Waardenburg Syndrome

An auditory pigmentary syndrome characterized by hypopigmentation of the skin, iris, hair and stria vascularis of the cochlea. Most patients present with two different colored eyes, white forelock and eyelashes, and premature graying of the hair. Moderate acrocephaly, lack of osseous fusion of the short tubular bones, oligodactyly of the feet, short stature, pericardial cysts, rectal prolapse, and deformed ears are reported. Other features include hypoplastic maxilla, asymmetry of hands, deformity of the first phalanx of the head, absence of the first digit of the foot, and bifid distal phalanges of the second and third toes.

(Figure)

Petrus Johannes Waardenburg Syndrome (Dutch ophthalmologist, 1886-1979); WS I.

All forms of WS together, estimates are that about 1:40,000 individuals of the general population are affected by this disorder, which may be responsible for up to 3% of patients with congenital deafness. In Kenya, the estimated frequency is reported at 1:20,000 persons. It is also reported at 1:212,000 individuals in the general population of the Netherlands.

(see also Clinical Aspects) Autosomal dominant inheritance characterizes Waardenburg Syndrome Type 1 (WS 1), which has been mapped to 2q35. If dystopia canthorum (lateral displacement of the inner canthi of the eyes) is absent, the syndrome is called WS Type 2. WS 3 is a severe form of this disorder in which both, heterozygosity and homozygosity of mutations in the PAX3 gene (paired box gene 3) have been reported.

Almost all cases are at least due in part to mutations of the PAX3 gene (paired box gene 3), which is involved in the formation of the caudal neural crest derivatives and the migration of myoblasts into the extremities. Children with this syndrome have a normal life expectancy.

Two major or one major plus two minor features must be present for the diagnosis. Major features: congenital sensory hearing loss and pigmentary disturbance of the iris with different-colored eyes or segmental heterochromia; hair hypopigmentation; affected first-degree relative. Minor features: congenital leukoderma, medial eyebrow flare, high nasal root, nasal alae hypoplasia, premature graying of scalp.

Four different types of Waardenburg Syndrome have been defined:

Waardenburg Syndrome Type 1 (WS 1): It was in 1947, when the Dutch ophthalmologist and geneticist Petrus Johannes Waardenburg first presented a patient with sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi of the eyes), hypertrichosis of the medial aspect of the eyebrows, broad nasal bridge, and pigment anomalies of skin (albinism), iris (heterochromia iridis) retina, and hair (white forelock or poliosis) to the Swiss Society of Genetics. After he found several more patients with similar findings, Waardenburg fully described what is now known as WS 1.

Waardenburg Syndrome Type 2 (WS 2): Has all the features of WS 1, except dystopia canthorum. Both WS 1 and WS 2 are transmitted as autosomal dominant conditions with the responsible gene being mapped to 2q35. Mutations in the microphthalmia-associated transcription factor (MITF) gene, located on chromosome band 3p14.1-p12.3, are responsible for some of the cases of WS 2, while others have been linked to band 1p.

Waardenburg syndrome type 3 (WS 3) (Synonym: Klein-Waardenburg Syndrome): Shows, in addition to the findings of WS 1, musculoskeletal abnormalities (e.g., hypoplasia of the musculoskeletal system with severe flexion contractures, spastic paraplegia, winged scapulae, aplasia of the first two ribs, sacral anomalies, carpal bone fusion, and bilateral syndactylies), microcephaly, and mental retardation. WS 3 is also autosomal-dominant transmitted and some of the patients have even been found to be homozygous for the defect. The defect has been mapped to the same locus as WS 1 and WS 2.

Waardenburg syndrome type 4 (WS 4) (Synonym: Waardenburg-Shah Syndrome): In addition to the features of WS 1, this type is associated with Hirschsprung disease. The inheritance is either autosomal recessive or autosomal dominant and the genetic defect seems to also involve either the endothelin-3 (EDN3) or the endothelin-B receptor (EDNRB) genes and has been mapped to several different gene loci (13q22, 22q13, 20q13.2-q13.3).

Depends on the severity of the disease. If there are significant contractures and muscular hypoplasia, then respiratory reserve may be reduced and evaluation with chest radiographs, arterial blood gas, and pulmonary function tests would be of value. The cardiac function should be assessed using echocardiography. The presence of facial abnormalities should be evaluated in preparation for difficult tracheal intubation. Assess the presence of pericardial cysts and cardiovascular compromise. Depending on the surgical procedure prolonged ventilation may be required.

Mental retardation and hearing deficit may result in poor cooperation at time of induction and premedication may be appropriate. Both direct laryngoscopy and tracheal intubation may be difficult and proper planning should be done. The accessibility to a laryngeal mask airway and/or fiberoptic equipment might be indicated. Intravenous access and positioning on the table may be difficult. Special attention must be provided to reduce pressure point using proper padding. Postoperative analgesia may be uneasy with mental retardation, musculoskeletal abnormalities, and reduced respiratory reserve.

Neuromuscular relaxants may be unnecessary and should be used cautiously. Succinylcholine is relatively contraindicated. Opioids should be used with caution if respiratory reserve is critical. Analgesia using regional techniques should be considered.