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.
Description
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 differentcolored 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 Hirschprung 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-Hirschprung disease, Waardenburg-Shah syndrome, Shah-Waardenburg syndrome, and Hirschprung 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 Hirschprung 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.
WS1
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 albinismthat 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. Hirschprung 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.
WS2A
People who 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.
WS2B
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.
WS3
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.
WS4
Individuals with WS4 usually do not have dystopia canthorum, and often do not have hearing loss. Hirschprung 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 Hirschprung disease. A small proportion of people with WS4 have been found to have an abnormal SOX10 gene.
Demographics
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.
WS2
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.
Diagnosis
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:
1 in 40,000 for all types; WS 3 and WS 4 are less common than WS 1 and WS 2
Dystopia 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 2A
AD
MITF
3
Same 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 2B
AD
"WS2B"
1
See WS 2A
WS 3
AD or sporadic
Deletions including PAX3
2
Similar symptoms to WS 1 but also features abnormalities of arm muscles and bones
WS 4
AR AR AD
EDNRB EDN3 SOX10
13 20 22
Usually dystopia canthorum is absent and incidence of hearing loss is reduced Hirschsprung disease
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 Hirschprung 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 Hirschprung 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.
Prognosis
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.
BOOKS
Gorlin, Robert J., Helga V. Toriello, and M. Michael Cohen. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press, 1995.
PERIODICALS
Mishriki, Yehia Y. "Facial Clues to an Inherited Syndrome." Postgraduate Medicine (July 2000): 107–110.
ORGANIZATIONS
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. faces@faces-cranio.org. <http://www.faces-cranio.org/>.
National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. nadinfo@nad.org. <http://www.nad.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>.
