A thorough history should be considered because it easily allows the physician to separate hereditary hearing impairment from other causes. Questions should cover embryopathies such as rubella, toxoplasmosis, or cytomegalovirus, as well as any ototoxic drug use. An audiologic assessment is mandatory and should include both parents and siblings. A pure-tone audiogram is usually sufficient. In children, testing of the auditory brainstem response and otoacoustic emissions can be performed. All forms of hearing loss can be seen in hereditary hearing impairment. Guidelines on how to approach patients with hereditary hearing impairment are outlined in Figure 54–2.
Guidelines for evaluating patients with hereditary hearing impairment.
A careful physical examination is recommended, especially to detect syndromic hearing loss. The patient's ears should be examined for abnormalities such as auricles and preauricular pits; in addition, one should look for pigmentary changes in the skin and hair and for a possible goiter. To complete a thorough assessment, an ophthalmologic examination and urinanalysis/renal ultrasound have to be taken into account. In addition, other specialists, such as pediatricians, ophthalmologists, cardiologists, and others, should be consulted as a part of the proper evaluation of these children.
Nonsyndromic Hereditary Hearing Impairment
Most cases of profound prelingual hearing loss are associated with DFNB and are almost exclusively due to cochlear defects. In postlingual cases, an autosomal dominant inheritance is predominant; the hearing loss is less severe and besides sensorineural defects, conductive impairments are found. In X-linked disease, hearing impairment in males is earlier in onset and more severe than in females since the disease is transmitted only through female family members. Either all of the frequencies or the high frequencies are affected.
Patients with nonsyndromic hereditary hearing impairment demonstrate a few common features. Usually, the hearing loss is symmetric. The U-shaped or “cookie-bite” form is classically indicative for hereditary hearing impairment. In most cases, the hearing threshold is sloping in the middle and high frequencies; rarely, only the low frequencies are affected. The hearing loss can vary from moderate to profound and can be either stable or progressive. One of the best-studied genes, GJB2, which accounts for the majority of inherited deafness, has only been associated with a prelingual onset. The phenotype of patients with GJB2 mutations varies enormously, even among siblings, from mild to profound, with audiometric curves that are either flat or sloping, and even in patients harboring the same mutation (c.35delG), indicating the presence of a hitherto unknown modifier gene. Some audio profiles are indicative of the possible underlying mutation. Moderate midfrequency hearing loss and autosomal recessive inheritance are seen in TECTA mutations; low-frequency hearing loss together with a dominant inheritance pattern points to mutations in WFS1.
Auditory neuropathy is characterized by the presence of otoacoustic emissions and absence of auditory brainstem responses. OTOF mutations seem to be the major cause for this form hearing impairment, the other gene being PJVK.
Syndromic Hereditary Hearing Impairment
Syndromic hearing loss may be conductive, sensorineural, or mixed; other clinical features must be considered to allow for the recognition of a distinct entity. More than 400 syndromes that include hearing loss have been described. Most of these syndromes are characterized only clinically, with their underlying molecular mechanisms still unknown. At present, auditory–pigmentary diseases are the largest and best-characterized group and include more than 55 syndromes.
The clinical features of the syndromes that follow are summarized in Table 54–2.
Pendred syndrome is the most common syndromic form of deafness, accounting for approximately 10% of cases. It presents with sensorineural hearing loss and goiter. Usually, the goiter is evident before puberty, but an adult onset has also been noted. Thyroid function is evenly divided with 50% euthyroid patients and 50% hypothyroid patients. In most cases, the hearing loss is congenital, bilateral, moderate to profound, and sloping in the higher frequencies and progressive in most cases. An enlarged vestibular aqueduct is a consistent finding, and Mondini-type malformations have also been associated. In various studies, caloric testing showed diverging results, with both normal and depressed vestibular function.
This syndrome is seen in at least 2–5% of patients with congenital hearing loss and includes the following clinical signs: dystopia canthorum; pigmentary abnormalities of the hair, iris, and skin; and sensorineural deafness in 20–50% of patients, depending on the classification type. Four clinical subtypes exist (Table 54–3). Abnormal functioning of the peripheral vestibular system can be found more often than hearing loss.
Table 54–3. Clinical Classification of Waardenburg Syndrome and Corresponding Genes. ||Download (.pdf)
Table 54–3. Clinical Classification of Waardenburg Syndrome and Corresponding Genes.
|Sensorineural Hearing Deficit|
|Iris Pigmentary Abnormality|
|Type I||Type II||Type III||Type IV|
|+ dystopia canthorum PAX3||− dystopia canthorum MITF,SNAI2, 2 unknown||− dystopia canthorum + upper limb abnormalities PAX3||− dystopia canthorum + Hirschsprung disease EDNRB, EDN3, SOX10|
Three different types of Usher syndrome, the most common eye/ear syndrome, can be distinguished clinically by the type of hearing impairment, the absence or presence of vestibular responses, and the onset of retinitis pigmentosa (Table 54–4). The genetic classification is incomplete and includes 11 genes. The prevalence of this disorder among deaf children may be as high as 8%. The advancing failure of vision has the greatest impact on the quality of life in patients with this syndrome.
Table 54–4. Classification of Usher Syndrome by Clinical Type and Its Corresponding Genes. ||Download (.pdf)
Table 54–4. Classification of Usher Syndrome by Clinical Type and Its Corresponding Genes.
|Hearing impairment||Profound, congenital||Sloping, congenital||Progressive|
|Onset of retinitis pigmentosa||First decade||First or second decade||variable|
|Genes||MYO7A, USH1C, CDH23, PCDH15, SANS, 1 unknown||USH2A, VLGR1, WHRN, 1 unknown||USH3|
Alport syndrome is distinguished by hematuria with progressive renal failure, initial high-tone sensorineural hearing loss, and ocular abnormalities such as lenticonus and retinal flecks. The syndrome is seen in at least 1% of patients with congenital hearing impairment.
The symptoms of this syndrome can be derived from its name: (1) branchial anomalies (clefts, cysts, or fistulas), (2) otologic anomalies (malformed pinna, preauricular pits, and hearing loss), and (3) renal malformations (hypoplastic kidneys and vesicoureteric reflux). Its prevalence is 2% in profoundly affected children. Sensorineural, conductive, or, most often, mixed hearing loss is seen. Hearing is affected with approximately 80% penetrance.
Neurofibromatosis Type II
Neurofibromatosis Type II is characterized by bilateral tumors of the eighth cranial nerve (the vestibulocochlear nerve) and any of the following: meningiomas, schwannomas, gliomas, or juvenile subcapsular cataracts. The symptoms mostly begin in late childhood to early adulthood. Hearing loss, predominantly unilateral, presents in approximately 50% of patients. A molecular diagnosis in sporadic patients is less reliable because a high percentage of mosaicism for mutations is seen. Genetic screening should be considered in an asymptomatic, undiagnosed child, who is at risk for NF2 disease.
The frequency of Jervell–Lange–Nielsen syndrome among those patients with a profound congenital hearing loss is approximately 0.25%. Sensorineural hearing loss is accompanied by syncopal attacks due to a prolonged QT interval. Death occurs in childhood if not treated.
Treacher Collins Syndrome
In Treacher Collins syndrome, the clinical diagnosis is facilitated as distinct craniofacial abnormalities are found. The hearing loss can be related to radiographic findings of malformed cochlear and vestibular apparatus, including the ossicles and external ear canal.
Three phenotypes corresponding to three defective genes have been described in Stickler syndrome. The clinical signs include eye symptoms (eg, myopia, astigmatisms, and cataracts), arthropathy, cleft palate, and sensorineural hearing loss. Hearing loss can be mild to profound, progressive, affecting all or the high frequencies.
Hoornaert KP et al. Stickler syndrome caused by COL2A1 mutations: genotype-phentoype correlation in a series of 100 patients. Eur J Hum Genet. 2010 Aug;18(8):872–880. (Good illustration of the complexity in genetic hearing impairment).
Laboratory tests are helpful in distinguishing nonsyndromic from syndromic hereditary hearing impairment. However, full laboratory and radiographic evaluations are expensive, and the rate for obtaining a definite diagnosis is reported to be approximately 40–70%, although a thorough analysis has not been done. Therefore, laboratory tests should be undertaken after careful deliberation. Urinanalysis is easy to perform and assesses the presence of proteinuria or hematuria (Alport syndrome). If Pendred syndrome is suspected, thyroid function tests should be requested.
CT or MRI (fast-spin echo technique or gadolinium-enhanced) are the imaging studies of choice. Abnormalities in the bony structures of the inner ear are detectable on a CT scan. A CT scan is generally recommended in the evaluation of childhood sensorineural hearing loss to detect inner ear malformations (for example large vestibular aqueduct–which is also the most common abnormality) that are associated with the higher risk of cerebrospinal fluid leak, meningitis, or traumatic hearing loss.
Various mutation detection methods exist and are in use. The methods are based on either conformation-based techniques such as single-stranded conformational polymorphism (SSCP) or on base-mismatch recognition such as denaturing gradient gel electrophoresis (DGGE). The former is more common. Both methods—SSCP, because of its simplicity, and DGGE, because of its high sensitivity—are the favored techniques. Another method DHPLC—denaturing high-performance liquid chromatography—is suitable for rapid, automated mutation screening. However, each of these methods has significant shortcomings, including expense, time, and limited sensitivity. Direct sequencing of the gene is the only technique available to identify any number and type of mutations. In the future, array-based automatic screening methods, which allow for analyzing multiple genes and mutations concurrently, will become popular.
Perchlorate Challenge Test
The perchlorate challenge test can be performed with Pendred syndrome, although it is not specific and its sensitivity is unknown.
An ophthalmologic examination (vision acuity, fundoscopy, and electroretiongramm to detect retinitis pigmentosa) is recommended to detect syndromic features (especially Alport, Stickler, and Usher syndromes) and to distinguish syndromic from nonsyndromic hereditary hearing impairments. Vestibular symptoms are not a typical feature of hereditary hearing impairment. However, if a patient reports dizziness or balance problems, functional testing of the peripheral vestibular system should be performed. For instance, absent vestibular responses can be seen in Usher syndrome Type I and in some forms of autosomal recessive deafness (DFNB4, etc.). Renal ultrasound scan may reveal dysplasia in Branchio-Oto-Renal syndrome. In suspected Jervell–Lange–Nielsen syndrome, an electrocardiogram should be performed.
Gorlin RJ, Toriello HV, Cohen MM Jr. Hereditary Hearing Loss and Its Syndromes. Oxford University Press, 1995. (Very comprehensive and detailed description of all syndromes known to be associated with hearing loss.)
Grundfast KM, Siparsky N, Chuong D et al. Genetics and molecular biology of deafness. Otolaryngol Clin North Am
(Very thoughtful proposal for a clinical approach to hereditary hearing disorders.)