Temporal bone abnormalities in children with GJB2 mutations.

OBJECTIVES: To determine the incidence of temporal bone abnormalities in children with sensorineural hearing loss (SNHL) and pathogenic biallelic GJB2 mutations. STUDY DESIGN: Retrospective analysis of a large cohort of pediatric patients with biallelic GJB2 mutations and SNHL (observational case series). METHODS: Blinded review of all available temporal bone computed tomographic (CT) and magnetic resonance imaging (MRI) studies in this cohort. RESULTS: Out of 158 patients with biallelic GJB2 mutations, 113 had CT and/or MRI studies available for review. Definite, although generally subtle, inner ear abnormalities were present in 12/113. There were malformations of the semicircular canals (SCC) in 4/12, of the internal auditory canal in 2/12, of the cochlear nerve canal (CNC) in 6, and unilateral cochlear malformation in 1/12. MRI in 1/5 showed mildly hypoplastic cochlear nerve. There was no correlation between SNHL severity and presence/absence/type of malformations or genotype. CONCLUSIONS: Our study of 113 biallelic GJB2 patients with SNHL and temporal bone imaging is the largest study to date. We found only 10% had any abnormalities, most subtle, and none had EVA. Additionally, there was no correlation between SNHL severity and presence/absence/type of malformations or genotype. Disparities between our group and previous reports may be due to differences in degree of hearing loss, types of mutations, populations studied, and radiologic factors for both image acquisition and interpretation.

Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss.

OBJECTIVES: To document the audiologic phenotype of children with biallelic GJB2 (connexin 26) mutations, and to correlate it with the genotype. DESIGN: Prospective, observational study. SETTING: Tertiary care children's hospital. PATIENTS: Infants and children with sensorineural hearing loss (SNHL). INTERVENTION: Sequencing of the GJB2 (connexin 26) gene. MAIN OUTCOME MEASURES: Degree and progression of SNHL. RESULTS: From December 1, 1998, through November 30, 2006, 126 children with biallelic GJB2 mutations were identified. Of the 30 different mutations identified, 13 (43%) were truncating and 17 (57%) were nontruncating; 62 patients had 2 truncating, 30 had 1 truncating and 1 nontruncating, and 17 had 2 nontruncating mutations. Eighty-four patients (67%) initially had measurable hearing in the mild to severe range in at least 1 of 4 frequencies (500, 1000, 2000, or 4000 Hz). Of these 84 patients with residual hearing, 47 (56%) had some degree of progressive hearing loss. Patients with 2 truncating mutations had significantly worse hearing compared with all other groups. Patients who had 1 or 2 copies of either an M34T or a V37I allele had the mildest hearing loss. CONCLUSIONS: Hearing loss owing to GJB2 mutations ranges from mild to profound and is usually congenital. More than 50% of patients will experience some hearing loss progression, generally gradually but occasionally precipitously. Hearing loss severity may be influenced by genetic factors, such as the degree of preserved protein function in nontruncating mutations, whereas hearing loss progression may be dependent on factors other than the connexin 26 protein. Genetic counseling for patients with GJB2 mutations should include the variable audiologic phenotype and the possibility of progression.

Additional clinical manifestations in children with sensorineural hearing loss and biallelic GJB2 mutations: who should be offered GJB2 testing?

Sensorineural hearing loss (SNHL), the most common sensory impairment noted at birth, occurs in 3 out of every 1,000 births live births. At least half of congenital SNHL is genetic in origin, with nonsyndromic, or isolated hearing loss, accounting for approximately 70% of the total genetic causes. Syndromic hearing loss (hearing loss associated with other clinical findings) makes up the remaining 30%. Worldwide, mutations in the gap junction beta 2 (GJB2) gene, encoding the connexin 26 (Cx26) protein, are responsible for approximately 30% of all cases of childhood SNHL. GJB2 mutations have been primarily associated with nonsyndromic forms of bilateral SNHL although rare syndromic forms involving dermatologic manifestations have also been reported. In general, unless skin findings are present, children with bilateral SNHL and other structural or developmental abnormalities are not generally thought of as candidates for GJB2 testing. We evaluated 163 individuals with biallelic GJB2 mutations and SNHL for the presence of other clinical findings. Twenty-nine of the 163 (18%) were found to have structural and/or developmental abnormalities in addition to the SNHL and four subjects had diagnoses that were felt to account for their hearing loss prior to being screened for GJB2 mutations. Although the GJB2 mutations are likely not responsible for these additional clinical manifestations, this study underscores the importance of considering GJB2 mutational analysis in individuals with more than just isolated SNHL given the high prevalence of GJB2-related hearing loss.

GJB2 mutations and degree of hearing loss: a multicenter study.

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.