Waardenburg Syndrome

Waardenburg syndrome is a group of genetic disorders with sensorineural hearing loss and pigmentary changes of hair, skin and eyes, caused by abnormal development of neural crest cells.

It affects about 1 in 40,000 people and accounts for 2 to 5% of congenital deafness. Types 1 and 2 are the commonest, type 3 has limb anomalies and type 4 has Hirschsprung disease.

Inheritance is usually autosomal dominant (types 1, 2 and 3), with autosomal recessive and dominant forms in type 4. Genes are PAX3 (types 1 and 3), MITF and SNAI2 (type 2) and SOX10, EDN3 and EDNRB (type 4).

Pathophysiology.

Neural crest cells give rise to melanocytes, enteric neurons and the cochlear stria vascularis. Loss of these cell types leads to white patches, pale irises, hearing loss through absence of melanocytes in the cochlea and, in type 4, absence of ganglion cells in the bowel.

• White forelock (30 to 40%), early grey hair, patches of depigmented skin, and pale blue or two coloured irises (heterochromia).
• Congenital sensorineural hearing loss, often bilateral and severe in type 2 and variable in type 1.
• Dystopia canthorum (lateral displacement of the inner corners of the eyes), a broad nasal root and synophrys in type 1 and type 3.
• Limb contractures in type 3. Constipation or intestinal obstruction in type 4.

Red flags.

• Newborn who has failed hearing screening.
• Neonatal obstruction or severe constipation (Hirschsprung disease).

• Clinical diagnosis from major and minor criteria. Measure the canthal distance and look for a white forelock, iris changes and skin depigmentation.
• Audiology at birth (otoacoustic emissions and auditory brainstem response) and for all affected relatives.
• Genetic testing (PAX3, MITF, SOX10, SNAI2, EDN3, EDNRB). Rectal biopsy for suspected Hirschsprung disease. Temporal bone imaging (inner ear malformations) before cochlear implant.

Differential diagnosis.

• Piebaldism (KIT variant), vitiligo and oculocutaneous albinism.
• Tietz syndrome, Alezzandrini syndrome and other syndromic hearing loss.
• Isolated deafness (GJB2) and other pigmentary disorders.

• Early hearing intervention: hearing aids for mild to moderate loss, and cochlear implantation for severe to profound loss, with speech therapy and educational support. Early treatment before 6 months of age gives the best outcome.
• Surgical treatment for Hirschsprung disease and for contractures in type 3.
• Sun protection for depigmented skin and camouflage cosmetics. No treatment restores hair colour.
• Genetic counselling: 50% risk in autosomal dominant types.

Special groups. Pregnancy in affected women: offer genetic counselling and consider prenatal testing, since cleft lip and palate and neural tube defects are reported with PAX3 variants.

Monitoring. Hearing and speech development every 6 months in early childhood, then yearly.

Referral and escalation. Audiology and ENT, genetics, and paediatric surgery for suspected Hirschsprung disease.