from a de novo mutation, meaning the genetic change occurred spontaneously and was not inherited from either parent. In these instances, the risk of recurrence in future children is low. The condition follows an autosomal dominant inheritance pattern, so an affected individual has a 50% chance of passing the mutation to their offspring, though reproduction is not commonly observed.
Recognizing Key Clinical Characteristics
The recognition of Mowat-Wilson syndrome often begins with a distinctive set of facial features that become more pronounced with age. These characteristics include:
- A square-shaped face and a broad forehead
- Widely spaced, deep-set eyes
- A prominent or pointed chin
- A broad nasal bridge with a rounded tip
- Large, uplifted earlobes with a central depression
Nearly all individuals with MWS experience a comprehensive developmental disorder, including intellectual disability that is typically moderate to severe. Motor skills such as sitting and walking are significantly delayed, often until mid-childhood or later. Expressive language is profoundly impacted, often resulting in severely limited or absent speech, although receptive language skills are usually better preserved.
A highly frequent medical issue is Hirschsprung disease (HSCR), an intestinal disorder affecting over half of individuals with MWS. This condition results from the absence of ganglion cells in the large intestine wall, which prevents normal muscle contractions needed for bowel movements. Chronic constipation is a common complaint even without HSCR.
Structural abnormalities affect other major organ systems. Congenital heart defects are common, affecting approximately 75% of individuals, often involving the pulmonary arteries, valves, or septal defects. Anomalies of the urogenital system are also frequent, particularly hypospadias (abnormal opening of the urethra) in males.
Many individuals experience issues related to the central nervous system, including microcephaly and structural brain abnormalities such as the absence or underdevelopment of the corpus callosum. Epilepsy is a frequent complication, affecting a large percentage of individuals, with seizures typically beginning early in life. Individuals with MWS are often described as having a characteristically happy demeanor and a frequent, open-mouthed smile.
Diagnosis and Supportive Care Strategies
Diagnosis begins when a clinician recognizes the distinctive clinical picture, combining characteristic facial features, developmental delay, and congenital anomalies like Hirschsprung disease. Once MWS is suspected, the diagnosis is confirmed through molecular genetic testing. This involves sequencing the ZEB2 gene to identify a pathogenic variant or using chromosomal microarray testing to detect a gene deletion. Genetic confirmation provides a definitive diagnosis and accurate counseling to the family.
Management requires a comprehensive, multidisciplinary approach involving several specialists, since MWS affects many body systems. A team typically includes a pediatrician, a clinical geneticist, a neurologist, a cardiologist, and a gastroenterologist or surgeon. Proactive surveillance is also important, including regular eye examinations and developmental assessments to guide therapeutic planning.
Supportive care focuses on managing symptoms and maximizing developmental potential through early and intensive intervention therapies. Physical, occupational, and speech therapy aim to improve motor skills and communication abilities. Although speech is severely impaired, alternative communication methods, such as sign language or communication devices, can be introduced.
Surgical correction is often necessary for congenital malformations, such as the repair of significant heart defects or the management of Hirschsprung disease. Seizures are managed medically with anticonvulsant medications. Overall care is symptomatic, meaning it addresses the specific issues present in each individual to improve their quality of life and developmental progress.