Waardenburg Syndrome - Causes, Symptoms, Diagnosis, and Management

Introduction:

The Waardenburg syndrome is a rare genetic disorder with an autosomal dominant pattern of inheritance. In Waardenburg syndrome, there is an abnormality in the distribution of melanocytes, causing areas of depigmentation in the patients. There is a loss of pigment cells, particularly in the eyes, skin, and hair. This syndrome has four classical types, out of which type I and type II are the most common ones.

Why Is It Called Waardenburg Syndrome (WS)?

This condition was first described by a Dutch ophthalmologist and a geneticist, Dr.Petrus Johannes Waardenburg, in the year 1951. Hence the syndrome is named after him. In his findings, he observed that during the development of the embryo, there were disturbances to the melanocytes that resulted in patchy areas of depigmentation.

What Is Meant By Autosomal Dominant Inheritance?

The word inheritance means that it is acquired from their parents. An autosomal dominant pattern is when one altered gene in a cell is enough to cause the defect. In most cases, the child may have at least one parent affected by the mutated gene. At the same time, an autosomal recessive trait is when there should be two mutated genes in a cell to cause the defect. Type III and type IV appear to be autosomal recessive traits. In these conditions, the parents may carry the mutated gene and are asymptomatic, but they have the potential to pass it on to their children.

What Is the Incidence of Waardenburg Syndrome?

• It is a rare genetic condition and is diagnosed soon after birth.

• It affects about one in 42000 cases across the world and one in 2,12,000 cases in the Netherlands (the only country that has low penetration in the world).

• It has got neither racial nor gender predilection. It affects any population and any age group.

• Type III is very rare, and 19 % of reported cases are type IV.

How Many Types Are Seen In Waardenburg Syndrome?

• There are four main types of which, types I and II, are commonly reported.

• Type III (Klein- Waardenburg syndrome) and type IV (Waardenburg Shah syndrome) are extremely rare.

What Causes Waardenburg Syndrome?

• During the development of the embryo (embryogenesis), there are disturbances to the neural crest-derived melanocytes that result in areas of depigmentation that are seen in patches. This results in the loss of pigmentary cells present in the eyes, skin, and hair.

• Another main reason is due to the mutations seen in the genes. These gene mutations affect the neural crest cells.

• Type I and III are due to mutations in the PAX3 gene at chromosome 2q.

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• Type II is further subdivided into 2A, 2B,2C, and 2D.

• Type 2A: Mutations seen in the MITF gene at chromosome 3q.

• Type 2B: Mutations in chromosome 1q.

• Type 2C: Mutations in chromosome 8q.

• Type2D: Mutations in SNAI2 gene at chromosome 8q.

• Type IV mutation is seen in the endothelin three receptor, which is autosomal recessive and rare.

What Are the Clinical Features?

The symptoms are usually seen soon after birth. These symptoms specifically alter the morphological appearance. They are associated with musculoskeletal defects and Hirschsprung syndrome. The symptoms vary in each type of Waardenburg syndrome. The most common symptoms are:

• Pigmentation changes (the eyes are differently colored).

• Auditory defects (deafness): These children do not respond to any sounds.

• White forelock.

• Broad nasal root.

What Are The Symptoms?

Type I: It is the most common type.

• Sensorineural deafness (deafness caused due to damage to the inner structures of the ear).

• Short philtrum, retro positioned maxilla (the upper jaw is displaced backward).

• Morphological changes in the facial structure with broad nasal root and wide-set eyes.

• Dystopia canthus (the medial corners of the eyes get displaced laterally).

• Synophrys (union of the eyebrows along the midline).

• Leukoderma (the skin appears white).

• White forelock (patch of white hair near the forehead).

• Heterochromia iridis (the colored part of the eye is different from the other). It can be complete, partial, or segmented.

• Iso hypochromia iridis (the bottom of the eye is abnormally pigmented and gives a pale blue appearance.

Type II: It is similar to type I, but they have normal canthi (the corners of the eyes where the upper and lower eyelids meet).

Type III: They present similar to type I, but the musculoskeletal abnormalities are more evident. They include:

• Hypoplasia (underdeveloped organs or any part of the body).

• Flexion contractures (loss of muscle movements, difficulty in stretching and extension).

• Syndactyly (digits are fused).

• Small carpal bones, underdeveloped first and second ribs.

• Sacral cysts (fluid accumulation around the nerves in the spinal cord).

Type IV: This type of Waardenburg syndrome is similar clinically to type II.

• In addition to those symptoms, it is associated with a syndrome called ‘Hirschsprung syndrome.’ It is a condition where there is a missing nerve in the large intestine that causes difficulty in passing stools.

• Severe constipation.

• Hyperpigmented patches over the normal skin.

How Is Waardenburg Syndrome Diagnosed?

The syndrome can be diagnosed soon after birth, or in some cases, they are diagnosed at least by early childhood. As the child grows, the morphological features may help to diagnose this condition. The clinician concludes the diagnosis from the clinical evaluation by looking at their physical appearance and by obtaining a proper history from their parents. In cases of known family history, genetic testing is indicated. There are no specific radiological tests for Waardenburg syndrome.

The Other Diagnostic Tests:

1) Computed Tomography (CT Scan): They help in diagnosing the inner ear problems that cause congenital sensorineural defects.

2) Colon and Rectal Biopsies: A small part of the affected tissue is taken and examined. They may rule out the presence of Hirschsprung disease.

3) Audiometry: They are special tests to assess the ability of the ear to hear sounds.

4) Detection Dystopia Canthum: This can be identified by measuring the three intraocular distances.

• The distance between the two inner canthi of the eye.
• The distance between the pupils of the eye.
• Distance between the outer canthi.

5) Chorionic Villi Sampling or Amniocentesis: The amniotic fluid is collected and tested for any mutations of the genes. It often detects the mutations in the PAX3 gene that is responsible for type I.

6) Slit Lamp Examination: The internal structure of the eye is examined using an illuminated microscope.

What Are the Other Conditions Similar to Waardenburg Syndrome?

• Piebaldism: This is a genetic condition that results in depigmentation of the skin.

• Tietze Syndrome: This is a rare condition associated with musculoskeletal deformities.

• Oculocutaneous Albinism: Absence of melanocytes with depigmentation in the skin, hair, and eyes.

• Vogt-Koyanagi-Harada Disease: There are abnormalities in the skin, hair, and eyes.

• Vitiligo: Numerous depigmented areas are seen on the skin.

How Is Waardenburg Syndrome Managed?

As Waardenburg syndrome is a genetic disorder, there is no permanent cure for this disease. However, supportive treatment will provide symptomatic relief and improve the quality of life.

• Cochlear Implant: An implant is a device that is inserted into the inner ear where the auditory nerve is stimulated and sends impulses to the brain. This is followed by special training in sign languages, lip-reading, etc.

• Skin: Due to depigmented areas, the skin is more vulnerable to sunburns and a high risk of skin cancers. So these patients are advised to limit their exposure to sunlight and use sun creams with sun protection formula and sunglasses.

• Eyes: Some patients are more sensitive to light, so tinted glasses and contact lenses are advised to reduce the sensitivity.

• Surgery: In the case of Hirschsprung disease, surgery may be needed to remove the retained bowel.

• Dietary Changes: They are advised to prevent the complication of constipation and to maintain regular bowel movements.

Conclusion:

Although it is a genetic condition, the average lifespan of the child will be normal. However, these children may face lifelong disabilities. The supportive treatments improve their quality of life but do not provide a permanent cure. If there is a known family history, and if the parents are expecting a child, then it is better to take genetic counseling and prenatal screenings to identify whether the defect has been passed on to the baby. Parents should be given counseling regarding this syndrome and thus motivate their children if they face low self-esteem due to their appearance.