Genetic deafness and blindness syndromes — formative SAQs

Question 1 (10 marks)

A newborn boy fails his universal hearing screen on both ears at day 3 and again at day 10. Diagnostic auditory brainstem response testing at six weeks confirms bilateral severe sensorineural hearing loss. His physical examination is entirely normal. There is no family history of hearing loss and no consanguinity. (a) Outline your initial aetiological workup. (b) Given negative GJB2 and CMV PCR with bilateral enlarged vestibular aqueducts, name the diagnosis and further workup. (c) State the recurrence risk and reproductive options. [1] [2]

Model answer

(a) The workup confirms the hearing loss with diagnostic ABR and OAE, then pursues the aetiology in a tiered sequence. CMV PCR on saliva or urine within the first three weeks of life excludes congenital cytomegalovirus, the most common non-genetic cause and a treatable one if identified early. An ECG is non-negotiable to exclude Jervell and Lange-Nielsen syndrome with its prolonged QT and sudden-death risk. GJB2 sequencing is the highest-yield single genetic test for congenital nonsyndromic sensorineural hearing loss. Temporal bone CT or MRI looks for enlarged vestibular aqueduct or cochlear malformation. A three-generation pedigree and parental examination complete the initial assessment. [2] [7]

(b) With negative GJB2 and CMV PCR but bilateral enlarged vestibular aqueducts on imaging, the diagnosis is Pendred syndrome caused by SLC26A4 variants affecting the pendrin transporter. The further workup includes SLC26A4 sequencing, thyroid function tests, and thyroid ultrasound, recognising that the goitre may be absent in childhood and biochemically euthyroid. The family is counselled that Pendred is autosomal recessive with variable expressivity, and that minor head trauma can worsen the hearing loss. [5]

(c) The recurrence risk for a confirmed autosomal-recessive condition is 25 per cent for each subsequent pregnancy. Reproductive options include prenatal diagnosis by chorionic villus sampling or amniocentesis with targeted SLC26A4 testing, and preimplantation genetic testing with in-vitro fertilisation. Cascade testing of first-degree relatives identifies carrier status and enables informed reproductive decisions. [1]

Question 2 (10 marks)

A four-year-old girl with known bilateral severe sensorineural hearing loss of unknown cause, managed with hearing aids since infancy, is brought by her parents who have noticed she is increasingly clumsy in dim light and bumps into furniture at night. Her development is otherwise normal. (a) What is the most likely diagnosis and its molecular basis? (b) What investigation confirms it and what surveillance follows? (c) Explain the current state of gene therapy for inherited retinal disease. [4]

Model answer

(a) The most likely diagnosis is Usher syndrome, the most common cause of combined deafness and blindness. The two-wave presentation — congenital or early-onset sensorineural hearing loss followed years later by retinitis pigmentosa presenting as night blindness — is its hallmark. The molecular basis is a loss-of-function variant in one of the Usher genes, most commonly MYO7A (type I) or USH2A (type II), which encode proteins essential for hair-cell and photoreceptor ciliary structure and transport. The visual component appears later because the photoreceptor degeneration progresses slowly, so the electroretinogram is abnormal years before the child notices symptoms. [4]

(b) The diagnosis is confirmed by ophthalmology assessment including electroretinography, which shows a reduced or extinguished rod response before symptomatic field loss, and by molecular testing of the Usher genes. The surveillance plan includes annual ophthalmology review with visual fields and ERG, low-vision assessment, mobility and orientation training, and educational planning for progressive visual impairment. Genetic counselling addresses the autosomal-recessive inheritance and the 25 per cent recurrence risk. [4] [2]

(c) Voretigene neparvovec is the first FDA-approved in-vivo gene therapy for an inherited disease, indicated for confirmed biallelic RPE65-related Leber congenital amaurosis, not for Usher syndrome. Delivered as subretinal injections of an AAV vector carrying a functional RPE65 gene, it restores the retinal visual cycle and improves multi-luminance mobility in patients with surviving photoreceptors. For Usher syndrome, gene-therapy trials are in early phases; current management is supportive. The key teaching point is that molecular diagnosis now carries therapeutic urgency because the genotype determines eligibility for approved and emerging therapies. [11]