Genetics of Waardenburg Syndrome
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Bruce Buehler, MD more...
Overview
Waardenburg syndrome (WS) is named after the Dutch ophthalmologist Petrus Johannes Waardenburg, who, in 1947, first described a patient with hearing loss, dystopia canthorum (ie, lateral displacement of the inner canthi of the eyes), and retinal pigmentary differences. In 1951, after identifying other patients with similar symptoms, Waardenburg defined the syndrome now classified as WS type 1 (WS1).[1] Findings in WS1 include hearing loss, dystopia canthorum, and pigmentary abnormalities of the hair, skin, and eyes (see the images below).
Marked facial asymmetry, lagophthalmos, drooping right corner of mouth. Image courtesy of Quadrant Health, Inc. 
Visage in profile demonstrates absence of nasofrontal angle, eyebrow hypertrichosis, upturned nasal tip, and shortened upper lip with pronounced cupid's bow. Image courtesy of Quadrant Health, Inc. 
Brother and sister with Waardenburg syndrome. In 1971, Arias defined the phenotype of WS type 2 (WS2), which includes all of the WS1 features except dystopia canthorum.[2] Both WS1 and WS2 are transmitted as autosomal dominant conditions with interfamilial and intrafamilial variability.
Two far rarer variant forms of WS have also been identified. WS type 3 (WS3), or Klein-Waardenburg syndrome, includes features of WS in association with severe contractures. WS type 4 (WS4), or Waardenburg-Shah syndrome, has features of WS in association with Hirschsprung disease. WS4 is a heterogeneous disorder with either autosomal recessive or autosomal dominant inheritance.
Pathophysiology
Both the auditory and the pigmentary abnormalities of Waardenburg syndrome (WS) can be explained by a failure of proper melanocyte differentiation. Melanocytes are required in the stria vascularis for normal cochlear function. With the exception of those in the retina, melanocytes are derived from the embryonic neural crest. Other tissues derived from the neural crest that are involved in WS1 and the rarer WS3 and WS4 variants include the frontal bone, limb muscles, and enteric ganglia.
Gene Mutations
Mutations in multiple genes cause the various forms of Waardenburg syndrome (WS). The 6 genes involved in WS are PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies.[3]
Evidence suggests that the MITF gene transactivates the tyrosinase gene, which is involved in melanocyte differentiation. PAX3 belongs to a family of paired-domain proteins that bind DNA and regulate gene expression; its molecular mechanism remains unclear. A study by Watanabe et al showed that PAX3 transactivates the MITF promoter.[4] Therefore, mutations in the PAX3 gene could affect regulation of the MITF gene, leading to abnormalities of melanocyte differentiation.
Waardenburg syndrome type 1
Most, if not all, cases of WS1 are caused by mutations in the PAX3 gene located on chromosome band 2q35. Deletions, frame shifts, splice site, and nonsense mutations, as well as whole gene deletions, have been reported. WS1 may be inherited in an autosomal dominant pattern or may be the result of a de novo mutation.
Two nonsense PAX3 mutations were identified in Chinese patients with WS1. One is heterozygous for a novel nonsense mutation, S209X, and the other is heterozygous for a previously reported mutation in the European population, R223X.[5] Both mutations created stop codons leading to truncation of the PAX3 protein. Novel mutations of PAX3, MITF, and SOX10 genes have been described in Chinese patients with WS1 or WS2.
Waardenburg syndrome type 2
Mutations in the MITF gene, located on chromosome band 3p14.1-p12.3, cause some cases of WS2. Deletions, missense, splice site, and nonsense mutations have been reported. These mutations may be inherited in an autosomal dominant pattern or may be de novo. Other cases of WS2 have been linked to another locus on 1p21-p13.3, still others remain unlinked to either locus.
Waardenburg syndrome type 3
Mutations in PAX3 have also been found in patients with a WS3 phenotype. WS3 may be inherited as a dominant disorder. In some cases, WS3 may be a manifestation of homozygous mutations of this gene.
Waardenburg syndrome type 4
WS4 is caused by homozygous mutations in either the EDN3 gene or the EDNRB gene; heterozygous mutations in either of these genes cause isolated Hirschsprung disease. Sangkhathat et al reported that whereas homozygous mutations of EDNRB may result in WS4 and mutated heterozygotes manifest isolated Hirschsprung disease in lower penetrance, findings in a family were consistent with previous observations that the full spectrum of WS4 occurred to the mutated homozygotes.[6]
Heterozygous mutations in the SOX10 gene also reportedly cause WS4. The SOX10 gene interacts with PAX3 in regulating the MITF gene. SOX10 mutations are associated with a more severe phenotype known as PCWH, consisting of peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.[7]
A zebrafish model for WS4 has been used to study this syndrome.[8]
Associated abnormalities
Microdeletions or contiguous gene defects may be involved in the pathogenesis of other malformations associated with this syndrome.[9]
Waardenburg anophthalmia syndrome has also been described in children with a homozygous mutation in the SPARC -related modular calcium-binding protein 1 gene (SMOC1).[10]
Waardenburg PJ. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951;3:195-253.
Arias S. Genetic heterogeneity in the Waardenburg syndrome. Birth Defects Orig Artic Ser. Mar 1971;07(4):87-101. [Medline].
Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. Apr 2010;31(4):391-406. [Medline].
Watanabe A, Takeda K, Ploplis B, Tachibana M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nat Genet. Mar 1998;18(3):283-6. [Medline].
Yang SZ, Cao JY, Zhang RN, et al. Nonsense mutations in the PAX3 gene cause Waardenburg syndrome type I in two Chinese patients. Chin Med J (Engl). Jan 5 2007;120(1):46-9. [Medline].
Sangkhathat S, Chiengkriwate P, Kusafuka T, Patrapinyokul S, Fukuzawa M. Novel mutation of Endothelin-B receptor gene in Waardenburg-Hirschsprung disease. Pediatr Surg Int. Dec 2005;21(12):960-3. [Medline].
Verheij JB, Sival DA, van der Hoeven JH, et al. Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature. Eur J Paediatr Neurol. Jan 2006;10(1):11-7. [Medline].
Dutton K, Abbas L, Spencer J, et al. A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. Dis Model Mech. Jan-Feb 2009;2(1-2):68-83. [Medline]. [Full Text].
Wu HT, Wainwright H, Beighton P. Tetraphocomelia with the Waardenburg syndrome and multiple malformations. Clin Dysmorphol. Apr 2009;18(2):112-5. [Medline].
Abouzeid H, Boisset G, Favez T, et al. Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome. Am J Hum Genet. Jan 7 2011;88(1):92-8. [Medline]. [Full Text].
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