Waardenburg syndrome: MedlinePlus Genetics

Description

Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.

There are four recognized types of Waardenburg syndrome, which are distinguished by their physical characteristics and sometimes by their genetic cause. Types I and II have very similar features, although people with type I almost always have eyes that appear widely spaced and people with type II do not. In addition, hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome) has signs and symptoms of both Waardenburg syndrome and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine.

Frequency

Waardenburg syndrome affects an estimated 1 in 40,000 people. It accounts for 2 to 5 percent of all cases of congenital hearing loss. Types I and II are the most common forms of Waardenburg syndrome, while types III and IV are rare.

Causes

Variants (also known as mutations) in the EDN3, EDNRB, MITF, PAX3, SNAI2, and SOX10 genes can cause Waardenburg syndrome. These genes are involved in the formation and development of several types of cells, including pigment-producing cells called melanocytes. Melanocytes make a pigment called melanin, which contributes to skin, hair, and eye color and plays an essential role in the normal function of the inner ear. Variants in any of these genes disrupt the normal development of melanocytes, leading to abnormal pigmentation of the skin, hair, and eyes and problems with hearing.

Waardenburg syndrome types I and III are caused by variants in the PAX3 gene. Variants in the MITF or SNAI2 gene can cause Waardenburg syndrome type II.

Variants in the SOX10, EDN3, or EDNRB gene can cause Waardenburg syndrome type IV. In addition to melanocyte development, these genes are important for the development of nerve cells in the large intestine. Variants in any of these genes result in hearing loss, changes in pigmentation, and intestinal problems related to Hirschsprung disease.

In some cases, the genetic cause of Waardenburg syndrome has not been identified.

Inheritance

Waardenburg syndrome is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. A small percentage of cases result from new variants in the gene; these cases occur in people with no history of the disorder in their family.

Some cases of Waardenburg syndrome type II and type IV appear to have an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have variants. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but do not show signs and symptoms of the condition.

Other Names for This Condition

Waardenburg's syndrome

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Clinical Trials

ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

PubMed

References

Huang S, Song J, He C, Cai X, Yuan K, Mei L, Feng Y. Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther. 2022 Sep;29(9):479-497. doi: 10.1038/s41434-021-00240-2. Epub 2021 Feb 25. Citation on PubMed
Milunsky JM. Waardenburg Syndrome Type I. 2001 Jul 30 [updated 2022 Oct 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1531/ Citation on PubMed
Nayak CS, Isaacson G. Worldwide distribution of Waardenburg syndrome. Ann Otol Rhinol Laryngol. 2003 Sep;112(9 Pt 1):817-20. doi: 10.1177/000348940311200913. Citation on PubMed
Newton VE. Clinical features of the Waardenburg syndromes. Adv Otorhinolaryngol. 2002;61:201-8. doi: 10.1159/000066810. No abstract available. Citation on PubMed
Pardono E, van Bever Y, van den Ende J, Havrenne PC, Iughetti P, Maestrelli SR, Costa F O, Richieri-Costa A, Frota-Pessoa O, Otto PA. Waardenburg syndrome: clinical differentiation between types I and II. Am J Med Genet A. 2003 Mar 15;117A(3):223-35. doi: 10.1002/ajmg.a.10193. Citation on PubMed
Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010 Apr;31(4):391-406. doi: 10.1002/humu.21211. Citation on PubMed
Zaman A, Capper R, Baddoo W. Waardenburg syndrome: more common than you think! Clin Otolaryngol. 2015 Feb;40(1):44-8. doi: 10.1111/coa.12312. No abstract available. Citation on PubMed

Waardenburg syndrome