Waardenburg-Shah syndrome (WSS) is a neurocristopathy characterized by the association of Waardenburg syndrome (sensorineural hearing loss and pigmentary abnormalities; see this term) and Hirschsprung disease (see this term). Prevalence is unknown but over 50 cases have been reported in the literature so far. Patients present in the neonatal period with pigmentary anomalies (including white forelock, white eyebrows and eyelashes, white skin patches and pigmentary anomalies of the irides) in association with intestinal obstruction. Neurosensorial deafness is common and early, and may be unilateral. Psychomotor development is normal. WSS is caused by abnormal migration or differentiation of neural crest cells during embryonic development. Three disease-causing genes have been identified so far: EDNRB (13q22.3) encoding the endothelin-B receptor, EDN3 (20q13.32) encoding an endothelin receptor ligand and SOX10 (22q13.1) encoding the SOX10 transcription factor. Mutations in the EDNRB and EDN3 genes are inherited in an autosomal recessive manner, with individuals carrying homozygous mutations manifesting WSS and those with heterozygous mutations in either gene presenting with isolated Hirschsprung disease or often being asymptomatic. SOX10 mutations are inherited in autosomal dominant manner and specific mutations (particularly those involving the 2 terminal coding exons) appear to result in a more severe WSS variant with neurologic findings characterized by peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH; see this term). Conversely, some patients with type 2 Waardenburg syndrome (Waardenburg syndrome without Hirschsprung disease; see this term) are carriers of heterozygous SOX10 mutations. No mutations in any of the three disease-causing genes are detected in between 20 and 40% of WSS/PCWH patients. Diagnosis is based on recognition of the clinical picture and can be confirmed by identification of a mutation in one of the disease-causing genes. The differential diagnosis should include other forms of Waardenburg syndrome (types 1, 2 and 3; see these terms), as well as other rare disorders such as piebaldism and the ABCD or BADS syndromes (also associated with mutations in the EDNRB gene; see these terms). Molecular prenatal diagnosis may be proposed to families in which the disease-causing mutation has been identified. Genetic counseling should be adapted according to the mode of inheritance associated with the detected mutation. Management is symptomatic only and should include surgical treatment for Hirschsprung disease and supportive management of the hearing impairment. The prognosis is often good but significant morbidity and mortality may be associated with this syndrome due to complications of Hirschsprung disease (related to the size of the aganglionic intestinal segment).
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