Diagnosis: Mowat-Wilson syndrome

Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may present at birth or later in childhood. It is characterized by intellectual disability, distinctive facial features, and seizures. Some affected individuals also have additional congenital anomalies, which may include Hirschsprung disease (present in 40–50% of individuals), a gastrointestinal condition involving narrowing of part of the large intestine. Other possible findings include ocular abnormalities, congenital heart defects, kidney abnormalities, malformations of the male genitalia, and short stature. Some individuals may only be diagnosed in later childhood or adulthood, especially if Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene, usually resulting from a de novo genetic change in the affected individual.

Diagnosis:
MWS is an autosomal dominant genetic disorder caused by a mutation in the ZEB2 gene, which usually leads to loss of function (most commonly) or reduced function (rarely) of this gene. The ZEB2 gene (formerly ZFHX1B or SIP1) is located on chromosome 2 at region 2q22.3. Genes provide instructions for producing a protein that plays a crucial role in the development of many organs and tissues before birth. When a mutation occurs in one copy of this gene, the resulting protein may be defective, ineffective, or absent. This affects the development of multiple organs and tissues throughout the body, particularly the brain. MWS almost always occurs as a new (sporadic or de novo) mutation, meaning the mutation arises in the egg or sperm and is not inherited from a parent.

In a very small number of families, more than one child has been affected. Among more than 300 reported individuals, recurrence has been described in only 5 families. The recurrence risk for parents of an affected child is therefore approximately 2% or less, usually due to germline mosaicism, where some reproductive cells carry the mutation.

Dominant genetic disorders occur when only one copy of an abnormal gene is sufficient for the disease to appear. Due to the severity of the condition, it is unlikely that affected individuals will have children of their own, and no individuals with reproductive capability and MWS have been reported. If an affected individual were to reproduce, there would be a 50% chance with each pregnancy of having an affected child.

MWS affects both males and females. It is estimated to occur in 1 in 50,000–100,000 births. MWS has been described in many different countries and ethnic groups worldwide.

MWS is usually diagnosed in childhood based on a detailed clinical evaluation, identification of characteristic physical features and facial appearance, and results from various specialized tests. Many of these features become more pronounced over time, making diagnosis easier in older individuals.

Evaluation of organ involvement may include imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, kidneys, or heart.

Clinical diagnosis can be confirmed by molecular genetic testing for mutations in the ZEB2 gene. Standard chromosome analysis may also be performed in MWS to exclude chromosomal rearrangements involving region 2q22, which are rare.

Symptoms:
Children with MWS achieve developmental milestones (such as sitting, crawling, and walking) significantly later than average. Speech is often delayed or absent, with few exceptions (mild Mowat-Wilson syndrome). Comprehension is usually better than expressive speech, and children may communicate using nonverbal methods such as signing or communication devices. They typically exhibit a happy demeanor and frequently smile.

Seizures are common, occurring in approximately 90% of individuals by the age of 10. In childhood, seizures may be difficult to control, but in adulthood they are usually not the main problem. A small subgroup of individuals will develop electrical status epilepticus during sleep (ESES), which may lead to loss of certain developmental and physical abilities if it persists without treatment.

Although infants with MWS may present with a variety of congenital abnormalities, it is important to note that affected children do not exhibit all anomalies associated with the condition. One common congenital abnormality is Hirschsprung disease, a gastrointestinal disorder characterized by the absence of certain nerve cells (ganglia) in the smooth muscle wall of part of the large intestine (colon). As a result, there is a lack or disruption of involuntary rhythmic contractions that move food through the gastrointestinal tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, abdominal bloating or distension, abnormal accumulation of stool in the colon, and enlargement of the colon above the affected segment (megacolon). Hirschsprung disease may ultimately lead to diarrhea, dehydration, and failure to thrive. Short stature is common in MWS, although some individuals have normal height.

A rare finding is absence of the spleen, an organ that helps fight certain types of infections. All individuals with MWS should be evaluated at diagnosis to determine whether the spleen is present, which can be done using abdominal ultrasound. Blood tests may also sometimes indicate splenic absence.

A subgroup of individuals with MWS has been identified who present with mild symptoms. This group may have no malformations or only subtle facial features, which can make diagnosis based solely on physical findings difficult. Such individuals may have only mild intellectual disability. Speech abilities are more advanced, and some are able to speak in short sentences from early childhood.

Treatment:
Treatment is symptomatic and should be tailored to the needs of each individual. A multidisciplinary team of specialists may be required to plan the best strategy to help each person achieve their full potential. As every individual is different, the treatment plan will be unique and is best discussed with the healthcare professionals involved in care.

In MWS, associated conditions—including Hirschsprung disease, cardiac abnormalities, and seizures—require intervention from appropriate specialists such as neurologists, cardiologists, and surgeons. Physical therapy, occupational therapy, and speech therapy can be helpful in supporting children with developmental delay to reach their full potential.

Treatment of Hirschsprung disease usually involves surgical intervention to relieve intestinal obstruction. A temporary opening of the colon is created in the abdominal wall (colostomy), followed by a second operation later to remove the non-functioning segment of the colon and reconnect the healthy parts of the intestine. Additional surgeries may be performed to treat specific congenital anomalies such as heart defects and urinary tract abnormalities.

In some cases, seizures were resistant to treatment in childhood but appear to become easier to manage in adolescence and adulthood. It is rare for individuals with MWS to experience regression of cognitive or motor skills. However, a subgroup with regression had electrical status epilepticus during sleep (ESES), which, after treatment, led to improvement of lost skills.

In individuals without a functional spleen, specific vaccinations may be considered, and sometimes daily antibiotic prophylaxis is used.

Genetic counseling is recommended for individuals with MWS as well as their families.

Mowat-Wilson syndrome

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