What Is Waardenburg Syndrome?

Overview

Waardenburg syndrome is a genetic disorder, which is inherited in an autosomal dominant manner. It is a rare condition caused by the abnormal distribution of melanocytes (the cells which give pigment to our skin) during development. This therefore leads to irregular patches of depigmentation and pale skin. The syndrome affects various parts of the body, including our eyes, skin, part of the cochlea (found within our inner ear), and our hair. Its distinctive features include having a wider bridge of the nose, displacement of the inner corners of the eyes with an abnormal position of the tear ducts, abnormalities in iris pigmentation, excessive hair growth in the inner part of the eyebrows, a white lock of hair (forelock), and hearing loss or deafness. 

Types of waardenburg syndrome

Waardenburg syndrome is categorised into four types, with type 1 and type 2 being the most common.

Type 1 is caused by mutations in the PAX3 gene and is characterised by congenital sensorineural deafness (a type of hearing loss), dystopia canthus (fusion of the inner eyelids), neural tube defects, cleft palate & cleft lip, and patchy depigmentation of the hair and skin. These symptoms can be accompanied by pigmentary abnormalities in the eyes.

Type 2 Waardenburg syndrome is associated with mutations in the MITF gene. Although the inner corners of both eyes are normal in type 2, there are other features similar to type 1.

Type 3 Waardenburg syndrome represents an extreme form of type 1 Waardenburg Syndrome, and includes abnormalities in the upper limbs.

Type 4 Waardenburg syndrome is caused by mutations in either the EDNRB or endothelin-3 genes, and is typically inherited in an autosomal recessive manner.¹ 

The occurrence of Waardenburg Syndrome is estimated to be approximately 1 in every 40,000 individuals.2

Causes of waardenburg syndrome

The PAX3 (paired box 3) gene plays a crucial role in both type 1 Waardenburg syndrome and type 3I Waardenburg syndrome (also known as Klein-Waardenburg syndrome). 

However, in a subset of patients who do not exhibit dystopia canthus (an outward displacement of the inner corner of the eyes typically seen in type 1 WS), another gene called microphthalmia-associated transcription factor (MITF) was found to be altered, leading to their classification as type 2 Waardenburg syndrome. 

Additionally, the endothelin pathway, involving the EDN3 (endothelin 3) and EDNRB (endothelin receptor type B) genes, was identified to be involved in the fourth subtype of Waardenburg syndrome, also known as Shah-Waardenburg syndrome.  This subtype is characterised by a combination of deafness, depigmentation, and Hirschsprung disease (intestinal ganglionitis).

More recently, mutations in the SOX10 gene have also been found in type II WS, with or without neurological impairment. It is important to note that mutations in these genes are often specific to individual cases, and there is a considerable variation both within and between families.

During development, pluripotent neural crest cells (NCC) migrate from the neural tube throughout the embryo along various pathways.  These cells give rise to different cell types, including melanocytes in the skin and inner ear, cells of the nervous system, and skeletal tissue.

Abnormalities in neural crest development can lead to significant human diseases. 

The characteristic combination of hearing loss and pigmentary abnormalities observed in Waardenburg syndrome arises from abnormalities in the proliferation, survival, migration, or differentiation of NCC-derived cells.³

Signs and symptoms of waardenburg syndrome

Type 1 Waardenburg Syndrome – this is a combination of hearing and pigmentary disorders, including hearing loss, pigmentary disturbances, and dystopia canthus.

Type 2 waardenburg syndrome – this distinct type of WS presents with hearing and pigmentary disorders, including hearing loss, pigmentary disturbances, and dystopia canthus.  Both types have an increased prevalence of sensorineural hearing loss and may exhibit heterochromia iris (having two different coloured eyes).

Type 3 waardenburg syndrome – is distinguished by the presence of additional abnormalities in the upper limbs, such as flexion contractures (bent joints which can’t be straightened), syndactyly (partial fusion of the fingers), and fusion of carpal bones (the bones of the wrist. These upper limb abnormalities accompany the features observed in type 1 and type 2.

Type 4 waardenburg syndrome – it is a very rare form and appears to follow an autosomal recessive pattern of inheritance.⁴

Management and treatment for waardenburg syndrome

Waardenburg syndrome currently has no definitive cure. However, the symptoms can be managed:

• Inner ear deafness can be managed by using hearing aids or cochlear implants
• A white forelock of hair can be disguised with hair dye
• Hypopigmentation, characterised by paler patches of skin, can be managed by applying various topical ointments to blend the affected areas with the surrounding skin colour. In instances where hypopigmentation affects a significant portion of the body, depigmentation treatments may be considered. These treatments involve bleaching the entire skin, aiming to reduce the visibility of lighter patches 
• Ptosis, characterized by an abnormal drooping of the upper eyelid, is one of the most commonly observed congenital abnormalities in children. However, it is a rare feature of Waardenburg syndrome. Surgery is an effective approach for correcting ptosis. The optimal timing for surgical intervention in cases of Waardenburg syndrome-associated ptosis remains uncertain. For mild to moderate ptosis, surgery is generally recommended between the ages of 3 and 6 years. In severe cases, early intervention is suggested to safeguard visual development and prevent amblyopia⁵

Diagnosis

Waardenburg syndrome is characterized by the absence of melanocytes, resulting in the involvement of skin, hair, eyes, or the cochlea. 

To diagnose Waardenburg syndrome, either two major criteria or one major criterion along with two minor criteria should be present.⁴

Major criteria include:

• Congenital sensorineural hearing loss
• Pigmentary disturbances of the iris, which may manifest as complete heterochromia iris (having two different coloured eyes), partial or segmental heterochromia iris, or hypoplastic blue iris
• White forelock of hair
• Dystopia canthus (outward displacement of the inner corner of the eyes)
• Presence of Waardenburg syndrome in a first-degree relative who has been previously diagnosed

Minor criteria include:

• Congenital leukoderma, which refers to multiple areas of hypopigmented skin
• Pigmentary disturbances of the iris, presenting as complete heterochromia iris or partial/segmental heterochromia iris
• Broad and high nasal root
• Hypoplasia of the alae nasi (the wing-like outer part of the nostrils)
• Premature greying of hair before the age of 30

FAQs

How can I prevent waardenburg syndrome?

Prevention of Waardenburg syndrome is not currently possible due to its underlying cause, which is a genetic mutation. To assess the risk of passing on a genetic condition to offspring, it is advised to consult healthcare regarding genetic testing.

How common is waardenburg syndrome?

The prevalence of Waardenburg syndrome is estimated to be approximately 1 in 42,000 individuals. Among the different types of Waardenburg syndrome, types 1 and 2 are the most commonly observed, accounting for approximately half and one-third of cases respectively. Type 4 constitutes about one-fifth of cases, while type 3 is relatively rare, comprising less than 2% of the total cases.

Who is at risk of waardenburg syndrome?

Waardenburg syndrome is a hereditary condition that can be inherited from one or both parents and it affects those assigned male and female at birth equally. In rare instances, the genetic mutation responsible for Waardenburg syndrome can occur spontaneously. For individuals with Waardenburg syndrome, there is a 50 per cent probability of passing the gene to their children if they are the only parent affected. If both parents have Waardenburg syndrome, there is a 100% chance of offspring being affected.

When should I see a doctor?

It is recommended to consult a healthcare provider as soon as possible to ensure early diagnosis and intervention, particularly if you are experiencing difficulties with hearing and pigmentary abnormalities.

Summary

Waardenburg syndrome is a genetic disorder that can manifest from birth, displaying a wide range of symptoms and varying in severity from person to person. Commonly observed characteristics include distinct facial abnormalities, reduced pigmentation of the hair, skin, and iris of both eyes, as well as congenital deafness. This disease can be caused due to mutations in the PAX3 gene, MITF gene, and endothelin-3 receptor. There is no definitive cure for the disease since it is caused by genetic abnormalities, however, various treatment options are available to help to manage the symptoms of this condition.