1

Introduction

Congenital hearing loss accounts for 60% of deafness, of which 30% are related to an underlying syndrome while the remaining are non-syndromic. Most genetic causes of hearing loss are inherited in an autosomal recessive manner. Connexin 26 (Cx 26) is the most commonly mutated protein among autosomal recessive prelingual, non-syndromic causes of hearing loss. It is thought that mutations in Cx 26 are responsible for up to 20% of cases of childhood deafness . The GJB 2 gene encodes a gap junction protein, Cx 26. Six connexin proteins combine in a circular formation to form a connexon. Connexons from adjacent cells line up forming a gap junction. Gap junctions in the cochlea play an important role in maintaining the transmembrane potassium electrochemical gradient . Cx 26 is found in the non-neural support epithelium of the cochlea including the stria vascularis, basement membrane, and the spiral limbus of the cochlea .

Cochlear implantation (CI) is a reliable auditory restorative option for patients with severe and profound sensorineural hearing loss. Factors that influence the hearing outcomes of implantee vary. Studies have demonstrated that age at implantation, amount of residual hearing and mode of communication can influence outcomes . The etiology of the hearing loss additionally plays a role in outcomes. In diseases known to impact the central nervous system and the auditory system such as infection with cytomegalovirus (CMV) and meningitis, the outcomes have been shown to be worse than diseases that exclusively affect the hair cells and cochlea . The association between Cx26 mutation and CI outcomes has been studied with conflicting results. A recent study analyzing speech outcomes in 11 patients with Cx 26 mutations following cochlear implant found that they had equal or better outcomes compared to a group of prelingually deafened patients of unknown etiology . Bauer et al. also found that patients with Cx 26 mutations had significantly better reading performance. Nonetheless, other studies have demonstrated no short term or long term differences in auditory outcomes between the two patient groups .

Pathological analysis of temporal bones from patients with the GJB2 mutation has demonstrated that Cx 26 pathology does not affect the spiral ganglion cells . The spiral ganglion cells are stimulated by the cochlear implant; hence patient post-operative outcomes may be expected to depend on their function. Moreover, mutations in Cx 26 do not appear to impact the central nervous system potentially contributing to improved outcomes .

We hypothesize that patients with profound sensorineural hearing loss and Cx 26 mutation have better outcomes following cochlear implantation compared to their age matched controls.

Short term (less than 12 months following initial implantation), intermediate term (12–24 months following initial implantation) and long term outcomes (greater than 24 months following initial implantation) were studied; as the full benefits of cochlear implants take 3–4 years to be realized . Moreover, linear regression model analysis was performed to determine the impact of patient factors such as age at implantation, gender and type of mutation on outcomes. This information could be useful to patients in their future visits when their prognosis and expected outcomes following CI are discussed.

2

Materials and methods

Following departmental and institutional review board approval, a retrospective chart review of the cochlear implant database was conducted. The charts of all patients who received a cochlear implant under age 18 at University Hospitals Case Medical Hospital, a tertiary care center, between January 2002 and December 2012 were reviewed. Patient charts, operative reports and laboratory testing were thoroughly reviewed for etiology of hearing loss. Charts were reviewed for demographic information and audiometric outcomes. Patients who had genetic testing that demonstrated homozygous mutations of the GJB2 gene, absence of other radiographically or clinically identifiable causes of hearing loss were included in the Cx 26 study group. A matched group of control subjects for age at first implantation (0–≤24 months, 25–<48 months and ≥ 48 months) was identified from the same cochlear implant database. All patients in the control group had an identifiable etiology of hearing loss unrelated to Cx 26 mutation or genetic analysis without evidence of mutation in the GJB2 gene. Patients who did not have an identifiable cause of hearing loss had negative connexin 26 genetic testing.

2

Materials and methods

Following departmental and institutional review board approval, a retrospective chart review of the cochlear implant database was conducted. The charts of all patients who received a cochlear implant under age 18 at University Hospitals Case Medical Hospital, a tertiary care center, between January 2002 and December 2012 were reviewed. Patient charts, operative reports and laboratory testing were thoroughly reviewed for etiology of hearing loss. Charts were reviewed for demographic information and audiometric outcomes. Patients who had genetic testing that demonstrated homozygous mutations of the GJB2 gene, absence of other radiographically or clinically identifiable causes of hearing loss were included in the Cx 26 study group. A matched group of control subjects for age at first implantation (0–≤24 months, 25–<48 months and ≥ 48 months) was identified from the same cochlear implant database. All patients in the control group had an identifiable etiology of hearing loss unrelated to Cx 26 mutation or genetic analysis without evidence of mutation in the GJB2 gene. Patients who did not have an identifiable cause of hearing loss had negative connexin 26 genetic testing.

3

Results

Twenty one patients of whom eighteen received bilateral sequential cochlear implantation were included in the Cx 26 group ( Table 1 ). Eighteen patients were included in the control group of whom twelve received bilateral sequential implantation ( Table 2 ). The mean average age of initial implantation was 2.4 ± 1.4 years for the connexin 26 group and 3.2 ± 2.5 years for the control group. In the Cx 26 group, 33% of the study subjects were male and 67% were female. In the control group 67% were male and 33% were female. Patients were implanted with related devices from the Cochlear Corporation Company (Cochlear Americas, Ltd, Centennial, CO). Full electrode insertion was achieved in all patients in the control and study groups. There were no intra- or immediate postoperative complications noted for the control and Cx 26 groups.

Table 1

Demographic and surgical data for the connexin 26 group.

Number	Gender	Passed newborn hearing	Age at first implant (years)	Age at second implant (years)	Type of CI	Insertion	Type of mutation	Zygosity	Primary/revision cochlear implant	Current mode of communication
1	Male	Yes	3.0	3.6	C24	F	35 del G	Homozygous	Primary	Oral
2	Female	No	4.1	7.1	C24	F	Unknown	Unknown	Primary	Oral
3	Female	No	3.3	3.6	N5	F	35 del G, 94C>T	Heterozygous	Primary	Oral
4	Female	Yes	2.2	3.3	C24	F	35 del G	Homozygous	Primary	Oral
5	Female	No	1.5	2.5	C24	F	35 del G	Homozygous	Primary	Oral
6	Female	No	1.2	2.2	C24	F	35 del G	Homozygous	Primary	Oral
7	Female	No	1.3	1.8	C24 right, N5 left	F	Unknown	Unknown	Primary	Oral
8	Male	No	2.0	2.5	N5	F	35 del G	Homozygous	Primary	Oral
9	Female	Unknown	2.9	3.4	C24 right, N5 left	F	35 del G	Homozygous	Primary	Oral
10	Female	Unknown	2.2	6.6	C24	F	35 del G	Homozygous	Primary	Oral
11	Female	No	1.0	1.6	N5 Right, C24 left	F	35 del G	Homozygous	Primary	Unknown
12	Male		5.1	N/A	C24	F	Unknown	Unknown	Primary	Oral
13	Female	No	1.1	1.4	C24	F	35 del G, 94C>T	Heterozygous	Revision	Oral
14	Female	No	1.0	1.4	C24	F	35 del G	Homozygous	Primary	Oral
15	Female	No	5.1	12.6	C24	F	35 del G	Homozygous	Primary	Oral
16	Male	No	1.6	3.7	C24	F	35 del G	Homozygous	Primary	Oral
17	Female	Unknown	2.3	N/A	NF	F	deletion (not 35 del G)	Heterozygous	Primary	Oral
18	Female	Unknown	1.4	1.9	C24	F	35 del G	Homozygous	Primary	Oral
19	Male	Unknown	2.6	3.1	C24	F	35 del G, 169C>T	Heterozygous	Primary	Oral
20	Male	Yes	0.5	3.7	C24	F	35 del G	Homozygous	Primary	Oral
21	Male	Unknown	5.4	N/A	C24	F	35 del G, 94C>T	Heterozygous	Primary	Oral

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