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Waardenburg-Shah syndrome (WSS), also known as Waardenburg syndrome type 4 (WS4) is characterized by the association of Waardenburg syndrome (sensorineural hearing loss and pigmentary abnormalities) and Hirschsprung disease (aganglionic megacolon).
ORPHA:897Classification level: Disorder
- Shah-Waardenburg syndrome
- Waardenburg syndrome type 4
- Waardenburg-Hirschsprung syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: Neonatal
- ICD-10: Q87.8
- OMIM: 277580 613265 613266
- UMLS: C1848519 C3266898
- MeSH: -
- GARD: 5524
- MedDRA: -
Prevalence is unknown. So far, less than 100 cases have been reported in the literature worldwide.
Patients usually present in the neonatal period with pigmentary anomalies (including white forelock, eyebrows and eyelashes, heterochromia of the irides, possibly retinal pigment abnormalities and/or hypopigmented patches on the skin), neurosensory deafness (frequently bilateral, but can be unilateral) and intestinal obstruction presenting as bilious vomiting, inability to pass meconium and abdominal distension since birth. Depending on the gene involved, morphological abnormalities of the temporal bone (especially utricle and semi-circular canals), anosmia (with or without agenesis of the olfactory bulbs) and hypogonadotropic hypogonadism can be associated. ABCD syndrome is a rare variant expression of WSS, characterized by albinism, black lock, cell migration disorder of the gut neurocytes and deafness.
WSS is caused by abnormal migration or differentiation of neural crest cells during embryonic development. This syndrome is genetically heterogeneous, composed of three etiological subtypes: WS4-A, WS4-B and WS4-C, caused by mutations in the EDNRB (13q22.3, coding for the endothelin-B receptor), EDN3 (20q13.32, coding for an endothelin receptor ligand) and SOX10 (22q13.1, coding for the SOX10 transcription factor) genes, respectively. These genes are involved in melanocyte development and nerve cells development in the intestine. Heterozygous mutations in EDNRB and EDN3 are often asymptomatic although patients may also present with less severe phenotypes (isolated Hirschsprung disease, isolated deafness, less extended hypopigmentation, or Waardenburg syndrome type 2). Specific mutations in SOX10 (particularly those predicted to truncate the protein at the level of the terminal coding exons) result in a more severe WSS variant with neurologic findings (neurologic Waardenburg-Shah syndrome, also called PCWH).
Diagnosis is determined by the presence of major and minor characteristic clinical features according to the Waardenburg Consortium criteria, as well as history and physical examination for Hirschsprung disease utilizing plain abdominal X-ray, barium enema, anorectal manometry and rectal biopsy. Genetic molecular analysis confirms the diagnosis.
The differential diagnosis includes other forms of Waardenburg syndrome, piebaldism and ermine phenotype, as well as other causes of hearing loss or Hirschsprung disease.
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. SOX10 mutations are inherited in an autosomal dominant manner. EDNRB and EDN3 mutations are inherited in an autosomal recessive manner in most families but are semi-dominant in some (with the index case usually carrying bi-allelic mutations, while heterozygous affected relatives present with isolated or milder signs of the disease).
Management and treatment
Management is only symptomatic. Surgical treatment is required for Hirschsprung disease. Hearing aids are recommended to ameliorate hearing impairment, as well as to improve language, communication and cognitive skills. Associated manifestations are treated as appropriate (e.g., cosmetics to manage the pigmentation defects, sunblock and sunglasses to protect skin and eyes from the sun).
The prognosis is often good, however, significant morbidity and mortality may be associated due to complications resulting from Hirschsprung disease (related to the size of the aganglionic intestinal segment).