eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Waardenburg Syndrome

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Sergiusz Jozwiak, MD, PhD, Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland; Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Mar 30, 2009

Introduction

Background

Waardenburg syndrome (WS) is named after the Dutch ophthalmologist 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 Waardenburg syndrome type 1 (WS1).¹ Findings in WS1 include hearing loss, dystopia canthorum, and pigmentary abnormalities of the hair, skin, and eyes.

Two far rarer variant forms of Waardenburg syndrome have also been identified. Waardenburg syndrome type 3 (WS3), or Klein-Waardenburg syndrome, includes features of Waardenburg syndrome in association with severe contractures. Waardenburg syndrome type 4 (WS4), or Waardenburg-Shah syndrome, has features of Waardenburg syndrome 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 could 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. Mutations in multiple genes cause the various forms of Waardenburg syndrome.

Most, if not all, cases of WS1 are caused by mutations in the PAX3 gene located on chromosome band 2q35. Mutations in PAX3 have also been found in patients with a WS3 phenotype. PAX3 belongs to a family of paired-domain proteins that bind DNA and regulate gene expression. Mutations in the microphthalmia-associated transcription factor (MITF) gene, located on chromosome band 3p14.1-p12.3, cause some cases of WS2. Other cases of WS2 have been linked to another locus on band 1p; still others remain unlinked to either locus.

Evidence suggests that the MITF gene transactivates the tyrosinase gene, which is involved in melanocyte differentiation. The molecular mechanism of the PAX3 gene remains unclear. A study by Watanabe in 1998 showed that PAX3 transactivates the MITF promotor.³ Therefore, mutations in the PAX3 gene could affect regulation of the MITF gene, leading to abnormalities of melanocyte differentiation.

WS4 is caused by homozygous mutations in either the endothelin-3 (EDN3) or the endothelin-B receptor (EDNRB) genes. Heterozygous mutations in either gene cause isolated Hirschsprung disease. 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: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH).⁴

Homozygous mutations of the EDNRB gene may result in WS4, whereas mutated heterozygotes manifest isolated Hirschsprung disease in lower penetrance.⁵ However, recent findings in a family were consistent with previous observations that the full spectrum of WS4 occurred to the mutate homozygotes.

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.⁶ Both mutations created stop codons leading to truncation of the PAX3 protein.

Microdeletions or contiguous gene defects may be involved in the pathogenesis of other malformations associated with this syndrome.⁷

A zebrafish model for Waardenburg syndrome type IV has been used to study this syndrome.⁸

Frequency

United States

Waardenburg syndrome prevalence is estimated at approximately 1 case per 42,000 individuals; WS1 and WS2 are believed to be equally common. This syndrome is considered responsible for 2-3% of cases of congenital deafness.

International

International prevalence of Waardenburg syndrome is believed to be equivalent to US rates. Providencia, a small Caribbean island, has an unexplained, unusually high frequency of individuals with hearing loss (5 cases per 1,000 population), with Waardenburg syndrome accounting for 29% of cases.⁹

Mortality/Morbidity

Affected individuals may have higher risk for neural tube defects, cleft lip and palate, limb abnormalities, and Hirschsprung disease. Mortality rates are comparable with unaffected individuals.

Race

Waardenburg syndrome has no known racial or ethnic predilection.

Sex

Males and females are affected with equal frequency.

Age

Waardenburg syndrome may be detected in newborns by obvious pigmentary differences and by hearing screening. In individuals with only mild features, Waardenburg syndrome may remain undiagnosed until another family member receives medical attention, usually because of congenital sensorineural hearing loss (SNHL).

Clinical

History

In 1992, the Waardenburg Syndrome Consortium proposed diagnostic criteria for Waardenburg syndrome type 1 (WS1).¹⁰ Individuals should be considered to have WS1 if they have 2 major or one major and 2 minor criteria from the list below. In 1995, Liu et al used the same list to define WS2.¹¹ Individuals with 2 major features who do not have dystopia canthorum are considered to have WS2. The following are the major and minor criteria:

• Major criteria
  • Congenital sensorineural hearing loss (SNHL)
  • Pigmentary disturbances of the iris
  • Hair hypopigmentation (ie, white forelock)
  • Affected first-degree relative
  • Dystopia canthorum, with a W index that exceeds 1.95
    • Calculate the W index using measurements in millimeters of the (a) inner canthal distance, (b) the interpupillary distance, and (c) the outer canthal distance, in the following formula: X = (2a - 0.2119c - 3.909)/c
      Y = (2a - 0.2479b – 3.909)/b
      W = X + Y + a/b
    • A result of more than 1.95 is consistent with a diagnosis of dystopia canthorum.
• Minor criteria
  • Congenital leucoderma (ie, several areas of hypopigmented skin)
  • Synophrys or medial eyebrow flare
  • Broad high nasal root
  • Hypoplasia of alae nasi
  • Prematurely graying hair (ie, predominately white by age 30 y)

Waardenburg syndrome has been associated in a few patients with urinary system anomalies.¹²

A screening program to detect Waardenburg syndrome throughout Columbia identified 95 affected individuals belonging to 95 families; the frequency rate of Waardenburg syndrome was 5.38% in the institutionalized deaf population.¹³ All patients had sensorineural deafness, and the most common features included broad nasal root (58.9%), an affected first-degree relative (37.9%), heterochromia irides (36.8%), skin hypopigmentation (31.6%), white forelock (28.0%), intense blue iris (27.4%), synophrys (12.6%), premature graying (10.5%), ptosis of the eyelids (9.5%), and hypoplasia alae nasi (1.1%).

Physical

• Facial features
  • Broad high nasal root
  • Synophrys, medial flaring of the eyebrows, or both
  • Hypoplastic alae nasi
  • Dystopia canthorum: This condition is not always clinically evident but is present in nearly all cases of WS1, distinguishing it from WS2.
• Skin features
  • Hypopigmentation, possibly on the face, trunk, or limbs with or without an associated white forelock
  • Patches of hyperpigmentation in some families with Waardenburg syndrome
• Hair features
  • White forelock (present at birth or developing later; may also disappear later)
  • White body hair, eyebrows, eyelashes
  • Dark tufts of hair or black forelock
  • Premature graying (ie, <30 y)
• Eye features
  • Complete or segmental heterochromia
  • Brilliant sapphire blue eyes
• Aural features (SNHL)
  • Variable incidence within and between families
  • Affects 58% of individuals with WS1 and 77% of individuals with WS2
  • Mild-to-profound hearing loss (profound SNHL most common in WS1 and WS2)
  • Low-frequency loss or U-shaped audiograms in some affected individuals
  • Can be bilateral, asymmetric, or unilateral
  • Typical hearing loss not progressive
• Less commonly associated findings
  • Neural tube defects
  • Sprengel shoulder (ie, congenital upward scapular displacement)
  • Cleft lip or palate
  • Hirschsprung disease (primarily in cases of WS4 but reported in families with WS1 and WS2)
  • Contractures and limb muscle hypoplasia (in patients with WS3)

Causes

• Most, if not all, cases of WS1 are caused by mutations in the PAX3 gene located on chromosome band 2q35.
  • Deletions, frameshifts, 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.
• WS3 is also caused by mutations in the PAX3 gene.
  • WS3 may be inherited as a dominant disorder.
  • In some cases, WS3 may be a manifestation of homozygous mutations of this gene.
• 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.
  • Some cases of WS2 have been linked to another locus on 1p21-p13.3, and some remain unlinked to either loci.
• WS4 is caused by homozygous mutations in either the EDN3 or the EDNRB gene.
  • Heterozygous mutations in either of these genes cause isolated Hirschsprung disease.
  • Heterozygous mutations in the SOX10 gene have also been reported to cause WS4.

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