Waardenburg syndrome

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Waardenburg syndrome
Classification and external resources
ICD-10E70.3 (ILDS E70.32)
DiseasesDB14021 33475
eMedicineped/2422 derm/690
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Waardenburg syndrome
Classification and external resources
ICD-10E70.3 (ILDS E70.32)
DiseasesDB14021 33475
eMedicineped/2422 derm/690

Waardenburg syndrome (also Waardenburg­ Shah Syndrome, Waardenburg-Klein syndrome, Mende's syndrome II, Van der Hoeve-Halbertsma-Waardenburg syndrome, Ptosis-Epicanthus syndrome, Van der Hoeve-Halbertsma-Gualdi syndrome, Waardenburg type Pierpont,[5] Van der Hoeve-Waardenburg-Klein syndrome, Waardenburg's syndrome II and Vogt’s syndrome) is a rare genetic disorder most often characterized by varying degrees of deafness, minor defects in structures arising from the neural crest, and pigmentation anomalies. Disruptions in myogenesis, particularly mutations in Pax3, can cause Waardenburg syndrome I and III.

It was first described in 1951.[1]

Eponyms and classification[edit]

Waardenburg syndrome is named after Dutch ophthalmologist Petrus Johannes Waardenburg (1886–1979), who described the syndrome in detail in 1951.[1][2] The condition he described is now categorized as WS1. Swiss ophthalmologist David Klein also made contributions towards the understanding of the syndrome.[3]

WS2 was identified in 1971, to describe cases where "dystopia canthorum" did not present.[4] WS2 is now split into subtypes, based upon the gene responsible.

Other types have been identified, but they are less common.

Mutations in the EDN3, EDNRB, MITF, PAX3, SNAI2, and SOX10 are the genes that are affected from Waardenburg Syndrome. Some of these genes are involved in the making of melanocytes, which makes the pigment melanin. Melanin is an important pigment in the development of hair, eye color, skin, and functions of the inner ear. So the mutation of these genes can lead to abnormal pigmentation and hearing loss.[5] PAX3 and MTIF gene mutation occurs in type I and II (WS1 and WS2). Type III (WS3) shows mutations of the PAX3 gene also. SOX10, EDN3, or EDNRB gene mutations occur in type IV. Type IV (WS4) can also affect portions of nerve cell development that potentially can lead to intestinal issues.

Signs and symptoms[edit]

There are five major and five minor diagnostic criteria for Waardenburg syndrome.




The overall incidence is ~1/42,000 to 1/50,000 people. Types I and II are the most common types of the syndrome, whereas types III and IV are rare. Type 4 is also known as Waardenburg‐Shah syndrome (association of Waardenburg syndrome with Hirschsprung disease).

Type 4 is rare with only 48 cases reported up to 2002.[6]

About 1 in 30 students in schools for the deaf have Waardenburg syndrome. All races and both sexes are affected equally. The highly variable presentation of the syndrome makes it difficult to arrive at precise figures for its prevalence.


Subtypes of the syndrome are traceable to different genetic variations:

TypeOMIMGeneLocusAlso known as
Type I, WS1193500PAX32q35-
Type IIa, WS2A (originally WS2)193510MITF3p14.1-p12.3-
Type IIb, WS2B600193WS2B1p21-p13.3-
Type IIc, WS2C606662WS2C8p23-
Type IId, WS2D (very rare)608890SNAI28q11-
Type III, WS3148820PAX32q35Klein-Waardenburg syndrome
Type IVa, WS4A277580EDNRB13q22
Type IVb, WS4B613265EDN320q13
Type IVc, WS4C613266SOX1022q13


Facial morphology of Waardenburg syndrome

Symptoms vary from one type of the syndrome to another and from one patient to another, but they include:

Waardenburg syndrome has also been associated with a variety of other congenital disorders, such as intestinal and spinal defects, elevation of the scapula, and cleft lip and palate. Sometimes this is concurrent with Hirschsprung disease.

Type I is associated with more permanent hearing loss as for Type III over time hearing will be lost. Both are similar physically but there is no way to diagnose by eye, but to distinguish differences genetic testing is needed. Type II is most common out of all and its phenotypes are permanent hearing loss and heterochromia iridis (two different colored eyes) While Type IV has most of the symptoms associated with type II patients also tend to develop Hirschsprung's disease, intestinal problems, which can be life-threatening and surgery is needed for enlarged colon and failure to pass feces.[8]


This condition is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene 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 mutations in the gene; these cases occur in people with no history of the disorder in their family.

Some cases of type II and type IV Waardenburg syndrome appear to have an autosomal recessive pattern of inheritance, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.

Types I and III inheritance of this trait is autosomal dominant. There is a 50% chance that a child of an affected parent will be affected. Symptoms vary and so the extremity of symptoms cannot be determined. Types II and IV is autosomal recessive, symptoms are not definite they vary just as the other type’s symptoms will. A study was done on a rare case of a double heterozygous child with each parent having only single mutations in MTIF or PAX3. The affect of double heterozygous mutations in the genes MTIF and PAX3 in WS1 and WS2 can increase the pigment-affected symptoms. It leads to the conclusion that the double mutation of MTIF is associated with the extremity of Waardenburg Syndrome and may affect the phenotypes or symptoms of the syndrome [9]


There is currently no treatment or cure for Waardenburg syndrome. The symptom most likely to be of practical importance is deafness, and this is treated as any other irreversible deafness would be. In marked cases there may be cosmetic issues. Other abnormalities (neurological, structural, Hirschsprung disease) associated with the syndrome are treated symptomatically.

In animals[edit]

Waardenburg syndrome is known to occur in ferrets. The affected individual will usually have a small white stripe along the top or back of the head and sometimes down the back of the neck (this is known as a "blaze" coat pattern), or a solid white head from nose to shoulders (known as a "panda" coat pattern). The ferret will often have a very slightly flatter skull than ferrets without the syndrome and may have unusually wide-set eyes. As a ferret's sense of hearing is poor to begin with, associated deafness is not easily noticeable except for a lack of reaction to loud noises. As the disorder is easily spread to offspring, the affected animal will not be used for breeding by private, reputable breeders, although it may still be neutered and sold as a pet. However, largely as a result of mass-breeding due to the "exotic" markings it gives, 75% of US ferrets with a blaze or white head sold from pet stores are deaf.[10]

Domesticated cats with blue eyes and white coats are often completely deaf.[11] Whether or not this is a result of Waardenburg syndrome remains unclear.[12] Deafness is far more common in white cats than in those with other coat colors. According to the ASPCA Complete Guide to Cats, "17 to 20 percent of white cats with nonblue eyes are deaf; 40 percent of "odd-eyed" white cats with one blue eye are deaf; and 65 to 85 percent of blue-eyed white cats are deaf."[13] In the 1980's, college genetic classes taught that the genes for deafness and white coat color were closely linked, resulting in the majority of cats with completely white coats and bluer eyes being deaf.[14] The newer evidence cited above refutes this simplistic idea.

In popular culture[edit]

In the season 6 episode of Bones (TV Series), 'The Signs in the Silence', the team must solve a case in which the suspected killer has Waardenburg syndrome.

Enzo Macleod, protagonist of Peter May's series The Enzo Files, has Waardenburg syndrome. His eyes are different colors and he has a white streak in his hair. See pp. 17-18 of "Extraordinary People" (2006) by Peter Mays.

The book Reconstructing Amelia by Kimberly McCreight features several characters with Waardenburg symptoms.

Other contributors[edit]

See also[edit]


  1. ^ a b Waardenburg PJ (September 1951). "A New Syndrome Combining Developmental Anomalies of the Eyelids, Eyebrows and Noseroot with Pigmentary Anomalies of the Iris and Head Hair and with Congenital Deafness; Dystopia canthi medialis et punctorum lacrimalium lateroversa, Hyperplasia supercilii medialis et radicis nasi, Heterochromia iridum totalis sive partialis, Albinismus circumscriptus (leucismus, poliosis) et Surditas congenita (surdimutitas)". Am. J. Hum. Genet. 3 (3): 195–253. PMC 1716407. PMID 14902764. 
  2. ^ Petrus Johannes Waardenburg at Who Named It?
  3. ^ Klein-Waardenburg syndrome at Who Named It?
  4. ^ Arias S (1971). "Genetic Heterogeneity in the Waardenburg Syndrome". Birth Defects Original Article Series 7 (4): 87–101. PMID 5006208. 
  5. ^ Kumar, Sudesh, and Kiran Rao. “Waardenburg Syndrome: A Rare Genetic Disorder, A Report of Two Cases.” Indian Journal of Human Genetics 18.2 (2012): 254-255. Academic Search Premier. Web. 4 Apr. 2014.,
  6. ^ Egbalian F (2008). "Waardenburg-Shah Syndrome; A Case Report and Review of the Literature". Iranian Journal of Pediatrics 18 (1): 71–74. 
  7. ^ "Premature Graying Of Hair". 
  8. ^ Baral, Viviane, et al. “Screening of MTIF and SOX10 Regulatory Regions In Waardenburg Syndrome Type 2. “Plos ONE 7.7 (2012): 1-8. Academic Search Premier. Web. 4 Apr. 2014.
  9. ^ Yang, T, et al. “Double Heterozygous Mutations Of MTIF and PAX3 Result in Waardenburg Syndrome With Increased Penetrance In Pigmentary defects.” Clinical Genetics 83.1 (2013): 78-62. Academic Search Premier. Web. 3 Apr. 2014.
  10. ^ Matulich E. "Deafness in Ferrets". Cypresskeep.com. 
  11. ^ Webb AA, Cullen CC (2010). "Coat color and coat color pattern-related neurologic and neuro-ophthalmic diseases". The Canadian Veterinary Journal 51 (6): 653–657. PMC 2871368. PMID 20808581. 
  12. ^ Geigy CA, Heid S, Steffen F, Danielson K, Jaggy A, Gaillard C (2007). "Does a pleiotropic gene explain deafness and blue irises in white cats?". Veterinary Journal 173 (3): 548–553. doi:10.1016/j.tvjl.2006.07.021. PMID 16956778. 
  13. ^ Richards J (1999). ASPCA Complete Guide to Cats: Everything You Need to Know About Choosing and Caring for Your Pet. Chronicle Books. p. 71. ISBN 9780811819299. 
  14. ^ DeeAnn Williams Visk, personal recollection.

External links[edit]