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Key Points

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  • Disease summary:

    • Waardenburg syndrome types 1 to 4 are a group of auditory-pigmentary syndromes that comprise sensorineural hearing loss (due to the absence of melanocytes in the stria vascularis of the cochlea), and hypomelanosis of the eyes, hair, and/or skin.

    • Since Waardenburg syndrome types 1 to 4 are disorders related to neural crest cells and their derivatives, they are considered to be neurocristopathies.

  • Hereditary basis:

    • Waardenburg syndrome is one of the most common syndromic causes of hearing loss and accounts for approximately 2% to 5% of all congenital sensorineural hearing loss.

    • Waardenburg syndrome demonstrates both inter- and intrafamilial variable expressivity, as well as locus and allelic heterogeneity.

    • Waardenburg syndrome type 1 (WS1), Waardenburg syndrome type 2 (WS2), and Waardenburg syndrome type 3 (WS3) are transmitted in an autosomal dominant manner, while Waardenburg syndrome type 4 (WS4) is inherited either as an autosomal recessive condition, with mutations within the endothelin-3 (EDN3) or endothelin-B receptor (EDNRB) genes, or as an autosomal dominant condition with heterozygous mutations within the SRY-related HMG-box 10 (SOX10) gene.

  • Differential diagnosis:

    • Well over 400 genetic syndromes that include hearing loss have been described. While nonsyndromic hearing loss accounts for the vast majority of hearing loss, syndromic hearing impairment is thought to account for up to 30% of prelingual deafness.

    • Piebaldism [MIM 172800] is an autosomal dominant condition that has a clinical phenotype similar to that of Waardenburg syndrome. A white forelock is commonly seen along with absent pigmentation of the medial forehead, eyebrows, chest, abdomen, and limbs. A characteristic feature is hyperpigmented borders surrounding the hypopigmented areas. In contrast to Waardenburg syndrome, hearing loss is not characteristic of this syndrome.

    • Tietze syndrome [MIM 103500] is an autosomal dominant condition characterized by congenital hearing loss and uniform hypopigmentation. Tietze syndrome is allelic to WS2 with heterozygous mutations within the MITF gene described in affected individuals. In contrast to WS2, the Tietze phenotype does not include heterochromia.

    • Craniofacial-deafness-hand syndrome [MIM 122880] is an autosomal dominant condition with characteristic facial features, profound sensorineural hearing loss, and radiologic abnormalities of the maxilla, nasal bones, and hands. This condition is also allelic to WS1 and WS3 with a heterozygous mutation within the PAX3 gene described in an affected individual.

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic Criteria for Waardenburg Syndrome Type 1 (as proposed by the Waardenburg Consortium)

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An individual must have two major criteria or one major and two minor criteria:

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  • Major criteria

    • Congenital sensorineural hearing loss

    • Hair hypopigmentation

      • White forelock

      • White hairs within eyebrow, eyelashes

    • Pigmentation abnormality of the iris

      • Complete heterochromia iridum (irides of different color)

      • Partial or segmental heterochromia (two different colors in same iris, typically brown and blue)

      • Hypoplastic blue irides, or brilliant blue (sapphire) irides

    • Dystopia canthorum: W index >1.95∗

    • First-degree relative (parent, sibling, or offspring) with WS1 as defined by the above criteria

  • Minor criteria

    • Skin hypopigmentation (congenital ...

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