Chapter 54. Hereditary Hearing Impairment

• In most cases, sensorineural hearing loss of unknown origin
• Positive family history often present
• Vestibular symptoms possible, but rare
• In syndromic cases, associated with other clinical abnormalities

Hearing loss is the most common sensory deficit in humans. The prevalence of congenital hearing loss in newborns is approximately 1–3 cases per 1000. More than 60% of these prelingual cases (ie, hearing loss before the acquisition of speech) are attributed to genetic causes. A further 1 in 1000 children becomes deaf before adulthood. In patients over 60 years of age, approximately half show a hearing loss >25 dB HL. A large percentage of these populations is estimated to be likely affected by genetic influences, although age-related epidemiologic studies of the genetic contribution to hearing loss are not available. Finally, more than 100 deafness genes are believed to exist. These figures illustrate the impact of hearing loss on the public health system and the importance of genetic factors.

The most common and useful distinction in hereditary hearing impairment is syndromic versus nonsyndromic hearing impairment. Seventy percent of hereditary hearing impairments are nonsyndromic, whereas a minority of 15–30% are syndromic (Figure 54–1).

Nonsyndromic Hereditary Hearing Impairment

Nonsyndromic hereditary hearing impairment is classified by the mode of inheritance. Autosomal recessive transmission (designated by prefix DFNB) is implicated in approximately 80% of cases, autosomal dominant transmission (DFNA) is present in approximately 20% of cases, and X-linked (DFN) and mitochondrial transmission are responsible for <2% of cases (see Figure 54–1). One single gene, GJB2 (Gap-Junction Beta 2 encoding for connexin 26), has emerged to be the most common cause of recessive deafness, and up to 40% of the onset of sporadic prelingual hearing impairment can be attributed to defects in this gene both in Europe and the United States. The prevalence is higher in southern Europe than in northern Europe, mainly owing to one single gene mutation, c.35delG. In a stretch of six guanines extending from position 30 to 35, one base pair is deleted. The high incidence of this mutation seems to be due to a common ancestor. Other common mutations include c.167delT in Ashkenazi Jews and c.235delC in the Japanese population. Also, a common digenic pattern of inheritance involving GJB2 and GJB6 has been detected. Patients with a monoallelic mutation in GJB2 harbor in addition a deletion of GJB6.

Mitochondrial genes constitute a small and unique group. Inheritance is entirely through the mother, because the maternal oocyte is the sole contributor of mitochondria. Although hearing loss occurs frequently in mitochondrial diseases, it is much more seldom the only symptom. The c.A1555G mutation in the MT-RNR1 gene is the most important one among inherited hearing impairment with mitochondrial transmission.

Syndromic Hereditary Hearing Impairment

Syndromic hearing impairment means that hearing loss is accompanied by other clinical abnormalities. More than 400 syndromes that include hearing loss have been described in detail. Currently, syndromic hearing loss is categorized as follows: (1) syndromes due to cytogenetic or chromosomal anomalies; (2) syndromes transmitted in a classic monogenic or mendelian inheritance; or (3) syndromes due to multifactorial influences, in which the phenotype results from a combination of genetic and environmental factors. The breakdown of the genetic code of the various syndromes will most certainly lead to a classification based on molecular-genetic findings.

Several distinctions are typical of hereditary hearing impairment. Usually, the disease is genetically highly heterogeneous, with many different genes responsible for auditory dysfunction. To complicate things further, different mutations in one gene can cause variable phenotypes (eg, connexin genes in the skin or the ears) or even syndromic and nonsyndromic hearing loss as seen in genes SLC26A4 (Pendred syndrome and DFNB4), MYH9 (May-Hegglin/Fechter syndrome and DFNA17), and WFS1 (Wolfram syndrome and DFNA6/DFNA14). Finally, a mutated gene can cause dominant and recessive forms of hearing loss. Typical examples include GJB2 and TECTA.

Nonsyndromic Hereditary Hearing Impairment

Most of the nonsyndromic genes that cause deafness are not restricted to the cochlea; the inner ear seems to be more sensitive to disruption of some cellular functions than are other organs. In most cases, the function of these genes is only slightly understood. Several genes involved in ion homeostasis and cytoskeleton (ie, hair-cell) structure that lead to deafness have been identified. Other genes include cell-to-cell interaction, transcription factors, extracellular matrix and a few genes with unknown functions. Nonsyndromic genes discovered by the end of 2009 are listed in Table 54–1, which includes their function and mode of inheritance.

Homeostasis

In the homeostasis group, the gap-junction proteins (connexins) are the most well known. Three types of connexin genes have been discovered; GJB2 is the most prevalent. The protein encoded by GJB2 (connexin 26) is involved in intercellular transport of ions, metabolites, and second messengers. Based on its expression in the human cochlea in the stria vascularis, the basement membrane, the limbus, and the spiral prominence, as well as in animal studies, the role of GJB2 seems to lie in recycling potassium ions back to the endolymph of the cochlear duct after stimulation of the sensory hair cells.

The Gene

OTOF is responsible for synaptic exocytosis of neurotransmitters in auditory hair cells.

Hair-Cell Structure

Unconventional and conventional myosins represent the largest group of genes involved in hair-cell structure and motility. Myosins are actin-dependent molecular motors. Unconventional myosins are found in different locations in the inner ear, including the hair cells. Their various functions include endocytosis, the regulation of ion channels, the movement of vesicles in the cytoplasm, and anchoring stereocilia.

Transcription Factors

Transcription factors are important for regulating the expression of other genes. The EYA4 protein, for example, regulates the early development of the organ of Corti and maintains its continued function postdevelopmentally.

Syndromic Hereditary Hearing Impairment

The list of genes responsible for syndromic hearing impairment encompasses diverse molecules, such as enzymes, transcription factors, and cytoskeletal and extracellular matrix components. Although syndromic deafness is mostly inherited in an autosomal dominant fashion, in some cases, the transmission from parents to children does not occur. A classic example is neurofibromatosis, in which approximately 50% of genetic mutations are spontaneous. A summary of genetic findings is listed in Table 54–2.

Pendred Syndrome

The gene for Pendred syndrome is named SLC26A4. Findings based on mouse model suggest a role as an anion exchanger that is likely to mediate HCO3—secretion into the endolymph.

Waardenburg Syndrome

Of the six genes identified in Waardenburg syndrome, four belong to the family of transcription factors that bind DNA and regulate its transcription. The other two genes are members of the group of endothelins and are involved in the development of neural crest-derived cells, which evolve into neurogenic or nonneurogenic sublineages, such as melanocyte precursors.

Usher Syndrome

Among the 10 mapped loci connected to Usher syndrome, nine genes are identified. The best-studied gene is MYO7A, which is implicated in development and functioning of stereocilia.

Alport Syndrome

Mutated collagen genes are responsible for the phenotype in Alport syndrome. Abnormalities in the basement membrane due to defective collagen Type IV have been demonstrated.

Branchio-Oto-Renal Syndrome

Another transcription factor, EYA1, plays a predominant role in the pathologic mechanisms of Branchio-oto-renal syndrome. Sixty percent of sporadic cases are accounted for by mutations in this gene.

Neurofibromatosis Type II

Merlin, the neurofibromatosis Type II gene product, acts as a tumor suppressor and is important for cell movement, cell shape, and communication.

Jervell–Lange–Nielsen Syndrome

Disturbances in the hemostasis of endolymph through the defunct subunits of potassium channels (eg, KCNE1 and KVLQT1) cause Jervell–Lange–Nielsen syndrome.

Treacher-Collins Syndrome

Most mutations in Treacher Collins syndrome result in the introduction of a stop codon with premature termination of the protein product, which disrupts ribosome biogenesis of the neural crest cells, the progenitors cells of bone and connective tissue of the the head.

Stickler Syndrome

Mutated collagen genes are also responsible for the phenotype in Stickler syndrome. Some evidence points to the organ of Corti as the target organ, at least in Type III.

It is most important to detect infants born with nonsyndromic hearing loss early in order to support normal language development. The appropriate management of auditory function is greatly facilitated by early diagnosis. Children in whom intervention begins before 6 months of age can acquire normal language development, in contrast to late intervention, with developmental language quotients of only 50–60%. Even in using risk factors for the proper identification of these children, 50% of infants born with hearing loss will not be identified. Therefore, universal hearing screening programs have been established. They are based on the measurement of otoacoustic emissions and auditory brainstem responses. These methods have been proved to be objective and highly sensitive in identifying infants with greater than mild hearing loss. Only about 15% of hearing-impaired children will be missed by newborn hearing screening because their hearing loss will manifest postnatally, sometimes as late as school age.

Symptoms and Signs

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.

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

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.

Waardenburg Syndrome

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.

Usher Syndrome

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.

Alport Syndrome

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.

Branchio-Oto-Renal Syndrome

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.

Jervell-Lange-Nielsen Syndrome

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.

Stickler Syndrome

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.

Laboratory Findings

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.

Imaging Studies

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.

Special Tests

Mutation Screening

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.

Special Examinations

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.

In syndromic cases, the challenge lies more in correctly identifying the syndrome than in missing the inherited forms. In isolated cases of sensorineural hearing loss, all forms of cochleopathies—not just those that are due to hereditary causes—must be included in the differential diagnosis. Congenital infections such as cytomegalovirus can mimic hereditary hearing loss. In chronic noise-induced hearing loss, a history of noise exposure is pathbreaking. A dip in the hearing threshold between 3 and 6 kHz is typical for this condition. Tinnitus may be present and is much more common than in inherited hearing loss. Trauma of the labyrinth can be suggested by the patient history and often results in an asymmetric hearing loss. Metabolic disorders such as hyperlipidemia or uremia are still disputed to be causative for sensorineural hearing loss.

Cochlear otosclerosis is rare as a single entity and is usually accompanied by conductive hearing impairment. Blood and vascular disorders have been associated with hearing impairment. The use of ototoxic drugs and agents should be ascertained by taking the patient history.

Depending on the degree and onset of the patient's hearing loss, various hearing aids, including cochlear implants, have to be evaluated in patients with hereditary hearing impairment. Gene therapy for hearing disorders has potential future applications. Currently, most studies focus on gene delivery. The problems to be overcome are the targeted correction of gene function without systemic side effects, and sustainable changes in the inner ear.

Generally spoken an accurate prediction is difficult in almost all cases of hereditary hearing impairment. Nonetheless, some prognostic information exists. The recurrence chance for parents having a child with GJB2-related hearing loss is 25% for the same genotype. The outcome is excellent in these children in case they receive a cochlear-implant. In some syndromic cases like Waardenburg syndrome Type II and Usher syndrome Type III, the hearing loss may be progressive; in Alport syndrome, the hearing loss usually occurs during childhood only.

• [Centrum Medische Genetica] http://www.uia.ac.be/cmg/
• (This website is a very comprehensive list of nonsyndromic loci and many syndromic loci, including genes, mouse models, and references.)
• [The Connexin-Deafness Homepage] http://crg.es/deafness/
• (This website is solely dedicated to connexin genes and deafness.)