What is Waardenburg syndrome?

Waardenburg syndrome is a rare genetic disorder characterised by deafness and abnormal pigmentation, such as:

• White forelock
• Hypopigmented (pale) patches of skin
• Heterochromia iridis (differently coloured eyes)

Waardenburg syndrome may also be associated with musculoskeletal defects and Hirschsprung syndrome.

Waardenburg syndrome is named after Petrus Johannes Waardenburg, a Dutch ophthalmologist, who noticed that heterochromia iridis often accompanied deafness.

Heterochromia iridis

White forelock

Who gets Waardenburg syndrome?

Waardenburg syndrome may be inherited or may arise spontaneously. It affects men and women equally, and can affect all races.

It has a population frequency of 1 in 42,000, and is responsible for 1–3% of all cases of congenital deafness.

What causes Waardenburg syndrome?

Waardenburg syndrome is thought to be a neurocristopathy. It is the result of abnormal neural crest differentiation during embryonic development.

Several different gene mutations can cause Waardenburg syndrome, leading to some differences in signs and symptoms. Expression and penetrance are also variable.

• WS1 and WS3 are caused by mutations in the PAX3 gene at chromosome 2q
• WS2A – MITF (microphthalmia associated transcription factor) gene, chromosome 3p
• WS2B – chromosome 1p
• WS2C – chromosome 8p
• WS2D – SNAI2 gene, chromosome 8q
• WS2E – SOX10 gene, chromosome 22q
• WS4A – EDNRB gene at 13q
• WS4B – EDN3 gene at 20q
• WS4C – SOX10 gene (as for WS2E)

Several types of mutation can cause Waardenburg syndrome – insertions, deletions, frameshifts, splice alterations, missense, or nonsense mutations.

Most types of Waardenburg syndrome are autosomal dominant, meaning that only one affected gene needs to be passed on to a child for them to have the syndrome. Transmission of defects in EDN3 or EDNRB is more complex. They are usually autosomal recessive, although cases of autosomal dominant transmission with incomplete penetrance have been described.

Other mutations in some of the above genes can cause related clinical syndromes, such as Tietz syndrome (MITF gene), piebaldism (SNAI2 gene), PCWH (SOX10 gene), or ABCD syndrome (EDNRB gene).

What are the clinical features of Waardenburg syndrome?

Features are present from birth. As it is a rare condition and clinical signs can be subtle, diagnosis may not be made until later in life. 

Four major clinical subtypes of Waardenburg syndrome have been identified.

Type 1

Type 1 is the most common subtype of Waardenburg syndrome. Features include:

• Sensorineural deafness
• Typical facial structure, with dystopia canthorum (lateral displacement of the medial corners of the eyes), broad nasal root, and synophrys (meeting of the eyebrows in the midline)
• Hypopigmented patches of skin and hair
• Pigmentary abnormalities of the eyes, such as heterochromia iridis (differently coloured eyes), which may be complete, partial, or segmental; isohypochromia iridis (pale blue eyes); or abnormal pigmentation of the fundus

Type 2

Type 2 has similar clinical features to type 1 Waardenburg syndrome, but the inner canthi are normal.

Type 3

Type 3 (Klein-Waardenburg syndrome) also has similar features to type 1 Waardenburg syndrome, but with musculoskeletal abnormalities, such as muscle hypoplasia, flexion contractures or syndactyly (fused digits).

Type 4

Type 4 (Shah-Waardenburg syndrome) has similar features to type 2 Waardenburg syndrome but with Hirschsprung syndrome (a condition resulting from missing nerve cells in the muscles of part or all of the large intestine).

How is Waardenburg syndrome diagnosed?

The diagnosis of Waardenburg syndrome is based on clinical features. In 1992 the Waardenburg Consortium developed major and minor criteria for diagnosis.

Major criteria

• Sensorineural deafness
• Iris pigmentary abnormality, such as heterochromia iridis – complete, partial, or segmental; isohypochromia iridis; or fundus pigmentary abnormalities
• Abnormalities of hair pigmentation, such as white forelock, eyebrows, or eyelashes
• Dystopia canthorum – lateral displacement of inner canthi
• First degree relative with Waardenburg syndrome

Minor criteria

• Hypopigmented patches of skin
• Synophrys
• Broad nasal root
• Hypoplasia of alae nasi
• Premature greying of the scalp

A clinical diagnosis of type 1 Waardenburg syndrome needs 2 major, or 1 major and 2 minor criteria.

The W index

The W index can be calculated to determine whether dystopia canthorum is present.

• a=inner canthal distance
• b=interpupillary distance
• c=outer canthal distance
• X=(2a-(0.2119c+3.909))/c
• Y=(2a-(0.2479b+3.909))/b
• W=X+Y+a/b
• W index > 1.95 is indicative of dystopia canthorum.

Genetic sequencing of the PAX3 gene for mutations causing Waardenburg syndrome may be performed as part of genetic counselling of family members. Prenatal testing for PAX3 mutations is possible by chorionic villus sampling or amniocentesis, but is rarely done. This is because of the clinical variation found within Waardenburg syndrome, since the presence of the mutation will not indicate which clinical features will be present, or their severity.

What is the treatment for Waardenburg syndrome?

There is no direct treatment for Waardenburg syndrome itself, and as it is a genetic condition there is no cure. Genetic counselling may be beneficial for affected patients who want to start a family.

• Audiology examinations should be performed for children with suspected Waardenburg syndrome to evaluate them for deafness. Hearing aids or cochlear implants may be needed.
• Patients with Hirschsprung syndrome may require surgery to remove the affected segment of bowel.
• Hypopigmented patches of skin are more susceptible to sun damage, so sun protection is important.

What is the outcome for Waardenburg syndrome?

Waardenburg syndrome is a chronic condition and the features will remain throughout life. Life expectancy is normal.