In 1998, Mowat and Wilson described a new syndrome with developmental delay, microcephaly and characteristic appearance combined with Hirschsprung’s disease.
Typical physical features of MWS, which may become more distinctive with age, are a high, prominent forehead, frontal bossing, uplifted earlobes with central depression, medially flaring eyebrows, sparse in the middle part, deep-set, widely spaced eyes, broad ridge of the nose, prominent columella, M-shaped upper lip, prominent and pointed chin, puffy anterior neck, and slim, long fingers. Most patients develop microcephaly; half of all cases have a final head circumference below the 3rd percentile. Approximately 80% suffer from epilepsy, onset is usually after the 2nd year of life. Common malformations include hypoplasia or agenesis of the corpus callosum, cardiac defects and urogential malformations, especially hypospadias. Approximately half of all patients are diagnosed with Hirschsprung’s disease; others have chronic constipation.
Most patients have a severe global developmental delay. On average, children learn to walk between the 4th and 6th year of life; gait is wide based with, the arms are held up and flexed. Speech is delayed or absent; a large number of patients speak only a few words. The children have happy personalities and smile frequently.
Regarding a differential diagnosis, the Angelman syndrome and the Pitt Hopkins syndrome should be considered among others.
The disease is caused by the haploinsufficiency of the ZEB2 gene in 2q22.3 due to mutations (nonsense or frameshift) (more than 80%) or deletions (about 15%). The gene consists of 10 exons, 9 of which are encoding (exon 2-10). ZEB2 is a transcription factor which is crucial for the formation of the neural crest and its deriving structures, explaining the frequent association with Hirschsprung’s disease.
Mutations and deletions in ZEB2 are usually de novo; therefore, the recurrence risk for siblings is low, unless one parent has a somatic or germ cell mosaicism.