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.

Figure 1

Incidence of progressive hearing loss after the baseline visit in patients who were not already showing profound hearing loss. Kaplan-Meier curves are adjusted for baseline age and initial hearing loss. MV indicates M34T or V371; NT, nontruncating; T, truncating.

Figure 2

Level of hearing in the better ear at the baseline visit in 118 patients with 2 GJB2 mutations based on the 4-frequency pure-tone average (PTA). MV indicates M34T or V371; NT, nontruncating; T, truncating.

Figure 3

Progressive hearing loss in an 8-year-old patient with 2 truncating GJB2 mutations. Hearing loss is shown in the right ear (A) and the left ear (B).