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Genetics of Waardenburg Syndrome

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Mar 17, 2015
 

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 r Marked facial asymmetry, lagophthalmos, drooping right corner of mouth. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
Visage in profile demonstrates absence of nasofron 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 Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
Brother and sister with Waardenburg syndrome. Imag Brother and sister with Waardenburg syndrome. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.

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.

WS, which is believed to account for 2-5% of patients with congenital hearing loss, has an estimated prevalence of 1 in 42,000 persons (or 0.24 per 10,000 persons). The actual prevalence, however, may be as high as 1.19-2.08 per 10,000 persons.[3]

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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.[4]

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.[5] Therefore, mutations in the PAX3 gene could affect regulation of the MITF gene, leading to abnormalities of melanocyte differentiation. A recent work identified 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF.[6] Sequencing and copy number analysis of both PAX3 and MITF should be considered as part of the routine molecular diagnostic evaluation of these patients.

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.[7] 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, which has been studied with a zebrafish model,[8] 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.[9]

Heterozygous mutations in the SOX10 gene also reportedly cause WS4.[10] 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, WS, and Hirschsprung disease.[11] Chronic constipation in WS may also represent a SOX10 mutation.[12]

Associated abnormalities

Microdeletions or contiguous gene defects may be involved in the pathogenesis of other malformations associated with this syndrome.[13]

Waardenburg anophthalmia syndrome has also been described in children with a homozygous mutation in the SPARC -related modular calcium-binding protein 1 gene (SMOC1).[14]

Mutations in the genes PAX3 and MITF have been described in WS, which is clinically characterized by congenital hearing loss and pigmentation anomalies.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Erawati V Bawle, MD, FAAP, FACMG Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Sergiusz Jozwiak, MD, PhD Professor and Head of Pediatric Neurology, Warsaw Medical University, Poland

Sergiusz Jozwiak, MD, PhD is a member of the following medical societies: Sigma Xi

Disclosure: Received honoraria from Novartis for speaking and teaching.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

Lynn Bason, MS Genetic Counselor, Department of Clinical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia

Lynn Bason, MS is a member of the following medical societies: American College of Medical Genetics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Ian Krantz, MD Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia

Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD Clinical Professor, Department of Pediatrics, University of South Carolina School of Medicine; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. 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.

  2. Arias S. Genetic heterogeneity in the Waardenburg syndrome. Birth Defects Orig Artic Ser. 1971 Mar. 07(4):87-101. [Medline].

  3. Zaman A, Capper R, Baddoo W. Waardenburg syndrome: more common than you think!. Clin Otolaryngol. 2014 Sep 9. [Medline].

  4. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010 Apr. 31(4):391-406. [Medline].

  5. Watanabe A, Takeda K, Ploplis B, Tachibana M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nat Genet. 1998 Mar. 18(3):283-6. [Medline].

  6. Wildhardt G, Zirn B, Graul-Neumann LM, Wechtenbruch J, Suckfüll M, Buske A, et al. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. BMJ Open. 2013. 3(3):[Medline].

  7. 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). 2007 Jan 5. 120(1):46-9. [Medline].

  8. 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. 2009 Jan-Feb. 2(1-2):68-83. [Medline]. [Full Text].

  9. Sangkhathat S, Chiengkriwate P, Kusafuka T, Patrapinyokul S, Fukuzawa M. Novel mutation of Endothelin-B receptor gene in Waardenburg-Hirschsprung disease. Pediatr Surg Int. 2005 Dec. 21(12):960-3. [Medline].

  10. Fernandez RM, Nunez-Ramos R, Enguix-Riego MV, et al. Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain. Am J Med Genet A. 2014 Feb. 164A(2):542-7. [Medline].

  11. 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. 2006 Jan. 10(1):11-7. [Medline].

  12. Arimoto Y, Namba K, Nakano A, et al. Chronic constipation recognized as a sign of a SOX10 mutation in a patient with Waardenburg syndrome. Gene. 2014 May 1. 540(2):258-62. [Medline].

  13. Wu HT, Wainwright H, Beighton P. Tetraphocomelia with the Waardenburg syndrome and multiple malformations. Clin Dysmorphol. 2009 Apr. 18(2):112-5. [Medline].

  14. 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. 2011 Jan 7. 88(1):92-8. [Medline]. [Full Text].

 
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Marked facial asymmetry, lagophthalmos, drooping right corner of mouth. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, 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 Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
Brother and sister with Waardenburg syndrome. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
 
 
 
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