Waardenburg syndrome (WS) is an uncommon autosomal inherited and genetically heterogeneous disorder of neural crest cell development named after the Dutch ophthalmologist P. J. Waardenburg in 1951.
Based on the clinical presentations, four subtypes are described. According to the diagnostic criteria proposed by the Waardenburg consortium, a person must have two major or one major plus two minor criteria in order to be diagnosed as WS type I [Table 1]. WS type II lacks dystopia canthorum of WS type I. Type III, also called Klein–Waardenburg syndrome, has associated limb abnormalities. Type III is the rarest form of WS. Shah–Waardenburg syndrome, type IV, is an unusual variant of WS associated with Hirschsprung’s disease (long-segment, short-segment or even limited to persistent constipation). It is named after Krishnakumar N. Shah who described 12 new-borns with Waardenburg syndrome associated with long segment Hirschsprung’s disease in 1981. WS belongs to the neurocristopathies, disorders caused by an alteration in the migration of the neural crest cells during the embryonic phase. These neural crest cells are important for the formation of several parts of the body, i.e. melanocytes, inner ear and enteric nervous system. Other features very rarely associated with WS include vestibular symptoms, urinary system abnormalities, neural tube defects, Sprengel anomaly, cleft-lip or palate, facial nerve palsy and plicated tongue, laryngomalacia, and severe cyanotic cardiopathy.
Heterozygous mutations in the PAX3 gene on chromosome 2 are seen in WS I (dominant trait). WS type III is also ascribed to PAX3 mutation, either to very specific heterozygous mutations or to bi-allelic mutants (most cases are therefore recessive). WS type II is usually transmitted as dominant trait and has been related either to MITF (mapped on chromosome 3) or SOX10 (chromosome 22) heterozygous mutations. Two cases of WS type II have been described with homozygous mutation of SNAI2 (chromosome 8). WS type IV is heterogeneous, ascribed either to SOX10 (dominant trait), EDN3 (recessive trait) or EDNRB (dominant or recessive trait) mutations.
It is noteworthy that the expressivity is variable among affected family members, i.e. some may have only white skin patches and others having also deafness and Hirschsprung’s disease.
Few patients with WS type IV have in addition neurological symptoms (neuropathy, central dysmyelinating leukodystrophy with ataxia, spasticity, intellectual deficiency, and autonomic dysregulation). This dominant disorder named PCWH is caused by some specific SOX10 mutations.
The differential diagnosis of white forelock and skin patches are vitiligo, piebaldism (rarely associated with deafness), Rozycki syndrome (leukoderma, congenital deafness, muscle wasting, and achalasia), Vogt–Koyanagi–Harada syndrome (uveitis, greying of hair, meningitis, and vitiligo of auto-immune origin), Tietz syndrome (deaf-mutism, blue eyes, and hypomelanosis, related to MITF heterozygous mutations and therefore allelic to WS type II), and tuberous sclerosis (autosomal dominant disorder with other skin manifestations, often seizures and intellectual deficiency, brain, kidney, cardiac, ocular and pulmonary lesions, but without deafness).
Table 1: Diagnostic criteria for Waardenburg syndrome type I
Major criteria Minor criteria
White forelock Broad/high nasal root
Pigmentary disturbances of the iris Hypoplasia of alae nasi
Congenital sensorineural hearing loss Synophrys or medial eyebrow flaring
Affected first-degree relative Skin hypopigmentation
Dystopia canthorum or laterally Prematurely greying of hair
Displaced medial canthi