Mowat-Wilson syndrome (MWS) is an MCA-MR condition first delineated among the heterogeneous group of patients with Hirschsprung disease and mental retardation (MR).
The condition is associated with microcephaly, epilepsy, a facial gestalt and severe mental retardation. The spectrum of possibly associated malformations is wide and encompasses, in decreasing frequency order, hypospadias, renal anomalies, congenital cardiac defect, agenesis/hypoplasia of the corpus callosum and Hirschsprung disease.
Synopsis
Hirschsprung disease
distinct facial appearance
microcephaly
agenesis of the corpus callosum
mental retardation
Etiology
germline mutations in the ZFHX1B gene coding for zinc finger homeo box 1 B protein (14681759)
Heterozygous de novo deletions encompassing the ZFHX1B (zinc finger homeo box 1B) gene or truncating mutations within the gene are found in over 100 cases.
Some rare splicing and missense mutations have also been reported. Loss of function by haploinsufficiency is the disease causing mechanism in humans.
ZFHX1B acts as a transcriptional repressor of smad protein targets and has key functions in early embryonic development in several animal models. A knock-out restricted to NCC precursors in mice demonstrated a wide range of anomalies in NCC derivatives.
References
Garavelli L, Mainardi PC. Mowat-Wilson syndrome. Orphanet J Rare Dis. 2007 Oct 24;2:42. PMID: 17958891