RESUMEN
OBJECTIVES: Mutations in EYA4 can cause nonsyndromic autosomal dominant sensorineural hearing impairment (DFNA10) or a syndromic variant with hearing impairment and dilated cardiomyopathy. A mutation in EYA4 was found in a Dutch family, causing DFNA10. This study is focused on characterizing the hearing impairment in this family. DESIGN: Whole exome sequencing was performed in the proband. In addition, peripheral blood samples were collected from 23 family members, and segregation analyses were performed. All participants underwent otorhinolaryngological examinations and pure-tone audiometry, and 12 participants underwent speech audiometry. In addition, an extended set of audiometric measurements was performed in five family members to evaluate the functional status of the cochlea. Vestibular testing was performed in three family members. Two individuals underwent echocardiography to evaluate the nonsyndromic phenotype. RESULTS: The authors present a Dutch family with a truncating mutation in EYA4 causing a mid-frequency hearing impairment. This mutation (c.464del) leads to a frameshift and a premature stop codon (p.Pro155fsX). This mutation is the most N-terminal mutation in EYA4 found to date. In addition, a missense mutation, predicted to be deleterious, was found in EYA4 in two family members. Echocardiography in two family members revealed no signs of dilated cardiomyopathy. Results of caloric and velocity step tests in three family members showed no abnormalities. Hearing impairment was found to be symmetric and progressive, beginning as a mid-frequency hearing impairment in childhood and developing into a high-frequency, moderate hearing impairment later in life. Furthermore, an extended set of audiometric measurements was performed in five family members. The results were comparable to those obtained in patients with other sensory types of hearing impairments, such as patients with Usher syndrome type IIA and presbyacusis, and not to those obtained in patients with (cochlear) conductive types of hearing impairment, such as DFNA8/12 and DFNA13. CONCLUSIONS: The mid-frequency hearing impairment in the present family was found to be symmetric and progressive, with a predominantly childhood onset. The results of psychophysical measurements revealed similarities to other conditions involving a sensory type of hearing impairment, such as Usher syndrome type IIA and presbyacusis. The study results suggest that EYA4 is expressed in the sensory cells of the cochlea. This phenotypic description will facilitate counseling for hearing impairment in DFNA10 patients.
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Familia , Pérdida Auditiva Sensorineural/fisiopatología , Percepción del Habla , Población Blanca/genética , Adolescente , Adulto , Anciano , Audiometría del Habla , Niño , Progresión de la Enfermedad , Femenino , Pérdida Auditiva Sensorineural/genética , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Transactivadores/genética , Pruebas de Función VestibularRESUMEN
Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.
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Microtia Congénita/diagnóstico , Microtia Congénita/terapia , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/terapia , Micrognatismo/diagnóstico , Micrognatismo/terapia , Rótula/anomalías , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/terapia , Microtia Congénita/genética , Femenino , Trastornos del Crecimiento/genética , Humanos , Masculino , Micrognatismo/genética , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Anomalías Urogenitales/terapiaRESUMEN
PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members. RESULTS: All affected individuals showed loss of neuroretinal rim of the optic nerve at fundoscopy with enlarged blind spots at perimetry. They showed a red-green color vision defect at color vision tests and deviations at visually evoked response tests. The audiograms of the affected individuals showed hearing loss and were relatively flat. The unaffected individuals showed no visual deviations or hearing impairment. The affected family members had no glucose intolerance. Leber hereditary optic neuropathy (LHON) mitochondrial mutations and mutations in the Optic atrophy-1 gene (OPA1) were excluded. In the affected individuals, a novel missense mutation c.2508G>C (p.Lys836Asn) in exon 8 of WFS1 was identified. CONCLUSIONS: This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1.
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Genes Dominantes/genética , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación/genética , Enfermedades del Nervio Óptico/complicaciones , Enfermedades del Nervio Óptico/genética , Adulto , Anciano de 80 o más Años , Secuencia de Aminoácidos , Secuencia de Bases , Secuencia Conservada , Análisis Mutacional de ADN , Diabetes Mellitus/genética , Evolución Molecular , Familia , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/fisiopatología , Pruebas Auditivas , Humanos , Masculino , Proteínas de la Membrana/química , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenómenos Fisiológicos Oculares , Enfermedades del Nervio Óptico/fisiopatología , Linaje , Fenotipo , Adulto JovenRESUMEN
PURPOSE: To describe the phenotype of Best vitelliform macular dystrophy (BVMD) and to evaluate genotype-phenotype and histopathologic correlations. METHODS: Retrospective analysis of patients with BVMD who underwent an extensive ophthalmic examination, including best-corrected Snellen visual acuity, fundus examination by indirect ophthalmoscopy, fundus photography, fundus autofluorescence, optical coherence tomography, fundus fluorescein angiography, and electrooculography. In addition, molecular genetic analysis of the BEST1 gene was performed in all patients. RESULTS: We examined 40 eyes of 20 patients with BVMD. Sixteen eyes (40%) had a well-defined BVMD stage, whereas 18 eyes displayed characteristics attributable to different stages. Six eyes had an atypical form of BVMD. Fundus autofluorescence and optical coherence tomography frequently detected abnormalities that were not visible on ophthalmoscopy. All patients carried a mutation in the BEST1 gene. Molecular genetic analysis identified 8 different BEST1 mutations in 15 families, including 2 novel mutations (p.Gly299Ala and p.Ile3Thr). Genotype-phenotype correlation was limited, as we observed a broad phenotypic range in association with a single BEST1 mutation. However, the p.Ala243Val seems to cause a mild and relatively invariable BVMD phenotype. CONCLUSION: A broad phenotypic variability may be observed in BVMD, even with a single BEST1 mutation. Fundus autofluorescence and optical coherence tomography are valuable noninvasive imaging techniques for phenotyping and follow-up of BVMD patients.
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Canales de Cloruro/genética , Proteínas del Ojo/genética , Degeneración Macular/genética , Degeneración Macular/patología , Mutación , Adolescente , Adulto , Bestrofinas , Niño , Electrooculografía , Femenino , Angiografía con Fluoresceína , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Biología Molecular , Oftalmoscopía , Fenotipo , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
Mutations in GJB2 (connexin26) are associated with skin disorders and deafness. The Clouston syndrome (MIM129500) is associated with mutations in GJB6 (connexin30). Here, we describe a patient suffering from a Clouston-syndrome-like phenotype of thin hair, deafness, nail dystrophy, and mild erythrokeratoderma, caused by a novel spontaneous missense mutation in GJB2. The heterozygous mutation in codon 42, AAC>AAG, changes asparagine to lysine (N14K). Interestingly, this asparagine is near two of the residues mutated in Keratitis-like ichthyosis deafness (KID) syndrome (G12R and S17F), yet the phenotype associated with N14K strongly differs from the KID phenotype. Instead, there is a clear phenotypic overlap with syndromes associated with connexin26 or 30 mutations. Our finding suggest that careful audiological evaluation of patients suffering from Clouston-syndrome-like phenotypes is warranted and expand the spectrum of connexin26-associated disease.