Heterochromia caused by Waardenburg syndrome in a 2-month-old infant

A 2-month-old male infant was referred to our ophthalmology clinic because of his iris discoloration. We observed complete iris heterochromia, with dark brown in the right iris and blue in the left iris (Figure 1). A family history revealed hearing loss in both maternal and paternal grandparents. We evaluated the patient’s auditory brain-stem response and found left-sided hearing impairment. After consultation with a pediatric geneticist, subsequent whole-exome sequencing showed a heterozygous nonsense variant, c.1066C>T (p.Arg356Ter), in the microphthalmia-associated transcription factor (MITF) gene. We diagnosed Waardenburg syndrome, type 2A. We referred the infant for additional investigations to detect rare features of Waardenburg syndrome such as congenital heart abnormalities and Hirschsprung disease. Cardiac echocardiography, conducted when the infant was 5 months of age, showed a left-to-right atrial shunt, while abdominal ultrasonography was unremarkable.

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Figure 1:

Iris heterochromia in a 2-month-old infant, with dark brown in the right iris (normal-coloured eye) and blue in the left iris.

Iris heterochromia is uncommon and can be congenital or acquired. The overall prevalence is estimated between 0.063% and 0.256%, with congenital heterochromia seen even less frequently.1 Congenital heterochromia is often an isolated condition, without other systemic manifestations or anomalies. However, the differential diagnosis of congenital heterochromia includes Horner syndrome (ipsilateral ptosis, miosis, and facial anhidrosis), Sturge–Weber syndrome (port-wine birthmark), neurofibromatosis type 1 (café-au-lait spots, optic gliomas, and Lisch nodules), and Waardenburg syndrome (sensorineural hearing loss, pigmentary abnormalities, and musculoskeletal abnormalities).2 Waardenburg syndrome can have varying expression of ocular manifestations in affected family members, where one may exhibit complete heterochromia while another may display partial heterochromia or no ocular manifestations.3 Clinicians should consider syndromic associations for patients with congenital heterochromia and make referrals to both an ophthalmologist and genetic services. Genetic analysis — including whole-exome sequencing, targeted Waardenburg syndrome panels, or ocular disorder panels — is useful in the diagnosis of syndromes associated with congenital heterochromia.