What is Waardenburg syndrome?

Risk Factors

Individuals without a family history presumably have de novo (sporadic) mutations. Advanced paternal age is a risk factor for sporadic mutations including those that cause WS. The new mutation rate is estimated at 0.4 per 100,000. Both sexes and people of all races are affected equally, with an overall prevalence of 1 in 32,400–42,000.

Etiology and Genetics

WS is a genetically heterogeneous group of conditions. Approximately 96 percent of individuals who meet the diagnostic criteria for WSI have a detectable mutation (90 percent) or a whole or partial gene deletion (6 percent) of the PAX3 gene located on chromosome 2q35. PAX3 mutations have also been found in individuals with WSIII. Mutations in the microphthalmia-associated transcription factor (MITF) gene, located on chromosome 3p14.1-p12.3, are found in approximately 15 percent of individuals with WSII. Additional subtypes of WSII have been linked to other loci including 1p, 8p23, 8q11 (SNAI2), and 22q13 (SOX10). WSIV is associated with mutations in the endothelin-B-receptor gene (EDNRP) on chromosome 13q22, the endothelin-3 gene (EDN3) on 20q13.2-q13.3, and the SOX 10 gene on 22q13.

WS is inherited in both an autosomal dominant (AD) and autosomal recessive (AR) manner. AD refers to a type of condition that can be inherited by a single parent. A person who is heterozygous (one working gene and one nonworking gene) is affected with the condition. The recurrence risk for the offspring of individuals who are affected is 50 percent. AR refers to a type of condition that has to be inherited by both parents. A person who is heterozygous is referred to as a carrier and is unaffected. When two carriers of the same nonworking gene have children, they have a 25-percent chance of having a child homozygous (with two nonworking genes) and thus, of having a child affected with the condition. WS types I, II, and in some cases IV (when SOX10) are AD. When WSIII occurs in families it is AD; however, it is usually sporadic. There have also been cases reported of individuals with WSIII who are homozygous for PAX3 mutations. WS type IV (when EDNRP and EDN3) is AR.

The genes that cause WS are important in the regulation of melanocyte development. Melanocytes produce melanin, which contributes to the pigmentation of skin, hair, and eye color and is important for the proper function of the cochlea. Mutations in any of these genes may result in hearing loss and changes in pigmentation. Genes responsible for WSIV (SOX10, EDN3, or EDNRB) are involved in the development of nerve cells in the large intestine, leading to problems related to Hirschsprung’s disease. All forms of WS show marked interfamilial and intrafamilial variability, indicating that modifier genes probably play a role in the expression of the disease.

Symptoms

Major features of WS include sensorineural hearing loss, a white forelock or premature graying of the hair, different colored eyes (one blue and one brown), and patchy skin dipigmentation. WSI is associated with dystopia canthorum, a condition in which the inner corners of the eyes are spaced farther apart than normal. WSII appears similar to WSI without dystopia canthorum. The principal feature of WSIII is musculoskeletal anomalies of the upper limbs, including hypoplasia (underdevelopment), contractures, and syndactyly (fused fingers). WSIV includes features of type II combined with Hirschsprung’s disease.

Screening and Diagnosis

The Waardenburg Consortium has proposed clinical diagnostic criteria. Molecular genetic testing may be available to confirm the diagnosis, clarify risks for family members, and provide prenatal diagnosis. Testing is offered clinically for all types. Population screening for WS is not available.

Treatment and Therapy

There is no cure for WS. Treatment depends on manifestations as appropriate. Often the most significant complication is hearing loss; benefits are gained from early detection and treatment with hearing aids or cochlear implants. Individuals may also require orthopedic interventions or treatment for Hirschsprung’s disease. For optimal care, patients should see a variety of specialists, including a clinical geneticist, genetic counselor, otolaryngologist, audiologist, speech-language pathologist, and possibly an ophthalmologist, dermatologist, craniofacial surgeon, and gastrointestinal specialist.

Prevention and Outcomes

Prenatal or preimplantation genetic diagnoses are available if the cause is known. Women at risk of having a child with WSI are recommended to take folic acid supplementation. Most individuals with WS have normal intelligence and live long, productive lives.

Bibliography

Bansal, Yuvika, et al. "Waardenburg Syndrome: A Case Report." Contact Lens and Anterior Eye 36.1 (2013): 49–51. Print.

Farrer, L. A., et al. “Waardenburg Syndrome (WS) Type I Is Caused by Defects at Multiple Loci, One of Which Is Near ALPP on Chromosome 2: First Report of the WS Consortium.” American Journal of Human Genetics 50 (1992): 902–13. Print.

Garg, Uma, and Ritesh Surana. "Waardenburg Syndrome 2." Indian Journal of Otology 18.4 (2012): 220–22. Print.

Kontorinis, Georgios, et al. "Inner Ear Anatomy in Waardenburg Syndrome: Radiological Assessment and Comparison with Normative Data." International Journal of Pediatric Otorhinolaryngology 78.8 (2014): 1320–26. Print.

Newton, V. E. “Clinical Features of the Waardenburg Syndromes.” Advances in Oto-Rhino-Laryngology 61 (2002): 201–8. Print.