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Waardenburg syndrome (WS) is a disorder characterized by varying degrees of deafness and minor defects in structures arising from neural crest, including pigmentation anomalies of eyes, hair, and skin. WS is classified into four clinical and genetic phenotypes.
The worldwide incidence is estimated at around 1/40,000. Waardenburg syndrome type 1 (WS1) and type 2 (WS2) are the most common types of Waardenburg syndrome. Waardenburg syndrome type3 (WS3) and type 4 (WS4; see these terms) are rarer, with only a few cases of WS3 described worldwide so far. WS accounts for about 3% of all institutionalized cases of congenital hearing loss.
Clinical manifestations vary within and between families. Frequent clinical manifestations include congenital sensorineural deafness, heterochromic or hypoplastic blue irides, white forelock or early graying of the scalp hair before the age of 30 years. All these manifestations, along with a suggestive family history are major criteria, as is dystopia canthorum in WS1 and WS3. Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella and hypoplastic alae nasi. WS is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria (early graying of the hair is considered either a major or minor criteria depending of the WS type). WS1 combines these criteria with dystopia canthorum. The absence of dystopia canthorum clinically differentiates WS2 from WS1, whereas WS3 is similar to WS1, but additionally includes upper limb abnormalities. WS4 is characterized as WS2 with added characteristics of Hirschsprung disease.
WS is genetically heterogeneous. To date, mutations in 6 different genes have been identified: PAX3 (2q36.1), MITF (3p14-p13), SNAI2 (8q11.21), SOX10 (22q13.1), EDNRB (13q22.3), and EDN3 (20q13.32). Mutations in PAX3 gene are associated with WS1 and WS3, while MITF gene is mutated in cases of WS2. Dysgenic inheritance of MITF mutation in combination with a TYR mutation (and/or the TYRR402Q hypomorphic allele) has been reported in two families with WS2 and ocular albinism (see this term). Homozygous SNAI2 deletions have been described in two WS2 patients. SOX10 mutations are found in WS4 and WS2 affected patients. Mutations in EDNRB and EDN3 genes have also been reported in WS4.