Waardenburg Syndrome

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Waardenburg syndrome


Waardenburg syndrome (WS) encompasses several different hereditary disorders, the main features of which variably include abnormal pigmentation, hearing loss, and a subtle difference in facial features. Certain other physical anomalies occur less frequently in WS.


In 1951, Dr. Petrus Waardenburg reported a syndrome of dystopia canthorum, heterochromia of the irides, and hearing loss. Dystopia canthorum (also called telecanthus) describes a subtle but unusual facial feature in which the inner corners of the eyes (canthi) are spaced farther apart than normal, yet the eyes (pupils) themselves are normally spaced. The result is that the eyes appear to be widely spaced, even though they are not. Heterochromia means different-colored, and irides is the plural form of iris—the colored portion of the eye. Thus, someone with heterochromia of the irides has different-colored eyes, often one brown and one blue. Another feature not originally noted by Dr. Waardenburg, but now considered a major sign of WS is a white forelock (white patch of hair extending back from the front of the scalp). In fact, disturbances in pigmentation (coloring) of various parts of the body are consistent features of WS. Uncommon but serious physical anomalies associated with WS include Hirschsprung disease (intestinal malformation), spina bifida , cleft lip/palate, and musculoskeletal abnormalities of the arms.

Five types of WS have been defined based on clinical symptoms or genetic linkage. As of 2000, six different genes were associated with WS. Most families show autosomal dominant inheritance , but autosomal recessive inheritance and sporadic (single) cases are also seen. People with WS are not at increased risk for mental retardation, and vision loss is not more common. For the majority of those with WS, hearing loss is the only major medical problem they will have.

WS1 is the "classic" form of WS, and if someone uses just the name Waardenburg syndrome (with no modifying number), they are most likely referring to the group of disorders as a whole or just WS1. WS2 may occasionally be referred to as WS without dystopia canthorum. WS3 is also known as Klein-Waardenburg syndrome, as well as WS with upper limb anomalies. Alternate names for WS4 include Waardenburg-Hirschsprung disease, Waardenburg-Shah syndrome, Shah-Waardenburg syndrome, and Hirschsprung disease with pigmentary anomaly.

Genetic profile

Since Dr. Waardenburg's original description of his patients in 1951, many more families with the same or similar symptoms have been reported. By 1971, it became clear that a proportion of families have WS without dystopia canthorum. At that point, Waardenburg syndrome was divided into two distinct types, WS1 and WS2. In addition, a few individuals with typical signs of WS1 were found to also have musculoskeletal symptoms. This form of the disorder was named Klein-Waardenburg syndrome, now also known as WS3. Further, some researchers noted yet a different pattern of anomalies involving pigmentation defects and Hirschsprung disease, which eventually became known as WS4. Finally, genetic testing of WS2 families has shown at least two subtypes—those that show genetic linkage are designated as WS2A and WS2B.

The four major types of WS have all been studied through DNA (genetic) analysis. There is some agreement between the clinical subtypes of WS and mutations in different genes, but genetic analysis has also served to confuse the naming scheme somewhat. The different types of WS, their inheritance patterns, and the genes associated with them, are listed below.


A number of different mutations in a single copy of the PAX3 gene on chromosome 2 are responsible for all cases of WS1, meaning it is always inherited as an autosomal dominant trait. The PAX3 gene plays a role in regulating other genes that have some function in producing melanocytes (pigment-producing cells). PAX3 was formerly known as the HUP2 gene.


People that have typical signs of WS2 are designated as having WS2A only if genetic testing shows them to have a mutation in the MITF gene on chromosome 3. As with WS1, all cases of WS2A appear to be autosomal dominant. There is evidence that MITF is one of the genes regulated by PAX3.


Some individuals with typical WS2 have had normal MITF gene analysis. A search for a different WS2 gene showed that some cases are linked to a gene on chromosome 1. This gene has been tentatively designated WS2B until its exact chromosomal location and protein product are identified. WS2B displays autosomal dominant inheritance.


Several people with a severe form of WS1 have been shown by genetic analysis to have a deletion of a small section of chromosome 2. Several genes are located in this section, including the PAX3 gene. Not all patients with WS3 have had the exact same genetic anomaly on chromosome 2, which may explain the variation in symptoms that have been reported. Some families with WS3 have displayed autosomal dominant inheritance, while other individuals with the condition have been sporadic cases.


Mutations in three different genes—EDNRB, EDN3, and SOX10 on chromosomes 13, 20, and 22 respectively—have been linked to WS4. Those cases of WS4 associated with the EDNRB and EDN3 show autosomal recessive inheritance, while the SOX10-associated cases are dominantly inherited.

Individuals with one of the autosomal dominant types of WS have a 50% risk of passing on the gene each time they have a child. A couple that has a child with WS4 linked to EDNRB or EDN3 faces a 25% risk for recurrence in each subsequent child. WS is quite variable, even within families. For instance, a parent with minimal pigment disturbance, mild facial features, and no hearing loss may have a child with pronounced physical features and deafness, and vice versa. There may be some correlation between specific gene mutations and the incidence of certain symptoms, but precise predictions are not possible.

As of 2000, the six genes listed above were those known to be associated with WS. It is expected, however, that more genes will be identified, especially since only a minority of WS2 cases have shown linkage to the MITF and WS2B genes.


The prevalence of WS is estimated at one in 40,000. About 3% of all children with congenital deafness have WS. WS1 and WS2 occur with approximately the same frequency. WS3 and WS4 are much less common than the other types. The majority of people with WS are Caucasian, but members of other ethnic groups may be affected as well.

Signs and symptoms


Dystopia canthorum is seen in 99% of people with WS1. Other facial features may include decreased length of the nasal bone, a broad/high nasal root (top of the nose), and increased length of the lower face. Seventy percent of people with WS1 have either a medial flare of the eyebrows or synophrys (joining of the eyebrows in the middle, also called blepharophimosis).

Some type of pigmentary disturbance is nearly always present, and involves hypopigmentation (decreased color) of the skin, hair, and/or irides. However, unlike the more common forms of albinism that often involve a generalized lack of pigment in the body, WS is characterized by patches of hypopigmentation—often termed "partial albinism." A white forelock or premature graying is seen in about 70% of people with WS1. The eyelashes and patches of body hair may also be hypopigmented. Heterochromia of the irides may be complete (25% of patients) or partial (5% of patients). In complete heterochromia, each eye is a different color. In partial heterochromia, an individual iris (in one or both eyes) is composed of two colors. Those people with WS1 who do not have iris heterochromia often have brilliant blue coloring of both eyes.

Although estimates vary, hearing loss of some type is present in about 60% of individuals with WS1. The true prevalence is difficult to determine because of the variable nature of the condition. About 80% of those with hearing loss are affected in both ears (bilateral). Profound hearing loss occurs in some 25% of all people diagnosed with WS1.

Spina bifida (open spine) is seen in a very small percentage of newborns with WS1, as is cleft lip/palate. Hirschsprung disease, a deformation in which the colon becomes enlarged (megacolon), is a somewhat more frequent anomaly. Sprengel anomaly (elevated shoulder blade) can also be seen. Overall, about 10% of children with WS1 have one of these anomalies.


The major clinical distinction between WS1 and WS2 is the absence of dystopia canthorum in WS2. Otherwise, the conditions mostly differ by incidences of the various symptoms. The incidence of hearing loss in WS2 is 80%, with about 30% having a profound loss. Heterochromia of the irides occurs in 50% of patients. White forelock, premature graying, and hypopigmented skin patches are each found in about 15–20% of people with WS2. Synophrys occurs in only 5% of patients.


WS3 could be considered a subtype of WS1, since both are associated with the PAX3 gene. The distinction is clinical, with the added feature in WS3 being abnormalities of the muscles and bones of the arms. Some cases of WS3 have been sporadic. Several individuals diagnosed with WS3 have been in families where other members have typical signs of WS1. Thus, in some cases, WS3 can be considered a severe form of PAX3-associated WS, and is a dramatic example of the variability that can occur within families.


Individuals with WS4 usually do not have dystopia canthorum, and often do not have hearing loss. Hirschsprung disease is the major distinguishing feature of WS4. In fact, individuals who carry a single abnormal EDNRB or EDN3 gene (as opposed to two abnormal copies of either gene in WS4) have only Hirschsprung disease. A small proportion of people with WS4 have been found to have an abnormal SOX10 gene.


In the early 1990s, a group of researchers known as the Waardenburg Consortium established criteria for diagnosing someone with WS1. They considered the major criteria of WS1 to be:

  • congenital sensorineural hearing loss (not due to some other obvious cause)
  • pigmentary disturbance of the iris
  • hair hypopigmentation of some type
  • dystopia canthorum
  • an affected first-degree relative (parent, sibling, or child)

Minor criteria established by the Waardenburg consortium include:

  • several areas of hypopigmented skin
  • synophrys or medial flare of the eyebrows
  • broad and high nasal root
  • hypoplastic alae nasi (cartilage and skin around the nostrils)
  • premature graying of hair

Waardenburg syndrome

WS 1ADPAX321 in 40,000 for all types; WS 3 and WS 4 are less common than WS 1 and WS 2Dystopia canthorum (99%); Medial flare of eyebrow or joining of eyebrows in the middle (70%); Hypopigmentation of skin, hair, and/or irides; Heterochromia of irides (30%); Hearing loss (60%)
WS 2AADMITF3Same symptoms as WS 1, but without dystopia conthorum; Incidence of symptoms varies from WS 1, e.g. hearing loss (80%), heterochromia of irides (50%), joining of eyebrows (5%)
WS 3AD or sporadicDeletions including PAX32Similar symptoms to WS 1 but also features abnormalities of arm muscles and bones
WS 4ARARADEDNRBEDN3SOX10132022Usually dystopia canthorum is absent and incidence of hearing loss is reduced Hirschsprung disease

In order to be diagnosed with WS1, a person must have two major criteria, or one major plus two minor criteria. A modification of the list for WS2 includes removing dystopia canthorum, and including premature graying as a major criterion. With those modifications, a person with no family history of the condition should have two major criteria to be considered for WS2, and someone with an affected family member need only have one major criterion. Diagnosing WS2 can be more difficult than diagnosing WS1 because of the lack of dystopia canthorum. In addition, some people with a white forelock or premature graying may color their hair, and thus conceal an important sign.

As indicated, the distinction between WS1 and WS3 is clinical, with musculoskeletal anomalies added to the list of criteria for WS1. The criteria for diagnosing WS4 would be similar to those for WS2, with the inclusion of Hirschsprung disease as a major criterion, and the probable exclusion of dystopia canthorum, broad nasal root, and severe hearing loss. In addition, by definition WS4 is not linked to PAX3, MITF, or WS2B, and is linked to one of the established WS4 genes (assuming genetic testing is available and informative).

Treatment and management

The primary medical consideration for people with WS is hearing loss. The most effective intervention is hearing aids. It is widely accepted that infants at risk for hearing loss, such as those who may inherit WS from a parent, can benefit from screening in the newborn period. An undiagnosed hearing deficit can result in delays in speech and learning. Children with profound hearing loss are eligible for special accommodations in their education, and the entire family can benefit by starting to use sign language very early.

Although spina bifida in WS is uncommon, the potential complications are serious. Infants with spina bifida usually have damage to the spinal cord at the level of the open spine, and consequently have either partial or total paralysis below that point. The opening in the spine can be repaired, but the neurological damage to the spinal cord is permanent. Cleft lip/palate is also uncommon in WS, but is a serious birth defect. Children with cleft lip/palate usually require several surgeries, but the outcome of the repair is generally very good. It would be prudent to screen any infant of a parent with WS for Hirschsprung disease. Surgical removal or repair of the affected segment of colon is often necessary. Depending on the severity of the musculoskeletal anomalies, a child with WS3 might require some sort of orthopedic intervention, such as casting, bracing, or surgery. A few children with WS3 have had only minor joint contractures of the arms and hands.

Genetic counseling is indicated for any family with WS. Prenatal diagnosis might be an option if genetic testing in the family is informative, but many couples may not choose invasive testing if they would not terminate a pregnancy for WS.


The majority of people with WS lead productive lives. In the absence of severe hearing loss, many people with WS would not be noticed as having a condition by anyone in the general population. If hearing loss is present, it usually does not get worse, and is often amenable to treatment. There is little hope for any preventive measures for WS, since all of the features of the syndrome occur early in embryonic development and are present at birth.



Gorlin, Robert J., Helga V. Toriello, and M. Michael Cohen. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press, 1995.


Mishriki, Yehia Y. "Facial Clues to an Inherited Syndrome." Postgraduate Medicine (July 2000): 107-110.


Alexander Graham Bell Association for the Deaf, Inc. 3417 Volta Place NW, Washington, DC 20007-2778. (800) 432-7543. <http://www.agbell.org>.

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 332-2373. [email protected] <http://www.facescranio.org/>.

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. [email protected] <http://www.facescranio.org/>.

National Organization for Albinism and Hypopigmentation. 1530 Locust St. #29, Philadelphia, PA 19102-4415. (215) 545-2322 or (800) 473-2310. <http://www.albinism.org>.

Research Registry for Hereditary Hearing Loss. 555 N. 30th St., Omaha, NE 68131. (800) 320-1171. <http://www.boystown.org/btnrh/deafgene.reg/waardsx.htm>.

Scott J. Polzin, MS