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Dermatologic Manifestations of Waardenburg Syndrome

  • Author: Lyubomir A Dourmishev, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Feb 10, 2016
 

Background

Waardenburg syndrome is a rare disease characterized by deafness in association with pigmentary anomalies and defects of neural crest-derived tissues.

Hammerschlag, in 1907, and Urbantschitsch, in 1910, both mentioned heterochromia iridium and partial albinism as occurring as complications of deafmutism. In 1916, van der Hoeve described a dystopia canthi medialis lateroversa in a pair of monozygotic twin girls with deafmutism. In 1951, Waardenburg[1] defined the syndrome with the following 6 main features:

  • Lateral displacement of the medial canthi combined with dystopia of the lacrimal puncta and blepharophimosis
  • Prominent broad nasal root
  • Hypertrichosis of the medial part of the eyebrows
  • White forelock
  • Heterochromia iridis
  • Deafmutism

In 1947, Klein reported a case of a 10-year-old girl with deafmutism, partial albinism of the skin and hair, hypochromia iridis, blepharophimosis with hypertelorism and absence of the nasofrontal angle, hypertrichosis of the eyebrows, and multiple associated abnormalities (myo-osteo-articulare dysplasia).

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Pathophysiology

Waardenburg syndrome is a rare disease with an autosomal dominant mode of inheritance. Several hypotheses, including the following, have been advanced to explain all the clinical features of the syndrome:

  • The deficient neural crest theory, suggesting a developmental abnormality of the neural crest as a cause of the disease: The association of Waardenburg syndrome and congenital aganglionic megacolon supports this hypothesis.
  • Waardenburg syndrome as a part of the first arch syndrome
  • A relationship of Waardenburg syndrome with status dysraphicus
  • The intrauterine necrosis theory

None of these possibilities explains all the features of Waardenburg syndrome. Inherited causes account for approximately 50% of individuals seen for childhood (prelingual) hearing loss, of which 70% are due to mutations in numerous single genes that impair auditory function alone (nonsyndromic). The remainder are associated with other developmental anomalies termed syndromic deafness.

Genes responsible for syndromic forms of hearing loss in Waardenburg syndrome include PAX3 on band 2q37, observed in types I and III, and MITF mapped on 3p12-p 14.1 for type II.[2, 3, 4] Waardenburg syndrome is autosomal dominant for most persons with types I, II, or III. Waardenburg syndrome type IV is autosomal recessive with variable penetrance and is due to SOX10 or endothelin-B receptor (EDNRB) gene mutations, which appear to correlate with the intestinal and/or neurological symptoms manifested in patients.[5, 6, 7, 8, 9, 10, 11]

Sznajer et al[12] described a novel SOX10 splice site mutation (c.698-2A > C) that resulted in severe type 4 Waardenburg syndrome without Hirschsprung disease. The child presented with vivid blue eye, mental retardation, synophrys, deafness, bilateral complete semicircular canals, and peripheral neuropathy.

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Epidemiology

Frequency

The frequency of Waardenburg syndrome is estimated to be 1 case per 212,000 persons in the general population of the Netherlands, but owing to a low penetrance of about 20%, the frequency of the entire syndrome (with or without deafness) is probably approximately 1 case per 42,000 persons. In Kenya, the estimated frequency is 1 case per 20,000 persons. The syndrome has been observed in 0.9-2.8% of persons with deafmutism.[13]

Race

Waardenburg syndrome affects people of all races worldwide.

Sex

The disease affects both sexes equally. No sex differences among persons with congenital deafmutism have been found.

Age

As an inheritable disease, Waardenburg syndrome can be recognized immediately or soon after birth. Some dermatologic features (eg, poliosis) change with age.

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Prognosis

Children with Waardenburg syndrome have a normal life expectancy. Morbidity is related to deafness and to defects of neural crest-derived tissues, including mental retardation, seizures, psychiatric disorders, skeletal anomalies, and eye disorders (including cataracts).

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Contributor Information and Disclosures
Author

Lyubomir A Dourmishev, MD, PhD Associate Professor, Department of Dermatology and Venereology, Medical University of Sofia, Bulgaria

Lyubomir A Dourmishev, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

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.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Albert C Yan, MD Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine

Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology, Society for Pediatric Dermatology, American Academy of Pediatrics

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 Sep. 3(3):195-253. [Medline].

  2. Tachibana M. Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A. Pigment Cell Res. 1997 Feb-Apr. 10(1-2):25-33. [Medline].

  3. 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. 18;3(3):[Medline].

  4. Zhang H, Luo H, Chen H, Mei L, He C, Jiang L, et al. Functionalanalysis of MITF gene mutations associated with Waardenburg syndrome type 2. FEBS. 30;586(23). 2012:4126-31. [Medline].

  5. Bondurand N, Pingault V, Goerich DE, et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000 Aug 12. 9(13):1907-17. [Medline].

  6. Chan KK, Wong CK, Lui VC, Tam PK, Sham MH. Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation. J Cell Biochem. 2003 Oct 15. 90(3):573-85. [Medline].

  7. DeStefano AL, Cupples LA, Arnos KS, et al. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet. 1998 May. 102(5):499-506. [Medline].

  8. Dundar M, Lowther G, Colgan J, et al. A case with Waardenburg syndrome presenting with two separate translocations--one reciprocal and one complex. Clin Dysmorphol. 2001 Jan. 10(1):65-6. [Medline].

  9. Morell R, Carey ML, Lalwani AK, Friedman TB, Asher JH Jr. Three mutations in the paired homeodomain of PAX3 that cause Waardenburg syndrome type 1. Hum Hered. 1997 Jan-Feb. 47(1):38-41. [Medline].

  10. Jung HJ, Jin SA, Choi SJ, Lee SC, Yun SJ. A de novo SOX10 mutation in apatient with Waardenburg syndrome type IV. J Am Acad Dermatol. 2013. 68(6):[Medline].

  11. Oshimo T, Fukai K, Abe Y, Hozumi Y, Yokoi T, Tanaka A, et al. Pediatric case report: clinical profile of a patient with PCWH withp.Q377X nonsense mutation in the SOX10 gene. J Dermatol. 2012. 39(12):1022-5. [Medline].

  12. Sznajer Y, Coldea C, Meire F, Delpierre I, Sekhara T, Touraine RL. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease. Am J Med Genet A. 2008 Apr 15. 146A(8):1038-41. [Medline].

  13. Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. Waardenburg syndrome. Int J Dermatol. 1999 Sep. 38(9):656-63. [Medline].

  14. Oysu C, Baserer N, Tinaz M. Audiometric manifestations of Waardenburg's syndrome. Ear Nose Throat J. 2000 Sep. 79(9):704-9. [Medline].

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  16. Shim WK, Derieg M, Powell BR, Hsia YE. Near-total intestinal aganglionosis in the Waardenburg-Shah syndrome. J Pediatr Surg. 1999 Dec. 34(12):1853-5. [Medline].

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  18. 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].

  19. Madden C, Halsted MJ, Hopkin RJ, Choo DI, Benton C, Greinwald JH Jr. Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope. 2003 Nov. 113(11):2035-41. [Medline].

  20. Chang T, Hashimoto K, Bawle EV. Spontaneous contraction of leukodermic patches in Waardenburg syndrome. J Dermatol. 1993 Nov. 20(11):707-11. [Medline].

  21. Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. Waardenburg's syndrome with facial palsy and lingua plicata: is that a new type of disease?. Cutis. 1999 Mar. 63(3):139-41. [Medline].

  22. Webb KM, Smith AJ, Dansby LM, Diskin CJ. Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?. Ther Apher Dial. 2015 Jun. 19(3):296-8. [Medline].

  23. Galasso C, Bombardieri R, Cerminara C, Stranci G, Curatolo P. Anophthalmia-Waardenburg syndrome with expanding phenotype: does neural crest play a role?. J Child Neurol. 2007 Nov. 22(11):1252-5. [Medline].

  24. Milunsky JM, Maher TA, Ito M, Milunsky A. The value of MLPA in Waardenburg syndrome. Genet Test. 2007 Summer. 11(2):179-82. [Medline].

  25. Broomfield SJ, Bruce IA, Henderson L, Ramsden RT, Green KM. Cochlear implantation in children with syndromic deafness. Int J Pediatr Otorhinolaryngol. 2013 Aug. 77 (8):1312-6. [Medline]. [Full Text].

 
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Marked facial asymmetry, lagophthalmos, a drooping right corner of the 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 a 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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