Mowat-Wilson syndrome (MWS) is characterized by developmental disorders, microcephaly, and distinctive physical features, often in association with Hirschsprung's disease. External characteristics include a high forehead, distinctive ears and eyes, and a specific facial profile. Most affected individuals show delayed development, with language acquisition being severely impaired. The syndrome is caused by haploinsufficiency of the ZEB2 gene.
Symptoms
In 1998 Mowat and Wilson described a new syndrome with a developmental disorder, microcephaly and characteristic external features in combination with Hirschsprung's disease.
Typical external features of MWS, some of which become more pronounced with age, include:
- A high forehead with prominent brow ridges
- Elevated earlobes with a central dimple
- Diffuse, medially sparse eyebrows
- Widely-spaced, deep-set eyes
- Broad nasal bridge
- Rounded nasal tip with prominent columella
- M-shaped upper lip
- Pronounced; pointed chin
- Excess soft tissue at the neck
- Long, slender fingers
Most affected individuals develop microcephaly, with half reaching a final height below the 3rd percentile. Approximately 80% have epilepsy, which usually begins at the age of 2.
Malformations mainly include hypoplasia or agenesis of the corpus callosum, heart defects, and urogenital malformations, especially hypospadias. About half of the patients have a confirmed Hirschsprung's disease, and another portion has chronic constipation.
In most cases, there is a severe global developmental disorder. On average, affected children learn to walk between the ages of 4 and 6, and their gait often remains wide-based with raised, bent arms. Language acquisition is severely impaired or absent, with many affected individuals knowing only a few words. The children are often described as cheerful and laughing frequently.
Causes
The disease is caused by haploinsufficiency of the ZEB2 gene in 2q22.3 due to pathogenic variants (nonsense or frameshift) (over 80%) or deletions (around 15%). The ZEB2 protein is a transcription factor that is important for the development of the neural crest and the structures derived from it; this may explain the frequent occurrence of Hirschsprung's disease.
Since pathogenic variants in the ZEB2 gene usually occur de novo, the risk of recurrence for siblings is low, unless a somatic or germline mosaic has been detected in one of the parents.
Differential diagnosis
Differential diagnoses include Angelman syndrome and Pitt-Hopkins syndrome.
References
Ivanovski et al. 2018, Genet Med 20:965 / Kilic et al. 2016, J Child Neurol 31:913 / Evans et al. 2012, Am J Med Genet 158A:358 / Garavelli et al. 2009, Am J Med Genet 149A:417 / Adam et al. 2007 Mar 28 [Updated 2019 Jul 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021 / Zweier et al. 2005, Eur J Med Genet 48:97 / Wilson et al. 2003, Am J Med Gent 119A:257 / Mowat et al. 2003, J Med Genet 40:305 / Zweier et al. 2002, Am J Med Genet 108:177
