Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss

Abstract

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.

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

“…High-frequency hearing loss was comparably defined over 2,000, 4,000, and 8,000 Hz. Clinically significant change was predefined as a difference of ≥10 dB, averaged across the three frequencies (40).…”

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss

“…However, progressive or later-onset hearing loss-with infants passing their newborn hearing screen-have also been described, particularly in association with nontruncating mutations. [39][40][41][42] Nonsyndromic hearing loss due to mutations at the DFNB1 locus may also be caused by (i) interaction of a GJB2 mutation on one allele and a deletion involving GJB6 on the other allele or (ii) biallelic deletions involving GJB6. [43][44][45] GJB6 deletions have been observed in multiple populations, although they appear to be a relatively uncommon explanation for hearing loss in the United States.…”

Acquired Hearing Loss in Children

“…For example, hearing loss associated with GJB2 (connexin 26) may present as very mild, or even normal, in the newborn period, then go on to progressively worsen. 6,7 Hearing loss associated with mutations in SLC26A4, usually associated with the presence of EVA, may present as mild, mixed, or even initially conductive and is often progressive and fluctuating. 8 Genetic susceptibility is well documented for hearing loss related to aminoglycosides and may also be a factor in patients with noise-related hearing loss and ototoxicity related to other medications.…”