Clinical Studies of Families With Hearing Loss Attributable to Mutations in the Connexin 26 Gene (GJB2/DFNB1)

Lack of Associated Symptoms

The results reported in this report confirm the nonsyndromic nature of Cx26 mutations. Only hearing is affected. From the clinician's perspective, this means that ancillary diagnostic tests may not be necessary. Preliminary data suggest that CT of temporal bone is not necessary. Whenever a new hearing-impaired child is seen, pediatricians, otolaryngologists, and geneticists are understandably concerned about the possibilities of Usher, Pendred, Jervall-Lange-Neilsen, and other syndromes. The finding that a Cx26 mutation is responsible for a particular case reduce the extent of additional diagnostic testing resulting in reduction of medical costs.

Data presented here show no evidence of human developmental problems. However, a knockout mutation in mouse of Cx26 is lethal,¹⁵suggesting that Cx26 plays some vital role in murine development. CT findings of the inner ear are normal. None of our cases presented with significant anomalies that could be proven to be associated with the Cx26 mutation. Although Cx26 is not implicated directly with conduction defects of the heart, there is established association with connexin 43¹⁶ raising the possibility that Cx26 mutations also might affect that organ. However, our data do not support this hypothesis, but our patients are young and may not as yet manifest cardiac problems (Table 2).

Progressive Hearing Loss

With regard to progression of hearing loss, 10/30 (with sufficient audiometric data to determine stability, fluctuation, or progression) were observed to show progression of their hearing impairment (Table 5and 6). In 8 of 10 cases, the four frequency average change was ≥10 dB, and for 4 of these patients, the average change was >20 dB (these changes are based on the mPTA and thus are averaged across four frequencies). A history of progression was not related to gender, nor was it related to the type of mutation present, although the sample size was limited for a comparison between genotypic groups. Clearly, there is some process occurring that leads to a worsening of hearing over time in some individuals with Cx26 mutations. We speculate that a larger number of children will show progressive hearing loss if followed from birth. The nature of the progression, its frequency, and the severity of the hearing loss at birth are issues that could be addressed better if Cx26 genotyping were performed in conjunction with failed newborn hearing screening so that the hearing of Cx26 cases were followed from birth.

Variability in Severity of Hearing Loss

We observed an unexpected wide range of hearing loss from mild-moderate to profound hearing loss, which needs some discussion. One hypothesis we considered was that the phenotype might be related to the specific mutation. However, the data do not support that hypothesis totally. A wide range of severity was observed across the homozygous 35delG genotypic category, but hearing impairment was more constant and severe for 167delT homozygotes. It may be that these differences are mutation-specific. For example, 167delT theoretically would produce a protein larger than that produced by the 35delG mutation, and it is possible that the 167delT protein actually may be functional enough to incorporate itself into the cell membrane and thereby to interfere with intercellular transport in a more drastic manner.

On the other hand, it may be that the differences between 35delG and 167delT are attributable to genetic background differences between Jewish and non-Jewish populations originating in Europe. If so, we might expect to observe more severe hearing loss for 35delG in the Ashkenazi Jewish population. It also is possible that there are nongenetic modifying factors that have yet to be identified.

The variability of hearing impairment for the 35delG homozygotes is perplexing. Most autosomal recessive disorders have fairly consistent phenotypes, especially within sibships, which is not observed for Cx26–35delG. This suggests the possibility of other factors modulating the expression of the mutant gene. One intriguing possibility is that there may be a second connexin gene that shares partial functional redundancy with Cx26. It is conceivable that a second connexin protein can act as a substitute under certain conditions. This would be consistent with the observation of some redundancy for other connexins. Perhaps there are modifying genes in other locations or environmental influences that activate or inactivate the promoter/enhancer regions. If Cx26 is involved in inner ear ion homeostasis, some of these patients are able to function with little loss of hearing, suggesting alternative or compensating homeostatic mechanisms. The loss of Cx26 may affect adversely the development of the auditory system, resulting in variability or asymmetry.

There may be environmental influences, such as noise, that are additive or synergistic with the defects caused by Cx26 mutation, thus increasing hearing loss. As our knowledge of chemicals and other factors that stabilize neural and sensory elements increases, it is conceivable that we may intervene successfully and arrest progression of sensory and neural hearing loss.

The profoundly deaf patients and some of the patients with severe-profound hearing loss will require aggressive language therapy if amplification is not successful. Many of these patients will be candidates for cochlear implantation, which works best when implanted by 24 months of age. Some clinicians are performing cochlear implants as early as 18 months on a clinical trial basis. In our sample, 17/49 have a profound hearing loss and are candidates for a cochlear implant. An additional 13/49 have severe-profound hearing loss, some of whom (approximately one third) will become candidates for cochlear implant. All will need language strategies implemented as early as possible.

Establishing progression on review of multiple audiograms over time is difficult and scientifically hazardous. The progressive nature of the hearing loss in one third of the Cx26 cases (for whom sufficient data exist) is notable and raises several important issues. This means that a child with a moderate loss may progress into the profound range; therapies are very different between these two magnitudes of hearing loss.

Families having a single child with moderate-severe hearing loss or worse will benefit from Cx26 analysis. The genetic nature of a sporadic case often is unappreciated. Testing for Cx26 can quickly identify a significant proportion as being recessive, when positive, genetic, audiologic, and developmental language counseling can be offered so that parents can make informed decisions.

The feasibility and benefit of screening for Cx26 mutation is quickly going to become an important public health issue. The importance of early detection of hearing impairment is well established. Cx26 mutation testing can not pick up all hearing-impaired infants, and it would be unreasonable to expect such testing to replace existing hearing screening programs. Whether ABR- or OAE-based infant hearing screening programs should include Cx26 mutation diagnosis is another matter. The use of Cx26 testing in conjunction with failed infant audiologic testing will help define a group in which ∼40% may not respond to early hearing aid use and will require total language intervention. Many of those children will be candidates for cochlear implantation. Future studies should be prospective, including surveys of newborns who fail diagnostic hearing testing. This will help determine the percentage of children with early progressive hearing loss and the number not responding to traditional hearing amplification at early critical stages of language development.