• Estimated Prevalence: Waardenburg syndrome is estimated to affect about 1 in 40,000 people worldwide, but can be more common in certain populations.

• Congenital Hearing Loss: The disease accounts for 2 to 5 percent of all cases of congenital hearing loss (hearing loss present at birth or shortly after).

Types: Types I and II are the most common forms of Waardenburg syndrome, while types III and IV are rarer.

Waardenburg syndrome is typically inherited in an autosomal dominant manner (see RareShare Guide on Genetic Inheritance). It is caused by mutations in several genes which can be inherited from a parent or occur spontaneously, including:

• PAX3 (Type 1 and Type 3), gene encoding a DNA binding protein involved in embryonic development and cell differentiation, important for formation of the bones and muscle tissue in the face and skull.

• MITF, SNAI2 (Type 2), genes for melanocyte inducing transcription factor involved in melanocyte development and snail family transcriptional repressor 2 which promotes the differentiation and migration of certain cells during development, respectively.

SOX10, EDN3, EDNRB (Type 4);  the SOX10 protein interacts with other proteins to regulate embryonic development;  EDN3 and EDNRB are Endothelien 3 and Endothelien Receptor Type B, proteins that  interact together to influence the

Symptoms vary depending on the subtype but commonly include:

• Hearing loss ranging from mild to profound, unilateral or bilateral

• Pigmentary abnormalities:

  • Heterochromia iridum (different-colored eyes or segments of different colors within one eye)

  • Pale blue eyes or brilliant blue eyes (even in non-Caucasian individuals)

  • White forelock (patch of white hair)

  • Premature graying

  • Patches of hypopigmented skin (vitiligo or leukoderma)

• Facial and structural anomalies:

  • Dystopia canthorum (increased distance between the inner corners of the eyelids while the inter-pupillary distance is normal) seen in Type 1

  • Broad nasal root;  high nasal bridge

  • Synophrys (unibrow)

  • Cleft lip

• Neurological or musculoskeletal anomalies (rare cases):

  • Limb deformities, difficulty completely straightening joints (Type 3 - Waardenburg-Klein syndrome)

  • Hirschsprung’s disease, a defect in which nerves are missing from parts of the intestine, causing constipation and other symptoms (Type 1 and Type 4 - Waardenburg-Shah syndrome).

Waardenburg syndrome is diagnosed based on physical evaluation, hearing tests, family history and genetic testing.

Clinical criteria may include documentation of hearing loss, pigmentary disturbances (in the hair, skin and eyes), measurements of eyelid and interpupillary distances, imaging to assess inner ear or skeletal defects, and the presence of the disease from a parent. Genetic testing can confirm mutations in the PAX3, MITF, SNAI2, SOX10, EDN3 or EDNRB genes.

There is no cure for Waardenburg syndrome. Treatment focuses on managing symptoms, which may include:

• Hearing aids and/or cochlear implants for hearing loss

• Speech therapy if hearing loss affects language development

• Regular ophthalmologic checkups to monitor vision changes

• Skin and hair pigment monitoring mostly for cosmetic reasons

• Special diets or medications to address constipation

• Surgical intervention to correct facial abnormalities or for severe cases of Hirschsprung’s disease (WS Type 4).

The prognosis for patients with Waardenburg syndrome is generally good, especially once hearing issues are addressed. Life expectancy is normal in most cases. Hearing loss is permanent, and pigmentary changes do not affect overall health. Type 4 patients may face complications from Hirschsprung’s disease.

1. Ahmed JN, Mui RK, Masood S. (2023). “Waardenburg Syndrome.” In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK560879/?utm_source=chatgpt.com .

2. Song J., Feng Y., Acke F.R., Coucke P., Vleminckx K., Dhooge I.J. (2016). “Hearing loss in Waardenburg syndrome: a systematic review.” Clin Genet, 89: 416–425. doi: 10.1111/cge.12631.

3. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M. (2000). “Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.” Hum Mol Genet, (13):1907-17. doi: 10.1093/hmg/9.13.1907. PMID: 10942418.

4. National Organization for Rare Disorders (NORD):  Waardenburg Syndrome.

5. Medline Plus - Waardenburg syndrome.