Paeds · genetics-dysmorphology-and-metabolism
Genetic deafness and blindness syndromes
Also known as Syndromic hearing loss · Usher syndrome · Pendred syndrome · Waardenburg syndrome · Jervell and Lange-Nielsen syndrome · Branchio-oto-renal syndrome · Leber congenital amaurosis · Norrie disease · Connexin 26 deafness · Dual sensory loss
A fellowship approach to genetic deafness and blindness syndromes: recognise the infant who fails newborn hearing screening as a candidate for GJB2 and Usher evaluation, build the diagnostic tier from audiology and ophthalmology through targeted gene panels, separate Usher as the dominant dual-sensory cause from single-sensory syndromes like Pendred, Waardenburg, Jervell and Lange-Nielsen, branchio-oto-renal, Leber congenital amaurosis and Norrie disease, and deliver early cochlear implantation, voretigene neparvovec for RPE65 retinal dystrophy, and cascade family testing.
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- An infant who fails newborn hearing screening and does not pass diagnostic ABR requires urgent aetiological workup — delay past six months compromises language outcomes
- Congenital sensorineural hearing loss with syncope or a family history of sudden death demands an ECG to exclude Jervell and Lange-Nielsen long QT before any anaesthesia
- A deaf child who develops night blindness or visual field loss has Usher syndrome until proven otherwise — refer for urgent ophthalmology and electroretinography
- Preauricular pits or branchial cleft remnants with hearing loss require a renal ultrasound to exclude branchio-oto-renal syndrome
- An infant with congenital nystagmus, poor visual fixation and an extinguished electroretinogram has Leber congenital amaurosis — molecular diagnosis opens gene-therapy eligibility
- A boy with congenital blindness who later develops progressive hearing loss and developmental delay has Norrie disease — X-linked inheritance means maternal carrier testing
- Every confirmed syndromic case triggers cascade testing of first-degree relatives — half of autosomal-recessive cases will have an affected or carrier sibling
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- Causes of congenital sensorineural hearing loss including GJB2 and congenital CMV
- Recognition of syndromic hearing loss (Pendred, Waardenburg, branchio-oto-renal)
- Indications for genetic testing in childhood deafness
- Usher syndrome and dual sensory loss — molecular genetics and surveillance
- Leber congenital amaurosis and voretigene neparvovec gene therapy
- Jervell and Lange-Nielsen syndrome and cardiac risk
- Assessing the infant who fails newborn hearing screening
- Coordinating audiology, ophthalmology, cardiology and genetics
- Genetic counselling of autosomal-recessive sensory loss
- Long case of a deaf child with progressive visual loss
- Counselling a family on Usher syndrome and reproductive options
- Genetic causes of childhood sensory impairment
- Communication and shared decision-making with Deaf families
- Safeguarding and transition in chronic sensory impairment
- Genetics of hereditary hearing loss — GJB2, SLC26A4, PAX3
- Leber congenital amaurosis and retinal dystrophies
- Jervell and Lange-Nielsen and cardiac-channelopathy deafness
- Examination of the child with hearing and visual impairment
- Counselling on genetic testing and cochlear implantation
- Hereditary hearing loss and the newborn hearing screen
- Leber congenital amaurosis and gene therapy
- Syndromic causes of childhood deafness and blindness
- Genetic deafness and blindness syndromes
- Newborn hearing screening and early intervention
- Multidisciplinary care of chronic sensory impairment
- Hereditary hearing loss — genetics and cochlear implantation
- Leber congenital amaurosis and voretigene neparvovec
- Syndromic dual sensory loss (Usher, Norrie)
The mark-winning candidate holds three layers together. The first is the child's sensory phenotype: what can they hear, what can they see, and at what age did the loss appear. The second is the molecular mechanism: a gap-junction protein, a motor protein, an ion channel, or a retinal visual-cycle enzyme, each pointing to a specific gene and inheritance pattern. The third is the hidden complication: a long QT interval, a renal anomaly, a goitre, or a progressive retinal degeneration that has not yet declared itself. Missing any layer is the classic examination error. [2] [4]
Overview & Definition
Genetic deafness and blindness syndromes are inherited disorders in which a single pathogenic gene variant produces sensorineural hearing loss, retinal or ocular blindness, or both. They are the dominant cause of permanent childhood sensory impairment once environmental factors such as congenital cytomegalovirus and prematurity are excluded, and they cluster into syndromic forms, where the sensory loss is accompanied by a second organ system, and nonsyndromic forms, where the ear or eye is the only site. [1] [2]
Hearing loss is the entry point for most of these children, because universal newborn hearing screening identifies congenital deafness within the first month of life. Roughly half of permanent childhood hearing loss is genetic, and of the genetic cases around 70 per cent are nonsyndromic with GJB2 as the single largest contributor, while 30 per cent are syndromic and carry the extra-organ findings that make the diagnosis. [1] [3]
Vision loss enters through the paediatric eye clinic, where the combination of congenital nystagmus, poor visual fixation, and a roving eye movement pattern raises Leber congenital amaurosis or Norrie disease. The crossover — a child who is both deaf and blind — is Usher syndrome territory, and recognising the crossover early is the single highest-yield clinical decision in this whole family of conditions. [4] [9]
References11ShowHide
- [1]Morton CC, Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med, 2006.PMID 16707752
- [2]Lieu JEC, Kenna M, Anne S, Davidson L. Hearing Loss in Children: A Review. JAMA, 2020.PMID 33258894
- [3]Shen J, Oza AM, Del Castillo I, Duzkale H, Matsunaga T, Pandya A, et al. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med, 2019.PMID 31160754
- [4]Castiglione A, Möller C Usher Syndrome. Audiol Res, 2022.PMID 35076463
- [5]Wémeau JL, Kopp P Pendred syndrome. Best Pract Res Clin Endocrinol Metab, 2017.PMID 28648509
- [6]Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat, 2010.PMID 20127975
- [7]Bitner-Glindzicz M, Tranebjaerg L. The Jervell and Lange-Nielsen syndrome. Adv Otorhinolaryngol, 2000.PMID 10868213
- [8]Kochhar A, Fischer SM, Kimberling WJ, Smith RJ. Branchio-oto-renal syndrome. Am J Med Genet A, 2007.PMID 17238186
- [9]Huang CH, Yang CM, Yang CH, Hou YC, Chen TC. Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations. Genes, 2021.PMID 34440435
- [10]De Silva SR, Arno G, Robson AG, Fakin A, Pontikos N, Mohamed MD, et al. The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Prog Retin Eye Res, 2021.PMID 32860923
- [11]Padhy SK, Takkar B, Narayanan R, Venkatesh P, Jalali S. Voretigene Neparvovec and Gene Therapy for Leber's Congenital Amaurosis: Review of Evidence to Date. Clin Ophthalmol, 2020.PMID 33268999