Electrifying Blue Eyes: The Genetic Mystery of Waardenburg Syndrome

Varsha Singh, B.Optom.

M. Optom Student, The Sankara Nethralaya Academy, Chennai, India

Waardenburg syndrome (WS), identified by Dutch ophthalmologist P. J. Waardenburg in 1951, is a genetic condition marked by six characteristic features: wide-set eyes, a broad nasal bridge, extra hair in the inner eyebrows, partial or complete heterochromia (different coloured eyes), a white forelock, and congenital deafness.⁽¹⁾ It is typically used to describe dominantly inherited cases of auditory-pigmentary syndromes, where there is a lack of melanocytes in the skin, hair, eyes, or the stria vascularis of the cochlea, leading to patchy depigmentation.⁽²⁾

WS is classified into four subtypes depending on the different concomitant clinical phenotypes.⁽³⁾ Waardenburg syndrome clinically presents with key phenotypic features, primarily sensorineural hearing loss (SNHL) and widespread pigmentation abnormalities.⁽⁴⁾

Table 1: Characteristics and genes involved in WS.

Data retrieved from; Huang, S., Song, J., He, C. et al. Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther 29, 479–497 (2022).

Incidence and Prevalence Data

Incidence rates of WS vary globally, with the highest reported in Kenyan Africans, where the prevalence is 1 in 42,000 (0.024 per 1,000).⁽²⁾  A recent study, however, reports an incidence ranging from 0.119 to 0.208 per 1,000.⁽⁵⁾ It accounts for 2–5% of patients with congenital hearing loss.⁽⁶⁾ The prevalence of hearing loss (HL) varies significantly across different clinical types: 52.3% in WS1, 91.6% in WS2, 57.1% in WS3, and 83.5% in WS4.⁽⁷⁾

Ocular Manifestation

Ocular abnormalities in WS vary widely in their manifestations. The characteristic ocular abnormality is abnormal iris pigmentation,⁽⁸⁾ which can manifest as complete heterochromia (different colours in each eye), partial heterochromia (segmented blue), or a stunted, bright blue iris,⁽⁹⁾ causing the eye to appear electrifying blue. In some cases, ptosis, choroidal hypopigmentation, hypopigmented fundi, branch retinal vein occlusion, high intraocular pressure, bilateral glaucoma, synophrys, epicanthal folds, telecanthus, strabismus, hyperopic amblyopia and rhegmatogenous retinal detachment have also been observed.^(8,10-16)

Conclusion

Waardenburg Syndrome involves pigmentation disorders and ocular abnormalities, including both external and intraocular defects. It requires a multidisciplinary approach, with otologists, ophthalmologists, dermatologists, paediatricians, and geneticists collaborating to customise interventions that address the various features of the syndrome. Ocular conditions can be managed with sunglasses for UV protection and coloured contact lenses in cases of heterochromia. External eye abnormalities, such as ptosis, epicanthal folds, or telecanthus, can be corrected with ocular plastic surgery, benefiting the child’s physical development.⁽⁸⁾

References:

1. Dourmishev, A. L., Dourmishev, L. A., Schwartz, R. A., & Janniger, C. K. (1999). Waardenburg syndrome. International Journal of Dermatology, 38(9), 656–663.
2. Read, A. P., & Newton, V. E. (1997). Waardenburg syndrome. Journal of medical genetics, 34(8), 656-665.
3. Koyama, H., Kashio, A., Sakata, A., Tsutsumiuchi, K., Matsumoto, Y., Karino, S., … & Yamasoba, T. (2016). The hearing outcomes of cochlear implantation in Waardenburg syndrome. BioMed Research International, 2016(1), 2854736.
4. Huang, S., Song, J., He, C., Cai, X., Yuan, K., Mei, L., & Feng, Y. (2022). Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene therapy, 29(9), 479-497.
5. Zaman, A., Capper, R., & Baddoo, W. (2015). Waardenburg syndrome: More common than you think. Clinical Otolaryngology. Retrieved from https://www.academia.edu/
6. Nayak C.S. & Isaacson G. (2003) Worldwide distribution of Waardenburg syndrome. Ann. Otol. Rhinol. Laryngol. 112, 817–820
7. Song, J., Feng, Y., Acke, F. R., Coucke, P., Vleminckx, K., & Dhooge, I. J. (2016). Hearing loss in Waardenburg syndrome: a systematic review. Clinical Genetics, 89(4), 416–425.
8. Liu, Y., Pan, H., Wang, J., Yao, Q., Lin, M., Ma, B., & Li, J. (2020). Ophthalmological features and treatments in five cases of Waardenburg syndrome. Experimental and Therapeutic Medicine, 20(4), 3072–3077.
9. Ohno, N., Kiyosawa, M., Mori, H., Wang, W. F., Takase, H., & Mochizuki, M. (2003). Clinical findings in Japanese patients with Waardenburg syndrome type 2. Japanese Journal of Ophthalmology, 47(1), 77–84.
10. Chen, H., Jiang, L., Xie, Z., Mei, L., He, C., Hu, Z., Xia, K., & Feng, Y. (2010). Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome. Biochemical and Biophysical Research Communications, 397(1), 70–74.
11. Tamayo, M. L., Gelvez, N., Rodriguez, M., Florez, S., Varon, C., Medina, D., & Bernal, J. E. (2008). Screening program for Waardenburg syndrome in Colombia: Clinical definition and phenotypic variability. American Journal of Medical Genetics Part A, 146(8), 1026–1031.
12. Kadoi, C., Hayasaka, S., & Yamamoto, S. (1996). Branch retinal vein occlusion in a patient with Waardenburg syndrome. Ophthalmologica, 210(6), 354–357.
13. Gupta, V., & Aggarwal, H. C. (2000). Open angle glaucoma as a manifestation of Waardenburg’s syndrome. Indian Journal of Ophthalmology, 48(1), 49–50.
14. Nork, T. M., Shihab, Z. M., Young, R. S., & Price, J. (1986). Pigment distribution in Waardenburg’s syndrome: A new hypothesis. Graefe’s Archive for Clinical and Experimental Ophthalmology, 224(6), 487–492.
15. Chua, S. W., Mohd Khialdin, S., Mustapha, M., Md Din, N., & Yong, M. H. (2022). Association of type II Waardenburg syndrome with hypermetropic amblyopia. International Journal of Ophthalmology, 15(4), 677–680.
16. Shin, J., & Lee, E. K. (2022). Rhegmatogenous retinal detachment in Waardenburg syndrome: A case report. Korean Journal of Ophthalmology: KJO, 36(5), 468–470.