Waardenburg syndrome

Waardenburg syndrome

Waardenburg syndrome (WS) is a rare disease.

This condition usually presents with the below clinical features

  • Pigmentation anomalies (abnormalities) of the eyes
  • Varying degrees of hearing abnormalities (deafness)
  • Hair and Skin structural defects / abnormalities – Certain minor defects in structures arising from neural crest, including hair and skin.

WS is classified into four phenotypes which are clinical and genetic.

These four phenotypes are as below

  • Waardenburg syndrome type 1 (WS1)
  • Waardenburg syndrome type 2 (WS2)
  • Waardenburg syndrome type 2 A (WS2A)
  • Waardenburg syndrome type 2 A (WS2A)
  • Waardenburg syndrome type 3 (WS3)
  • Waardenburg syndrome type 4 (WS4)

How common is Waardenburg syndrome?

This condition Usually affects 1 to 9 in 100000

The worldwide incidence is estimated at around 1/40,000.

The most common types of Waardenburg syndrome are the Waardenburg syndrome type 1 (WS1) and type 2 (WS2).

The rare types of Waardenburg syndrome are the Waardenburg syndrome type3 (WS3) and type 4 (WS4).

So Far only a very few cases of WS3 have been reported worldwide.

Roughly around 3% of all institutionalized cases of congenital hearing loss is due to Waardenburg syndrome.

Inheritance Pattern

Autosomal dominant or Autosomal recessive 

Age of onset

  • Infancy
  • Neonatal

What are the symptoms of Waardenburg syndrome?

Very Common Symptoms

  • Abnormal facial shape 
  • Abnormality of skin pigmentation
  • Abnormality of vision 
  • Conductive hearing impairment 
  • Hearing impairment 
  • Heterochromia iridis 
  • Hypopigmentation of hair 
  • Hypopigmented skin patches 
  • Premature graying of hair
  • Prominent nasal bridge
  • Synophrys 

Common Symptoms

  • Abnormal eyebrow morphology
  • Abnormal lip morphology 
  • Abnormality of the eye 
  • Abnormality of the face
  • Abnormality of the mouth 
  • Lacrimation abnormality 
  • Telecanthus
  • Underdeveloped nasal alae
  • White forelock
  • Wide nasal bridge 

Occasional Symptoms

  • Abnormality of the gastrointestinal tract 
  • Abnormality of the uterus 
  • Abnormality of the vagina 
  • Aganglionic megacolon 
  • Aplasia/Hypoplasia of the colon 
  • Intestinal obstruction 
  • Myelomeningocele
  • Oral cleft 
  • Ptosis

What are the clinical features?

Clinical features of this condition vary within and between families.

Frequent clinical manifestations include congenital sensorineural deafness, heterochromic or hypoplastic blue irides, white forelock or early graying of the scalp hair before the age of 30 years.

All these manifestations, along with a suggestive family history are major criteria, as is dystopia canthorum in WS1 and WS3.

Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella and hypoplastic alae nasi.

WS is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria (early graying of the hair is considered either a major or minor criteria depending of the WS type).

WS1 combines these criteria with dystopia canthorum. The absence of dystopia canthorum clinically differentiates WS2 from WS1, whereas WS3 is similar to WS1, but additionally includes upper limb abnormalities.

WS4 is characterized as WS2 with added characteristics of Hirschsprung disease.

What causes Waardenburg syndrome?

This condition is genetically heterogeneous.

To date, mutations in 6 different genes have been identified: 

Here are the mutations in 6 different genes

  1. PAX3 (2q36.1)
  2. MITF (3p14-p13) 
  3. SNAI2 (8q11.21)
  4. SOX10 (22q13.1) 
  5. EDNRB (13q22.3)
  6. EDN3 (20q13.32)

Mutations in PAX3 gene are associated with WS1 and WS3, while MITF gene is mutated in cases of WS2.

Digenic inheritance of MITF mutation in combination with a TYR mutation (and/or the TYRR402Q hypomorphic allele) has been reported in two families with WS2 and ocular albinism (see this term).

Homozygous SNAI2 deletions have been described in two WS2 patients. SOX10 mutations are found in WS4 and WS2 affected patients.

Mutations in EDNRB and EDN3 genes have also been reported in WS4.

How is this condition diagnosed?

Suspected WS, diagnostic evaluation may include use of a caliper to measure the distances between the inner angles of the eyes (inner canthi), the outer angles of the eyes (outer canthi), and the pupils (interpupillary distances). 

Slit-lamp examination (illuminated microscope to visualize internal structures of the eyes);

specialized hearing (auditory) tests;

Advanced imaging techniques, to evaluate inner ear abnormalities, skeletal defects (e.g., seen in WS3), Hirschsprung disease (e.g., seen in WS4).


Waardenburg syndrome


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