Scientific background
In 1998 Mowat and Wilson described a new syndrome with a developmental disorder, microcephaly and characteristic external features in combination with Hirschsprung disease.
Characteristic external features of Mowat-Wilson syndrome (MWS), some of which become more pronounced with age, include high forehead with frontal bossing; uplifted earlobes with a central depression; diffuse, medially sparse eyebrows; widely-spaced, deep-set eyes; a broad nasal root; rounded nasal tip with prominent columella; M-shaped upper lip; a prominent, pointed chin; excess soft tissue of the neck; and long, slender fingers. Most of the affected individuals develop microcephaly and half of them have a final height below the 3rd percentile. About 80% have epilepsy which usually starts at the age of 2. Malformations include hypoplasia or agenesis of the corpus callosum, heart defects, and genitourinary malformations, especially hypospadias. About half of the patients have proven Hirschsprung disease, and a further portion have a chronic constipation.
In most cases, there is a severe global developmental disorder. On average, the affected children learn to walk between the ages of 4 and 6. The gait pattern often remains wide-based with raised, bent arms. Speech development is severely impaired or absent, with many affected individuals knowing only a few words. The children are often described as cheerful and laughing frequently.
Differential diagnoses include Angelman syndrome and Pitt-Hopkins syndrome.
The disease is caused by haploinsufficiency of the ZEB2 gene in 2q22.3 due to pathogenic variants (nonsense or frameshift) (over 80%) or deletions (about 15%). The ZEB2 protein is a transcription factor that is important for the development of the neural crest and its derived structures; this may explain the frequent occurrence of Hirschsprung disease.
Since pathogenic variants in the ZEB2 gene usually occur de novo, the recurrence risk for siblings is low unless a somatic or germ cell mosaic has been detected in one parent.
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
