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Waardenburg Syndrome

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Updated November 13, 2011

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Waardenburg Syndrome

Child with Waardenburg

Waardenburg syndrome is named after Dutch eye doctor Petrus Johannes Waardenburg, who observed that individuals with differently colored eyes often had hearing loss as well. Indeed, a primary characteristic of Waardenburg is hearing loss - along with blue/brown eyes or two brilliant blue eyes. Another easily recognizable trait is white hair on the head.

There are four types of Waardenburg syndrome and many sub-types. They differ based on their physical characteristics and on their specific genetic causes.

How rare is Waardenburg syndrome? According to the National Institutes of Health, approximately one in every 10,000 to 20,000 people will have Waardenburg. Plus, since the first two types (Types I and II) are more common and are associated with hearing loss, it can be assumed that the majority of individuals with Waardenburg will have hearing loss.

Type I Waardenburg

Type I Waardenburg is a more common type and is caused by a mutation in the PAX3 gene. The PAX3 gene is part of a gene family that is important in the development of tissues and organs. This gene makes a protein that controls other genes responsible for the development of specific cells and parts of the body, such as facial bones and melanocytes (cells that make the pigment melanin).

Melanin is responsible for the color of our eyes, hair and skin. Melanocytes are also needed in the inner ear for hearing. Therefore, a mutation in the PAX3 gene means that melanin pigment cells cannot develop properly, leading to various problems. These problems include patches of white hair, and patches or areas of skin that lack pigmentation. The eyes can also have patchy pigmentation. Lack of melanin also contributes to the sensorineural deafness associated with the syndrome. The amount of hearing loss can be anywhere from moderate to profound.

Type I Waardenburg is generally autosomal dominant - it's inherited from just one parent.

Type II Waardenburg

Type II Waardenburg, also a more common type, may also have hearing loss in addition to the color changes in the hair, skin and eyes. The main difference between Type I and Type II is that in Type II, the eyes are not widely spaced. While this type is suspected to be caused by mutations in the PAX3 gene, it is also believed to be caused by mutations in the MITF (microphthalmia-associated transcription factor) and SNAI2 genes. Type II can be inherited in both the autosomal dominant manner (one parent) and in an autosomal recessive manner, meaning that two parents have to have the gene to be able to produce a child with Type II Waardenburg.

In addition, there are five subtypes of Type II Waardenburg. These subtypes are Type IIA, which is caused by a mutation in the MITF gene on chromosome 3; Type IIB, which is associated with chromosome 1; Type IIC and IID, which involve chromosome 8; and Type IIE, a mutation on chromosome 22.

Type III Waardenburg

Then there is Type III, a very rare type. What distinguishes Type III (also caused by a mutation in the PAX3 gene) from the others is that in Type III, there are upper limb abnormalities, such as malformations in the arms and the hands. For example, fingers can be fused together. This type of Waardenburg is also known as Klein-Waardenburg syndrome. Type III can arise spontaneously (no genetic link; a mutation just happens) or can be inherited from one parent.

In one unusual case, specialists in India diagnosed Waardenburg Type III in a 7-year-old boy who had fused middle and ring fingers on both hands, plus two fused toes. One leg had a white skin patch. His eyes were different colors. He had a broad nasal root (the area between the eyes) and some white hair. The child's father was normal and had no symptoms. But the mother did have symptoms, including deafness. She was later diagnosed with Type I, not Type III.

Type IV Waardenburg

The final type of Waardenburg syndrome, also rare, is Type IV. This type is also known as Waardenburg-Shah syndrome. Besides the typical features of Waardenburg, this form also includes Hirschsprung disease, a digestive problem that causes constipation or intestinal blockage. Type IV is usually passed down from one parent, but it can also be inherited from both parents.

Type IV also has subtypes, each one caused by a different gene mutation.

Sources:

Ghosh SK, Bandyopadhyay D, Ghosh A, Biswas SK, Mandal RK. Waardenburg syndrome: A report of three cases. Indian J Dermatol Venereol Leprol. 2010 Sep-Oct;76(5):550-2. http://www.ijdvl.com/article.asp?issn=0378-6323;year=2010;volume=76;issue=5;spage=550;epage=552;aulast=Ghosh.

National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/.

Various pages. Online Mendelian Inheritance in Man (OMIM). An Online Catalog of Human Genes and Genetic Disorders. http://omim.org/.

Various pages. Genetics Home Reference. http://ghr.nlm.nih.gov/.

Waardenburg Syndrome. National Institute on Deafness and Other Communication Disorders. http://www.nidcd.nih.gov/health/hearing/pages/waard.aspx. Accessed October 2011.

Waardenburg Syndrome. Genetic and Rare Diseases Information Center. http://rarediseases.info.nih.gov/GARD/Condition/5525/Waardenburg_syndrome.aspx

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