This study reports the effectiveness of applying a diagnostic battery without selection bias to determine the cause of hearing loss in children presenting with severe to profound SNHL. Although undergoing all tests in the battery certainly achieves the highest diagnostic yield, it requires many healthcare visits and considerable effort on the part of the child's caretakers. Furthermore, this approach does not represent efficient utilization of healthcare resources. The data from this study should not be interpreted to conclude that every deaf child needs a complete battery of tests. Rather, analysis of the data is used to determine the fewest diagnostic tests that can still provide a diagnostic yield that is comparable to that of the entire battery.
To that end, we confirm several studies in the literature that find diagnostic radiologic imaging to be effective in determining a possible cause for hearing loss. A CT of the temporal bone and an MRI of the brain and IAC with contrast are similarly effective in finding inner ear anomalies (18% and 17%, respectively). The inner ear anomalies identified by each study are nearly identical—with CT identifying a few enlarged vestibular aqueducts missed by MRI and MRI identifying a few hypoplastic or aplastic cochlear nerves missed by CT. Outside the inner ear, however, MRI also identified pathologic disease in the brain consistent with congenital CMV infection. Thus, the overall diagnostic yield of MRI is higher than that of CT (24% versus 18%).
If only 1 study can be chosen, the higher diagnostic yield of MRI must be weighed against its extra cost, the additional time required to perform the study, and the requirement for sedation. Our data suggest that in cases where the child has passed newborn hearing screening and/or has a suspected environmental cause of hearing loss, MRI may be more useful than CT in that it can identify a pathologic disease outside the temporal bone. Alternatively, if a syndromic hearing loss is expected, CT and MRI are similarly effective. Intracerebral anomalies identified by MRI, although they may not necessarily yield a definitive cause for hearing loss, might guide expectations regarding the success of future auditory rehabilitation and speech and language development. In 1 particular case in this study, MRI identified a medulloblastoma that would not otherwise have been discovered. This patient required life-saving surgical intervention and then radiation therapy and chemotherapy. Thus, despite significant overlap of findings within the temporal bone, both CT and MRI are warranted as bases for a minimal diagnostic battery.
The finding in 1997 that 50% of autosomal-recessive nonsyndromic hearing loss were due to mutations in the GJB2
gene that encodes connexin 26 significantly improved the prospects of genetic testing for hearing loss (15
). The fact that connexin 26 anomalies were responsible for 5% to 10% of all pediatric hearing loss made genetic testing for GJB2
mutations a reasonable option rather than just a “shot in the dark” (17
). Our finding that connexin 26 sequence analysis has a diagnostic yield of 15% compares similarly to rates of connexin 26 mutations reported in the literature (18
). A compelling finding was that the subset of children identified with connexin 26 mutations was almost completely distinct from the subset of children identified with inner ear anomalies by diagnostic imaging. Indeed, only 1 of 33 children with a connexin 26 mutation was found to have an inner ear anomaly. As might be expected, connexin 26 analysis was only useful in cases of nonsyndromic SNHL. Interestingly, connexin 26 mutations continued to be prevalent in children who passed newborn hearing screenings. A minimal diagnostic test battery consisting of connexin 26 gene sequencing analysis in conjunction with diagnostic imaging studies achieved an overall diagnostic yield of 38%, a 14% increment in diagnostic yield over imaging alone.
Congenital hearing loss can result from 1 of more than 400 syndromes and be associated with defects in virtually any organ system (reviewed by Toriello et al. [19
]). Therefore, collaboration between specialists may be essential in identifying a syndrome. The clinical geneticist has a familiarity with the constellation of physical findings beyond that of any one particular specialist; in addition, the geneticist is more knowledgeable regarding which particular gene mutation tests are available and can make recommendations regarding which specific gene tests may be most likely to yield a genetic diagnosis. We found that consulting a clinical geneticist could provide a diagnostic yield of 25% independently. However, including this consultation after both imaging and connexin 26 sequence analysis had been performed added a marginal increment of only 4% to the overall diagnostic yield.
Hearing loss is disproportionately associated with abnormalities of ocular structures. Therefore, every child in the study was also referred to an ophthalmologist. Certainly, identification of a subtle ocular abnormality such as retinitis pigmentosa could indicate Usher syndrome as the cause for hearing loss. We found that although an ophthalmologic consultation independently had a diagnostic yield of 8%, it contributed less than 1% to the overall yield of a minimal diagnostic battery. Thus, from a diagnostic perspective alone, an ophthalmologic consultation may not be warranted. One exception may be in the case of children with suspected syndromic hearing loss—in which the independent diagnostic yield is 42%. In any case, congenital hearing loss of all types has been associated with decreased visual reception skills with age (20
). Therefore, at the very least, the child's visual acuity should be evaluated and optimized to minimize his or her sensory disabilities and maximize the potential for normal development. Indeed, myopia was the most common diagnosis resulting from ophthalmologic consultation in this study.
Renal US is a commonly performed diagnostic imaging procedure in the workup of pediatric hearing loss, but we found a renal anomaly consistent with BOR syndrome in only 4% of patients, and of these patients, not one was confirmed with BOR syndrome. On the other hand, several cases of previously undiagnosed renal anomalies were discovered, precipitating consultations to nephrologists for further management and follow-up. None of these findings were potentially life-threatening, however, suggesting that a more judicious use of renal US would be reasonable. Branchio-oto-renal syndrome, in the absence of branchial arch findings or auricular deformities, occurs quite rarely, and the diagnostic yield of renal US might be improved significantly by limiting testing only to those patients with such clinical findings.
Electrocardiogram testing is similar to renal US in that it is another diagnostic procedure that is low in yield when applied to all children with congenital hearing loss. Analogously, recommendations have been made in the literature to limit ECG testing to patients with a previous history or a family history of syncope. Unlike BOR syndrome, however, Jervell and Lange-Nielsen syndrome and its prolonged QT interval is life-threatening and can present with an initial symptom of sudden death. Furthermore, in our testing, ECG serendipitously identified other cardiac conduction anomalies that may also have been dire and necessitated cardiology evaluations. Given the relatively low cost and short time required to perform the test, an ECG may be warranted within a diagnostic battery.
Several studies suggest that performing a standard battery of laboratory tests is not particularly useful in identifying the cause for congenital hearing loss (10
). Abnormal laboratory findings for autoimmune serologies occur nearly 25% of the time but almost never correlate with clinical hearing loss (11
). Testing for syphilis is often either overlooked or not performed; we therefore included this in our diagnostic test battery. We found this test to be low yielding (0.5%). We agree with previous recommendations that rather than blanketing all deaf children with multiple blood tests, specific laboratory tests be ordered on the basis of the patient's history and physical examination.
As our understanding of the molecular basis of hearing improves, a significant percentage of hearing loss that is presently idiopathic will likely be found to have a genetic basis. In the last 5 years, however, rapid escalation in the numbers of genes responsible for nonsyndromic hearing loss has made a definitive diagnosis of this disease process more likely. At present, however, aside from connexin 26, no consensus exists regarding which additional genes need to be tested. In an excellent review of the genetic approach toward diagnosing pediatric hearing loss, Rehm (21
) proposes an algorithm that accounts for patterns of inheritance, timing of hearing loss, audiogram profile, and associated clinical findings in recommending specific genes to be tested. On the other hand, cost reductions in gene testing technology are likely to soon render obsolete any need for algorithmic testing. Gene-Chip microarray technology, which allows large numbers of genetic tests to be performed in parallel, will ultimately realize the goal of screening for every known mutation in every known gene associated with hearing loss. Thus, in the near future, after history, physical, and audiometric testing, a reasonable recommendation for ancillary tests in the workup of a congenitally deaf child might consist only of diagnostic radiologic imaging of the temporal bone and GeneChip microarray analysis.