This article includes discussion of Waardenburg syndrome, WS1, WS2, WS3, Klein-Waardenburg syndrome, WS4, Shah-Waardenburg syndrome, and Waardenburg-Hirschsprung disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Waardenburg syndrome was first reported by van der Hoeve in 1916. In 1951, Waardenburg defined 6 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 4 forms. Patients with Waardenburg syndrome (WS) 1 have a characteristic pleasant feline appearance. In WS2, 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 neurosensorial deafness and other neurologic manifestations observed in WS3 and WS4 justify the inclusion of Waardenburg syndrome as a neurocutaneous syndrome. SOX10 mutations in WS4 are associated with a more severe neurologic phenotype: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). It has been demonstrated that the same deletions at the SOX10 gene locus may cause WS2 and WS4.
Historical note and terminology
Waardenburg syndrome was first reported by the Dutch ophthalmologist Jan van der Hoeve in 1916 in 2 deaf twin girls with a special type of blepharophimosis (van der Hoeve 1916). 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 (Waardenburg 1948). He mentioned the report of 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 (Klein 1947). Klein's patient also had a severe musculoskeletal involvement. In 1948, Klein showed this patient to Waardenburg, who later did a search among 1050 patients of 5 Dutch institutions for the deaf. Afterward, other ophthalmologists, including Halbertsma in 1929 and Gualdi in 1930, studied this ocular anomaly and confirmed its dominant inheritance (Klein 1983).
In 1951, Waardenburg published the first comprehensive review of this new syndrome (Waardenburg 1951) in which he fully acknowledged Van der Hoeve's initial description and subsequent publications about this syndrome. Waardenburg, defined by 6 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 (Read and Newton 1997). In 1971, Arias drew attention to these patients as a separate division of the syndrome, which he named Waardenburg syndrome type II (Arias 1971). 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 (Shah et al 1981). 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 (Sarnat and Flores-Sarnat 2005). On the other hand, Waardenburg syndrome can be considered a disease because the etiology is known.
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