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  • Updated 03.27.2023
  • Released 10.04.2003
  • Expires For CME 03.27.2026

Waardenburg syndrome



Waardenburg syndrome was first reported by van der Hoeve in 1916. In 1951, Waardenburg defined six main features: (1) dystopia canthorum, (2) prominent broad nasal root, (3) synophrys, (4) white forelock, (5) heterochromia iridis, and (6) congenital deaf-mutism. Four types of Waardenburg syndrome have now been delineated on the basis of clinical and genetic criteria. The molecular defective gene has been identified in all four forms. Patients with Waardenburg syndrome type I have a characteristic pleasant feline appearance. In Waardenburg syndrome type II, dystopia canthorum is absent. Deafness and all the facial and hypopigmentation features are due to a disturbance in the neural crest, the origin of melanocytes. The congenital anomalies plus neurosensorial deafness, neural tube defects, and other neurologic manifestations observed in Waardenburg syndrome justify its inclusion as a neurocutaneous syndrome. SOX10 mutations in Waardenburg syndrome type IV are associated with a more severe neurologic phenotype: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. It has been demonstrated that the same deletions at the SOX10 gene locus also may cause Waardenburg syndrome type II. Additional systemic findings have also subsequently been described.

Key points

• Waardenburg syndrome is a hereditary neurocristopathy that occurs in all ethnic groups, affecting mainly skin, hair, and audition.

• There are four clinical presentations of this syndrome. Waardenburg first described the syndrome. Type I is the most frequent and benign form.

• The four presentations manifest pigmentary and auditory deficits that can be identified at birth but require specific investigations and confirmation to enable early intervention and prevent further complications.

• Genetic defects have been identified in this hereditary condition in all four phenotypes. Consanguinity is frequent.

• In some instances early abdominal surgery is required, as in Waardenburg syndrome type IV with aganglionic megacolon.

Historical note and terminology

Waardenburg syndrome was first reported by the Dutch ophthalmologist Jan van der Hoeve in 1916 in two deaf twin girls with a special type of blepharophimosis (131). In December 1947, Dr. Petrus J Waardenburg, a Dutch ophthalmologist and geneticist, presented a deaf-mute man with "dystopia punctorum lacrimarum, blepharophimosis, and partial iris atrophy" to a meeting of the Dutch Ophthalmological Society (138). He acknowledged the report of the van der Hoeve twins with the same eye abnormalities who were “coincidentally” also deaf-mute. In August 1947, David Klein presented a 10-year-old girl with a severe auditory-pigmentary syndrome and dystopia canthorum to the Swiss Society of Genetics in Geneva (64). In addition, Klein’s patient had a severe musculoskeletal involvement. In 1948, Klein showed this patient to Waardenburg, who later did a search among 1050 patients of five Dutch institutions for the deaf. Other ophthalmologists who studied this ocular anomaly and confirmed its dominant inheritance were Halbertsma in 1929, cited by Waardenburg and Klein, and Gualdi in 1930 (65).

In 1951, Waardenburg published the first comprehensive review of this new syndrome (139) in which he fully acknowledged Van der Hoeve’s initial description and subsequent publications about this syndrome. Waardenburg defined six main features: (1) lateral displacement of the medial canthi combined with dystopia of the lacrimal punctum and blepharophimosis, (2) prominent broad nasal root, (3) hypertrichosis of the medial part of the eyebrows, (4) white forelock, (5) heterochromia iridis, and (6) deaf-mutism. Waardenburg characterized the syndrome as autosomal dominant with high penetrance of dystopia (159/161) but reduced penetrance of all other features.

Waardenburg observed several patients with heterochromia or isochromic hypoplastic irides but without canthus dystopia, but he did not investigate them further (104). In 1971, Arias drew attention to these patients as a separate division of the syndrome, which he named Waardenburg syndrome type II (05). Two of Waardenburg's original families had this variant, but both were small, and Waardenburg overlooked the familial "nonpenetrance" of dystopia. In 1981, Shah and colleagues described 12 infants with several characteristics of Waardenburg syndrome associated with Hirschsprung disease (108). For the congenital cutaneous lesions and the neurosensory deafness (plus other nervous system abnormalities), Waardenburg syndrome should now be included in the group of primary neurocutaneous syndromes (106). Waardenburg syndrome can be considered a disease because the etiology is known; however, it also represents a syndrome due to the constellation of clinical findings.

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