Waardenburg syndrome - Report of two cases

INTRODUCTION

Neural crest cells are multipotent cells arising near neural tubes and give rise to structures such as skin melanocytes, inner ear cells, glia, some cells of the nervous system, and craniofacial structures. Disorders of neural crest cells are termed neurocristopathies.^[1,2] Waardenburg syndrome type-1 (WS-1: OMIM#193500) classified as neurocristopathies is an autosomal dominant disorder caused by mutations in the PAX3 gene. The disorder is characterised by sensorineural hearing loss, dystopia canthorum and pigmentary abnormalities of hair, skin and eyes and is classified under auditory pigmentation disorder.^[3] The disorder is clinically heterogeneous. Here, we present two cases of WS-1 from India.

CASE SERIES

Case-2

One girl born to a non-consanguineously married couple with uneventful antenatal and birth history presented to us with complaints of being unable to speak or hear. Other milestones are normal for age [Figures 1a and b]. On examination, the baby was not responding to sound, and white forelock, heterochromia iridium, dystopia canthorum and hypopigmented skin over the dorsum of hands and legs were present [Figures 2a and b]. Mother also has a white forelock and dystopia canthorum. Brain stem auditory-evoked potentials showed no wave suggestive of bilateral auditory pathway dysfunction. Exome sequencing revealed homozygous mutation c.268T>C (p.Tyr90His) in the PAX3 gene. Based on the above findings a diagnosis of WS-1 was made and confirmed by genetic testing.

Close

Figure 1:

(a and b) Clinical photograph of case two showing white forelock, heterochromia iridium and dystopia canthorum.

Export to PPT

Close

Figure 2:

(a and b) Clinical photographs of case two showing hypopigmented skin over the dorsum of the hand and leg.

Export to PPT

In both cases, routine investigations, complete hemogram, liver function, renal function tests, magnetic resonance imaging of the brain, lactate, ammonia, arterial blood gas and Tandem mass spectrum were normal.

DISCUSSION

WS is phenotypically recognised under four types, type-1(OMIM#193500) and type-2 (OMIM#193510) have similar features except type-1 has dystopia canthorum. Type-3 (OMIM#148820) additionally has dystopia canthorum along with upper limb anomalies. Type-4 (OMIM#277580) also known as Waardenburg-Shah syndrome additionally has Hirschsprung disease (HD). Peripheral demyelinating neuropathy, central dysmyelination, WS and HD (PCWH syndrome) a subtype of type-4 have features of mental retardation, peripheral neuropathy, spasticity, and cerebellar ataxia.

Clinical features in type-1 WS include sensorineural hearing loss (47–58%), heterochromia irides (15–31%), hypoplastic blue irides (15–18%), white forelock (43–48%), early greying (23–38%), leukoderma (22–36%), high nasal root (52–100%) and medial eyebrow flare (63–73%).^[4-6] The differential diagnosis considered was Piebaldism (OMIM#172800) caused due to mutations in the dominant mutations in KIT or SNAI2 gene. The common features between this and WS are pigmentary changes and white forelock of hair; however, deafness and iris defects are rarely reported. The other disorder is Tietz syndrome (OMIM#103500) caused by dominant mutations in the MITF gene. The features common are albinism and deafness,

Farrer et al. suggested diagnostic criteria for WS, based on the presence of two major or one major and two minor criteria suffices for the diagnosis of WS-1^[7] and confirmed by genetic testing. In the current report, case-1 and 2 had all the five major features thus fitting the diagnosis: congenital sensorineural hearing loss, white forelock and hair hypopigmentation, heterochromia iridium and dystopia canthorum and a first-degree relative affected with the same features.

Paired box-3 (PAX3) gene is located on chromosome 2q35 and functions in the preservation of pluripotency of stem cells, specification of cell lineage, proliferation, and inhibition against terminal differentiation, migration and apoptosis. PAX3 alteration is seen in many cancers like rhabdomyosarcoma. It also plays a developmental role in the nervous system, neural crest-derived cells and skeletal and cardiac tissue.^[8,9] Both our cases previously reported mutation in the PAX3 gene were noted.

CONCLUSION

A combination of sensorineural deafness, pigmentation abnormalities of skin, iris and hair with dystopia canthorum, a diagnosis of WS-1 needs to be considered.