Mowat–Wilson syndrome

Overview

Mowat–Wilson syndrome (MWS) is a rare genetic disorder that affects multiple body systems and is characterized by distinct facial features, developmental delay, intellectual disability, epilepsy, and congenital anomalies such as Hirschsprung disease, heart defects, and genitourinary abnormalities. First described in 1998 by Drs. Mowat and Wilson, the syndrome is now recognized as a recognizable clinical entity with a broad spectrum of severity.

One of the hallmark features of MWS is the combination of intellectual disability with specific congenital malformations and a recognizable facial appearance. Most individuals with MWS are non-verbal or have limited speech, and they typically have happy, friendly dispositions. Although the condition is lifelong, early interventions and supportive care can help improve quality of life and developmental outcomes.

Causes

Mowat–Wilson syndrome is caused by mutations or deletions in the ZEB2 gene (also known as SIP1), located on chromosome 2q22.3. The ZEB2 gene provides instructions for making a protein that plays a crucial role in the development of the nervous system and other organs.

Genetic Characteristics

• Autosomal dominant inheritance: MWS is typically caused by a new (de novo) mutation and is not inherited from either parent.

• De novo mutations: In most cases, affected individuals have no family history of the condition, and the mutation arises spontaneously.

• Parental transmission: Rarely, the condition can be inherited if a parent is mosaic for the mutation.

Loss of function in the ZEB2 gene disrupts normal development of the brain, digestive tract, heart, and other organ systems, accounting for the multi-systemic nature of the syndrome.

Symptoms

Symptoms of Mowat–Wilson syndrome vary in severity but typically include a combination of facial dysmorphism, neurological impairment, congenital malformations, and gastrointestinal, cardiac, or urogenital anomalies.

1. Facial Features (Highly Characteristic)

• Broad, square-shaped chin

• Deep-set, widely spaced eyes

• Medially flared eyebrows with a prominent arch

• Open mouth with prominent upper lip and uplifted earlobes

• Rounded nasal tip with a broad nasal bridge

2. Neurological and Developmental Features

• Moderate to severe intellectual disability

• Delayed developmental milestones (sitting, walking, speech)

• Absent or minimal speech (many individuals remain non-verbal)

• Seizures or epilepsy (common in over 70% of cases)

• Hypotonia (low muscle tone)

3. Gastrointestinal Features

• Hirschsprung disease (absence of nerve cells in parts of the colon, causing bowel obstruction)

• Chronic constipation or megacolon in cases without Hirschsprung disease

4. Congenital Malformations

• Congenital heart defects (e.g., atrial or ventricular septal defects, patent ductus arteriosus)

• Genitourinary anomalies (e.g., hypospadias, cryptorchidism in males; uterine anomalies in females)

• Microcephaly (small head circumference)

5. Other Features

• Happy, sociable behavior

• Hearing loss (sensorineural or conductive)

• Feeding difficulties during infancy

• Visual impairments (strabismus, refractive errors)

Not every individual has all features, and the clinical presentation may vary from mild to severe.

Diagnosis

Diagnosis of Mowat–Wilson syndrome is based on clinical features, supported by genetic testing. Because the syndrome has distinct physical features and a recognizable pattern of anomalies, an experienced clinician may suspect MWS even before confirmatory testing.

Steps in the Diagnostic Process

• Clinical examination: Identification of characteristic facial features and congenital anomalies

• Developmental assessment: Evaluation of motor and language delays

• Genetic testing: Sequencing of the ZEB2 gene to detect mutations or deletions

• Array CGH: To detect larger deletions encompassing the ZEB2 gene

Supportive Investigations

• Brain MRI to assess structural abnormalities

• Echocardiography for congenital heart defects

• Barium enema or rectal biopsy for Hirschsprung disease

• Renal ultrasound and urological assessment

Early diagnosis is important to initiate targeted interventions and coordinate multidisciplinary care.

Treatment

There is no cure for Mowat–Wilson syndrome. Treatment is symptomatic and supportive, focusing on managing medical complications, improving developmental outcomes, and enhancing quality of life. A multidisciplinary team is essential and may include pediatricians, neurologists, cardiologists, gastroenterologists, speech and occupational therapists, and special education professionals.

1. Developmental and Educational Support

• Early intervention programs for speech, occupational, and physical therapy

• Special education tailored to individual learning needs

• Augmentative and alternative communication (AAC) for non-verbal individuals

2. Medical Management

• Antiepileptic medications for seizure control

• Treatment of gastrointestinal problems (e.g., surgery for Hirschsprung disease)

• Management of cardiac defects (medical or surgical)

• Surgical correction of urogenital anomalies

3. Supportive Care

• Feeding support (e.g., feeding therapy, gastrostomy if needed)

• Regular hearing and vision assessments

• Behavioral therapy and psychosocial support for families

Genetic counseling is recommended for parents, as the recurrence risk is low but not zero due to possible parental germline mosaicism.

Prognosis

The prognosis of Mowat–Wilson syndrome varies depending on the severity of associated medical problems. With proper care and early intervention, many children can achieve improved function and a better quality of life. Intellectual disability and speech delays are typically permanent, but behavioral traits such as sociability and emotional warmth are often preserved.

Factors Influencing Prognosis

• Severity of congenital anomalies (e.g., heart or gastrointestinal defects)

• Degree of developmental delay

• Presence and control of epilepsy

Life expectancy may be reduced in cases with severe congenital defects or uncontrolled seizures, but many individuals survive into adulthood. Ongoing follow-up and a coordinated care approach are essential to support the evolving needs of individuals with MWS and their families.