Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH.

Locus DFNB4 -acueducto vestibular dilatado- comportamiento audio-vestibular / Locus DFNB4 -enlarged vestibular aqueduct- behavior audio vestibular / Locus DFNB4 - aqueduto vestibular dilatada - comportamentoaudio-vestibular

Introducción: el acueducto vestibular dilatado, denominado en la literatura internacional EVA, porEnlarged Vestibular Aqueduct, ha sido reportadopor afectar hasta el 15% de la población pediátrica con hipoacusia neurosensorial. En su génesis compartecon Pendred en el Locus DFNB4, el Gen SLC26A4en el cromosma 7q22-31.1. No se conoce bienel comportamiento y la evolución de esta entidad,debido a la gran variabilidad genotípica y fenotípicaque presenta...

Introduction: Dilated Vestibular Aqueduct, known in the international literature Enlarged Vestibular Aqueduct (EVA) has been reported to affect up to 15% of the pediatric population with hearing loss Sensory Neuro. In its genesis shares with pendred in the locus DFNB4 the SLC26A4 gene in the cromosma 7q22-31.1. It is not well understood and evolution behavior of this entity, due to the great variability genotypic and phenotypic presented...

Introdução: Aqueduto vestibular dilatada conhecido na literatura internacional Enlarged Vestibular Aqueduct (EVA) tem sido relatada a afetar até 15% da população pediátrica com perda auditiva sensorial neuro. Em suas ações genesis com Pendred no Locus DFNB4 o gene SLC26A4 na 7q22-31.1 cromosma. Elenão é bem compreendida e o comportamento de evolução dessa entidade, devido à grande variabilidade genotípica e fenotípica apresentada...

Síndrome do aqueduto vestibular alargado: uma causa de disacusia neurossensorial / The large vestibular aqueduct syndrome: a cause of neurosensory dysacusia

TEMA: a síndrome do aqueduto vestibular alargado (SAVA) é caracterizada pelo alargamento do aqueduto vestibular associada a disacusia. O grau da perda auditiva é variável, podendo ser flutuante, progressiva ou súbita. Sintomas vestibulares podem estar presentes. O diagnóstico é realizado por exames de imagem. OBJETIVO: relatar um caso de SAVA. MÉTODO: lactente, gênero feminino, realizou tomografia computadorizada de ouvidos e exames de audição. RESULTADO: constatou-se alargamento do aqueduto vestibular maior que 1,5mm de diâmetro e perda auditiva neurossensorial à direita. CONCLUSÃO: com a avaliação auditiva precoce é possível o diagnóstico da disacusia, mesmo em crianças com disacusias unilaterais. Embora a literatura consultada mostre que o diagnóstico da SAVA ocorra tardiamente, no presente caso, o diagnóstico etiológico foi possibilitado pela tomografia computadorizada.

BACKGROUND: the large vestibular aqueduct syndrome (LVAS) is characterized by the enlargement of the vestibular aqueduct associated with sensorioneural hearing loss. The level of hearing loss varies and may be fluctuant, progressive or sudden. Vestibular symptoms may be present. The diagnosis is reached by imaging methods. AIM: To report an LVAS case. METHOD: a female infant was submitted to a computerized tomography of the ears and to audiologic tests. RESULTS: enlargement of the vestibular aqueduct of more than 1.5mm and sensorioneural hearing loss in the right ear were observed. CONCLUSION: with an early hearing evaluation it is possible to diagnose hearing loss, even in children were this loss is unilateral. Although the literature indicates that the diagnosis of LVAS occurs at a later age, in this case the etiologic diagnosis was enabled by computerized tomography.

Implante coclear e síndrome do aqueduto vestibular alargado em crianças / Cochlear implant and large vestibular aqueduct syndrome in children

Crianças com SAVA podem ter deficiências auditivas moderadas a severas durante fases precoces da infância, porém sua audição residual permite que elas desenvolvam linguagem oral com aparelhos auditivos convencionais e possam estar completamente integradas a condições escolares regulares. Contudo, estas crianças apresentam uma deterioração de sua habilidade auditiva com o decorrer do tempo e o implante coclear está sendo utilizado como uma opção para manter a habilidade auditiva. OBJETIVO: Avaliação da habilidade auditiva de 3 crianças com SAVA submetidas a implante coclear. MATERIAIS: Estudo retrospectivo baseado em revisão de prontuários. RESULTADOS: Em reconhecimento de palavras em campo aberto paciente 1, 80 por cento, paciente 2, 87,5 por cento, paciente 3, 4 por cento. CONCLUSÃO: Os pacientes com aqueduto vestibular alargado são considerados bons candidatos para implante coclear pelos principais centros de implante coclear do mundo, por desenvolverem, em sua maioria, bons resultados de percepção de fala, o que leva estes pacientes a uma boa inserção social.

Children with LVAS can develop a severe sensorineural hearing loss early in childhood, but they can be rehabilitated with hearing aids to continue their regular studies and to have a normal life. The problem is that they can deteriorate their hearing capacity, and at this point a cochlear implant can be used to preserve their hearing skills and vocalization. AIM: to evaluate the hearing skills of 3 children with LVAS referred to cochlear implants. MATERIAL: retrospective study based on medical charts' review. RESULTS: Speech recognition in open field: patient 1, 80 percent; patient 2, 87.5 percent; patient 3, 4 percent. CONCLUSION: Children with LVAS are considered good candidates for Cochlear implant surgery by the most important centers of the world because most of them can develop good speech recognition, providing them a good social life.