Waardenburg syndrome type 2

Introduction

Waardenburg syndrome (WS) is a rare clinical entity, with the worldwide incidence of 1 in 40,000.¹ WS is an autosomal dominant disorder of neural crest cell development. There are 4 variants of WS, in which WS type I (WS1) and WS type 2 (WS2) are commoner than the other variants. WS1 is an auditory-pigmentary disorder with hypopigmentation of skin, iris and hair, along with lateral displacement of the inner canthi (dystopia canthorum) and congenital sensorineural hearing loss.² On the other hand WS2 is characterized by absence of dystopia canthorum. Sensorineural hearing loss and heterochromia iridium are the two more commoner features of WS2.³ WS type 3 has dystopia canthorum and presence of upper limb abnormalities. WS type 4 has Hirschsprung disease in addition and is also known as Waardenburg-Shah syndrome. We report an infant with WS2 for its rarity and discuss pertinent review of literature.

Case report

5-Month-old female infant presented with history of multiple non-progressive hypopigmented skin lesions and ‘red looking eyes at night’ since birth. She was a product of non-consanguineous marriage with no relevant family history. Antenatal history was uneventful and she was born through vaginal delivery at term. Her birth weight was 3.1 kg and her developmental milestones were normal as per mother. So far she was being treated as vitiligo, by various doctors. On presentation she weighed 5.9 kg with head circumference of 41 cm (both normal for age). She was having multiple hypopigmented macules and patches of varying sizes in extremities and trunk (Fig. 1, Fig. 2). She also had hypopigmented hairs over scalp, more so anteriorly (Fig. 3). Both irides were hypopigmented with blue tinge and on taking a photograph in dark, she had brilliant red reflex (Fig. 4). Though neurological examination revealed no abnormality, but clinically there was no response to loud noise when assessed for hearing. She underwent Brainstem Evoked Response Audiometry (BERA), which revealed no identifiable peak V till 90 dB in both sides, suggesting bilateral severe to profound hearing loss. The Waardenburg index (W index)⁴ was calculated and was found to be 0.57. In the index case, the W index was less than 1.95, which in presence of other characteristic clinical features differentiated it to be a case of WS2. Presently she is scheduled for cochlear implantation.

Fig. 1.

Hypopigmented patch over extremity.

Fig. 2.

Hypopigmented patch over trunk.

Fig. 3.

Hypopigmented hairs over scalp, white forelock, blue irides.

Fig. 4.

Blue irides with brilliant red reflex.

Discussion

Waardenburg himself delineated the 6 chief characteristics of WS named after him, including (1) telecanthus (lateral displacement of the medial canthus), (2) a broad nasal root, (3) synophrys of the eyebrows, (4) a white forelock (termed piebaldism), (5) heterochromia irides, and (6) deaf-mutism.⁵ Later on the diagnostic criteria of WS as per Waardenburg Consortium were laid down.⁴ The major criteria for diagnosing WS are congenital sensorineural hearing loss, white forelock/hair hypopigmentation, pigmentary abnormalities of the iris (complete heterochromia iridum/partial or segmental heterochromia/hypoplastic blue irides or brilliant blue irides), dystopia canthorum with W index >1.95 and an affected first-degree relative. The minor criteria are skin hypopigmentation (congenital leukoderma), synophrys and/or medial eyebrow flare, broad/high nasal root or low hanging columella, underdeveloped alae nasi and premature grey hair (age <30 years). W index is calculated as follows. The measurements necessary to calculate the W index (in mm) are inner canthal distance (a), interpupillary distance (b), and outer canthal distance (c).

$$\begin{array}{l}\text{Calculate}X=(2a-(0.2119c+3.909))/c\hfill \\ \text{Calculate}Y=(2a-(0.2479b+3.909))/b\hfill \\ \text{Calculate}W=X+Y+a/b\hfill \end{array}$$

A W index result >1.95 is the distinguishing feature of WS1. Two major features should be present to make the diagnosis of WS2 and the major features are the same as listed above except dystopia canthorum and inclusion of premature greying.³

The pathogenesis of WS2 is attributed to the mutations in genes including PAX3, MITF, SNAI2, SOX10, ENDRB, and EDN3, eventually leading to abnormal development of neural crest cells, thereby affecting activation and migration of melanoblasts, survival of melanocytes and development of facial bones.⁶

Sensorineural hearing loss, heterochromic irides, blue irides are commoner with WS2, whereas white forelock, leukoderma, high nasal root and medial eyebrow flare are commoner with WS1. The most frequent cutaneous pigmentary abnormality in WS is the white forelock (17–58.4% of patients) followed by white macules (15% of patients).⁷ Often the white macules are misdiagnosed as vitiligo, if ocular features and hearing deficit are not appreciated, as it was in our case prior to reporting to us. The ophthalmological features include, dystopia canthorum, which is the most frequent feature in WS1, followed by hypopigmentation of the iris and retina.⁸ Prevalence of hearing loss, which is sensorineural in nature, significantly vary among the different clinical types as shown in a recent systematic review and was maximum with WS2 (91.6%).⁹ The outcome of cochlear implantation is considered good in such cases¹⁰ and our patient is being worked up for an early cochlear implant so that the infant achieves the maximum potential of speech. The family history of similar illness in first degree relatives and abnormal nasal features were absent in our case. Though the diagnosis as in our case was established clinically, this condition being a genetically heterogeneous condition, the future plan is to establish molecular diagnosis by next generation sequencing (NGS) needed for further genetic counselling for the next pregnancy of the mother.

To conclude, we have presented a rare case of WS2, who will undergo cochlear implantation soon. The aim of reporting this case is the rarity of this condition and to sensitize the readers of association of hearing loss with hypopigmented skin and iris.

Conflicts of interest

The authors have none to declare.