Commentary: Waardenburg syndrome: Genetics and ocular features

Waardenburg Syndrome (WS) is named after the ophthalmologist who first described the association between deafness, depigmentation, and dysmorphology.[1] It is the most common cause of syndromic hearing loss with variable degrees of pigmentation defects and ocular changes like heterochromia iridis, iris hypopigmentation, medial eyebrow flare (synophrys), and dystopia canthorum.[2] Four subtypes of WS have been defined, with type I and II being the most common.[1] Type I WS (WS1) is inherited as an autosomal dominant (AD) disease.[3] Dystopia canthorum is the distinguishing and constant feature in this subtype. Iris heterochromia and strabismus are other ocular features. Other main features are broad, high nasal root, medial hypertrichosis, synophrys, hypoplasia of the alae nasi, patent metopic suture, piebaldism, and congenital non-progressive sensorineural hearing loss. These features show marked inter- and intra-familial variability.[3] Some authors also report progressive post-lingual hearing loss associated with WS.[4] Nearly all patients with WS1 have Paired Box 3 (PAX3) mutation.[3] Type 2 WS (WS2) has identical auditory and pigmentary features to WS1 but lacks dystopia canthorum. It is inherited as AD, and 15% have microphthalmia-associated transcription factor (MITF) mutation.[3] Type 3 WS (WS3) or Klein–Waardenburg syndrome is a variant of WS1 with musculoskeletal abnormalities like limb muscles hypoplasia and joint contracture. Usually a PAX3 heterozygote, it is inherited as AD.[3] Type 4 WS (WS4) or Shah–Waardenburg syndrome is associated with Hirschsprung’s Disease (HD). It is primarily autosomal-recessive (AR) and associated with endothelin 3 (EDN3) or endothelin receptor type B (EDNRB) mutations.[3] Various other genes have also been implicated in the pathogenesis of this disorder, namely, sex-determining region Y—Box 10 (SOX10) for WS2 and WS4 and snail family transcriptional repressor 2 (SNAI2) for WS2.[1] EDNRB mutation has been detected in WS1 also.[1]

Agrawal et al. have reported a case which was diagnosed as WS1 upon the presence of the following features: congenital sensorineural hearing loss, heterochromia iridium, dystopia canthorum, and broad and high nasal root.[5] Dystopia canthorum is the distinguishing ocular feature for WS1, which is absent in WS2. In addition, bilateral sectoral, as well as diffuse iris depigmentation, has also been described in patients of WS1.[6] Shields et al.[6] have reported on anterior segment optical coherence tomography (OCT) findings that revealed the hypopigmented iris to be thinner and with shallower crypts than the normal iris.^[6T] Sectoral as well as diffuse choroidal hypopigmentation have also been reported by them. Posterior-segment OCT showed a normal retina, but the subfoveal choroid in the hypopigmented eye was slightly thinner than the choroid in the normal eye. Fundus autofluorescence demonstrated mild hyper autofluorescence (scleral unmasking) in the hypopigmented choroid.[6] Juvenile open-angle glaucoma has also been associated with WS.[7] The myriad of phenotypes and discovery of new mutations mandate a thorough genetic workup in all patients presenting with clinical features of WS.