In 1998 Mowat and Wilson described a new syndrome with a developmental disorder, microcephaly and characteristic features in combination with Hirschsprung’s disease.
Characteristic external features of MWS, some of which become more pronounced with age, include high forehead with accentuated frontal humps, raised earlobes with a central dent, diffuse medially sparse eyebrows, deep-set eyes, wide interocular distance, broad nasal root, rounded nasal tip with prominent columella, M-shaped upper lip, accentuated pointed chin, soft tissue fullness of the neck, slender long fingers. Most of the affected individuals develop microcephaly, half of them have a final height below the 3rd percentile. About 80% have epilepsy which usually manifests 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 a proven Hirschsprung’s disease, another part has a chronic constipation.
In most cases, a severe global developmental disorder is present. On average, the affected children learn to walk between the ages of 4 and 6. The gait pattern often remains broad-based with raised bent arms. Speech development is severely impaired to absent with many affected individuals knowing only a few words. The children are often described as cheerful with frequent laughter.
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 which may explain the frequent occurrence of Hirschsprung’s 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 was detected in one parent.
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