The Case of the Blue/Brown-Eyed Girl

Sudip D. Thakar, BSc; Kimberly G. Yen, MD


May 24, 2016


Waardenburg syndrome is an autosomal dominant homeotic genetic disorder that affects 1 in every 40,000 individuals.[5]

Waardenburg syndrome is differentiated into four different types, on the basis of its phenotypic presentation. Type I is associated with heterochromia iridis, congenital sensorineural hearing impairment, poliosis, and dystopia canthorum; type II is similar to type I, with the exception of dystopia canthorum; type III has the features of type I, with the addition of upper-limb abnormalities; and individuals with type IV have Hirschsprung disease.[6] The patient in this case had features most consistent with type I; types I and II are the most common types.[4]

The diagnostic criteria for Waardenburg syndrome type I were established by the Waardenburg Consortium and require that the patient meet either two major criteria, or one major criterion and two minor criteria[7]:

  • Major criteria

    • Congenital sensorineural hearing loss

    • White forelock, hair hypopigmentation

    • Pigmentation abnormality of the iris

      • Complete heterochromia iridis

      • Partial/segmental heterochromia

      • Hypoplastic blue irides or brilliant blue irides

    • Dystopia canthorum

    • Affected first-degree relative

  • Minor criteria

    • Skin hypopigmentation

    • Synophrys/medial eyebrow flare

    • Broad/high nasal root, prominent columella

    • Hypoplastic alae nasi

    • Premature gray hair (before age 30 years)

Of patients with type I disease, 60% will present with significant hearing loss either unilaterally or bilaterally.[8] Poliosis is present in approximately 33% of cases and typically presents in the mid-forehead region.[4] Hypoplastic irides are present in 10% of cases, whereas heterochromia (segmental or complete) are present in 30%.[4] Choroidal hypopigmentation also has been described in the literature.[9] Visual acuity is generally not affected. Other occasional or rare findings include cleft lip and palate, spina bifida, or vestibular symptoms.[8]

The PAX3 gene is the most frequently implicated gene in Waardenburg syndrome type I and has a high penetrance.[8] This homeotic gene encodes for regulatory proteins and transcription factors that contribute to cell proliferation and differentiation during embryonic development, thus giving rise to the unique set of tissues that are affected.[4]

Genetic counseling should be provided to affected individuals, because children have a 50% chance of inheriting the autosomal dominant trait from a parent.

In patients with hearing loss, cochlear implants and auditory habilitation also should be considered, because they have been shown to improve hearing.[10]

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