Учебники / Otolaryngology - Basic Science and Clinical Review

perchlorate is given. The perchlorate discharge test alone is nonspecific, but particularly suggestive in a patient with temporal bone computed tomographic (CT) findings.

Mutations in this gene also have been found in a form of nonsyndromic deafness and in enlarged vestibular aqueduct syndrome (see DFNB4).

ALPORT SYNDROME

Gene map loci: Xq22, 2q36–q37

Gene (Xq22): COL4A5

Gene (2q36-q37): COL4A3, COL4A4

X-linked or autosomal recessive

This syndrome is characterized by progressive nephritis with uremia that is often heralded by hematuria in the first years of life (“red diaper”). Renal insufficiency ultimately develops.The renal lesion is a glomerulitis; red cell casts often accompany the gross or microscopic hematuria.

Approximately 50% of patients have progressive SNHL, although the degree of impairment varies widely. SNHL starts later than the renal manifestations. There have been reports of improved hearing thresholds with therapy to improve renal status. Histopathological findings include degeneration of the stria vascularis, spiral ganglia, hair cells, and endolymphatic hydrops. Collagen types 4 3, 4 4, and 4 5 are found in the basilar membrane, parts of the spiral ligament, and stria vascularis. The X-linked phenotype has been shown to be the result of mutation in the gene for the -S chain of basement membrane collagen (COL4A5).Although the mechanism of hearing loss is not known, loss of integrity of the basement membrane in the spiral sulcus might affect adhesion of the tectorial membrane, and in the basilar membrane and its junction with the spiral ligament, translation of mechanical energy may be affected.

JERVELL AND LANGE-NIELSEN SYNDROME

Gene map locus: 11p15.5, 21q22.l–q22.2, and others (heterogeneous)

Gene (11p15.5): KVLQT1

Gene (21q22.1–q22.2): KCNE1

Autosomal recessive

The molecular abnormality in Jervell and Lange-Nielsen syndrome (JLNS) is in potassium ion channels. Endolymph homeostasis is controlled in part by the delayed rectifier potassium channel. Mutations can occur in one or two genes coding for potassium channel proteins. JLNS patients have congenital, severe-to-profound SNHL, prolongation of the QT interval, torsade de pointe arrhythmias

(turning of the points, in reference to the apparent alternating positive and negative QRS complexes), and sudden syncopal episodes.

The electrocardiogram in childhood can be initially normal.There is often a family (or personal) history of syncope, or sudden death in a sibling.The cardiac arrhythmia known as torsade de pointe is responsible for mortality. Prompt antiarrhythmic treatment has reduced the high mortality associated with this disease. Patients may be candidates for an automatic implantable defibrillator.

NORRIE DISEASE

Gene map locus: Xp11.4

Gene: Norrin

X-linked

Features of Norrie’s disease include

•Progressive SNHL in less than half of affected persons

•Specific ophthalmalogic findings (pseudotumor of the retina, retinal hyperplasia, cataracts, etc.). Ophthalmology consult can help make this diagnosis in a male with abnormal mental status or mental retardation presenting with progressive SNHL.

•Mental impairment

USHER SYNDROME

This disorder is the most common autosomal recessive syndromic form of childhood SNHL. It affects approximately one half of the 16,000 deaf-blind persons in the United States and 3 to 10% of the congenitally deaf population. Usher’s syndrome is characterized by hearing impairment and retinitis pigmentosa (RP). The vision loss from RP is progressive, heralded by complaints of night blindness or visual field defects. Ophthalmologic consultation is helpful, but it may not reveal RP until years after onset of SNHL, unless an electroretinogram is performed. In addition to aural habilitation, because blindness ultimately develops, early intervention should include visual habilitation (e.g., Braille). DNA tests are available and can be used to avoid invasive tests (electroretinogram) in children with suspected Usher’s syndrome (congenital deafness and delayed gross motor development from vestibular dysfunction).

Usher syndrome is classified into three different types on the basis of clinical findings.

UsherType 1

Gene map loci: l1q13.5, 11p15.1, but highly heterogeneous, with seven different loci

Gene: MYO7A, USH1C, and others

Type 1 is the most common and most severe type of Usher syndrome. It is genetically heterogeneous and has seven subtypes (1A–1G). Clinically, type 1 features

•Profound congenital deafness with absent vestibular function. Children typically do not walk until more than 1 year of age and have balance difficulties: clumsiness, frequent falling, and difficulty swimming (because of poor vestibular function).

•Progressive blindness with onset of RP by age 10 years

Mutations in the MYO7A gene occur in type 1B and account for 75% of cases of Usher syndrome type 1. Mutations in the MYO7A gene also account for other nonsyndromic forms of SNHL (DFNB2 and DFNA11). Myosin 7A is an unconventional motor molecule present in the rods and cones of the retina, and in the cochlear and vestibular sensory hair cells during both human and mouse embryonic development. This motor protein is present in the stereocilia and near the hair cell–supportive cell junction; in mice, myosin 7A plays a role in forming and stabilizing the hair bundles.The Shaker-1 mouse is an animal model of Usher’s syndrome type 1 with a similar genetic mutation, similar histological appearance of the degeneration of the organ of Corti, and deficits in both hearing and vestibular function. This mouse model facilitated mapping of the gene in humans.

UsherType 2

Gene map locus: 1q41 and others

Gene: USH2A

Type 2 is less common and less severe than type 1. Clinical features include

•Moderate to severe congenital deafness, with typically sloping audiogram, and normal vestibular function. Types 1 and 2 can be differentiated by tests of vestibular function.

•Onset of RP in late teens

UsherType 3

Gene map locus: 3q21–3q25

Gene: USH3

Type 3 is the least common form of Usher’s syndrome and has only recently been confirmed as a distinct entity. The SNHL, vestibular dysfunction, and RP are variable and progressive.

WAARDENBURG SYNDROME

Autosomal dominant

Waardenburg’s is the most commonly recognized syndromic deafness. There is variable expression: hearing impairment is present in no more than half of the affected patients. Syndromic features other than hearing loss should be sought in the family history of newly diagnosed cases of SNHL to rule out the syndrome. There are two major types ofWaardenburgs that together account for almost all cases. Abnormal migration of neural crest cells occurs.

Type 1

Gene map locus: 2q35

Autosomal dominant

The one invariable feature of Waardenburg type 1 is dystopia canthorum: apparent broad spacing of the eyes due to lateral displacement of the medial canthi. This appearance is sometimes described as a “broad nasal root.” True hypertelorism is not present: the interpupillary distance is normal.

Spotty pigmentation frequently occurs along with dystopia canthorum but is not necessary for diagnosis of type 1 and is not always present. White forelock is striking but unusual; much more common are patches of depigmented skin, patches of gray or white hair (including eyelashes), or very premature grayness. The eyes may each be of a different hue (heterochromia iridis), or there may be light sapphire blue eyes in a darkly pigmented person.

SNHL is present in only 20% of Waardenburg syndrome type 1 patients, and it may be unilateral or mild enough to be unapparent on family history. SNHL is often progressive. PAX3 mutations are responsible for most type 1 cases.

The Splotch mouse is an animal model ofWaardenburg type 1.The use of this mouse model, in conjunction with human studies, facilitated gene mapping.

Type 2

Type 2 is characterized by pigmentary abnormalities without dystopia canthorum. Although no dystopia canthorum is present, patchy pigmentation occurs (e.g., heterochromia iridis, white skin patches and/or white hair patches, or premature grayness). Hearing loss is more common than in type 1; 50% of Waardenburg’s type 2 patients have SNHL. Again, SNHL is frequently progressive and may be unilateral.

Mutations in MITF and PAX3 (both genes code for transcription factors) are responsible for Waardenburg syndrome type 2.

GENETIC CAUSES OF CONDUCTIVE

(AND MIXED) HEARING LOSS

Otosclerosis Otospongiosis

Gene map locus: 15q26.1–q territory

Otosclerosis features include isolated endochondral bone sclerosis of the labyrinthine capsule, commonly resulting in the fixation of the stapediovestibular joint of the oval window. Stapes surgery can improve hearing thresholds by as much as 55 dB.Other parts of the temporal bone can be affected. Nearly 10% of affected persons develop inner ear deafness (cochlear otosclerosis) for which there is no cure, but drugs such as disphosphonates and calcium-fluoride compounds have been used to slow down the progression of sensorineural hearing loss.

•Clinical otosclerosis has a prevalence of 0.2 to 1% among Caucasian adults and occurs approximately twice as frequently in females as in males. Segregation analysis performed in relatives and patients with familial otosclerosis indicates that a rare dominant gene is involved along with an extensive polygenic component. Less than 20% of affected patients in these families carry the dominant gene. Sporadic cases would be expected to have an even lower incidence of this gene. Penetrance varies according to age and sex. One otosclerosis gene has been mapped to chromosome 15.

Mixed Deafness with Stapes Fixation and Perilymphatic Gusher (DFN3)

Gene map locus: Xq21.1

X-linked

The mutant gene in DFN3 is in a transcription factor with a POU domain known as brain-4.

This X-linked mixed type of deafness is characterized by the following:

•Expression is mostly in males (homozygotes) who exhibit mixed hearing loss with a progressive SNHL component and impaired vestibular function.

•The conductive component is secondary to a congenitally fixed stapes. Profound sensorineural deafness can mask the conductive component.

•Perilymphatic gusher, with postoperative drop in sensorineural thresholds, occurs with stapes surgery, which is contraindicated.

•Dilatation of the lateral end of the internal auditory canal is a frequent finding on temporal

Figure 19-3 A high-resolution computed tomographic scan of a patient’s inner ear at the modiolar level showing dilation of the internal auditory canal (IAC,labeled B),hypoplasia of the basal turn of the cochlea with no detectable bony modiolus (C) providing a route of direct communication between the subarachnoid space of the posterior cranial fossa (A) and the perilymphatic space of the inner ear. Stapes fenestration surgery is contraindicated in this patient due to the high risk of hearing loss from a cerebrospinal fluid “gusher.”

bone imaging. Preoperative CT imaging in young men with progressive mixed loss (particularly with maternal history of hearing loss) is indicated to avoid stapes surgery in DFN3 patients (Fig. 19-3).

•Mothers of affected sons (obligate heterozygotes) have mild SNHL and normal vestibular function.

Osteogenesis ImperfectaType 1 (Osteogenesis Imperfecta with Blue Sclerae)

Chromosomal locus: 7q22.1 and others

Autosomal dominant

There are multiple forms of osteogenesis imperfecta (OI), some of which are clinically mild. Many involve mixed hearing loss and stapes fixation. OI1 features:

•Bone fragility: fractures are rare in the neonatal period, but fracture tendency (even with minimal trauma) is constant from childhood to puberty, and decreases thereafter until late life.

•Blue sclerae that remain blue throughout life

•Abnormal collagen type 1 (in most cases)

Conductive or mixed hearing loss occurs in 50% of families; beginning in the late teens the SNHL gradually progresses to profound deafness, associated with tinnitus and vertigo by age 50 to 60 years. Conductive hearing loss is secondary to a fixed stapes, often with fractured crura and a thickened footplate.

Stapes surgery is helpful for closure of the air–bone gap. Stapes surgery in OI patients yields the same functional results as would be expected in otosclerosis patients, even though the underlying etiology is different.

Otitis Media

Otitis media is a spectrum of diseases with a high prevalence in the population; thus an inherited susceptibility for otitis media is not readily apparent. Genetic factors can modulate the host’s response to infectious agents and the development of disease. Epidemiological data and twin studies have shown that heritable factors affect the individual susceptibility to both recurrent acute and chronic serous otitis media. Furthermore, it has been reported that the incidence of otitis media is significantly lower in patients with otosclerosis, an autosomal dominant hereditary condition with low penetrance, suggesting that the genetic factors associated with otosclerosis infer a protective effect. The genetic mechanism of resistance and/or susceptibility to otitis media is not yet known.

NONSYNDROMIC SENSORINEURAL

HEARING LOSS

SNHL in a child or young adult without known acquired cause and without any associated unusual physical features is called nonsyndromic deafness. Most nonsyndromic forms of deafness are monogenic and rare, with the exception of one form caused by inheritance of a homozygous autosomal recessive mutant gene for the gap junction protein connexin 26. Genetic heterogeneity and incomplete knowledge of most forms of nonsyndromic SNHL are important challenges to understanding the molecular pathogenesis of nonsyndromic SNHL; however, a classification scheme based on the primary gene defect has been proposed. Fig. 19-4 shows some of the genes involved in nonsyndromic hereditary hearing loss according to their effect on inner ear structures: hair cell, supportive cell, and tectorial membrane.

Connexin 26 (CX26): DFNB1 and DFNA3

Gene map locus: l3ql l–q12

Gene: GJB2

Mutations in this gap junction protein gene account for the highest known percentage of nonsyndromic congenital SNHL, estimated between 10 and 80% of nonsyndromic SNHL cases, depending on the reference population.

Mutations in this gene can cause either autosomal dominant (DFNA3) or autosomal recessive (DFNB1) deafness, depending on the exact change in the nucleotides. Most cases are recessive.

DFNB1 is characterized by congenital, nonprogressive, mild to profound sensorineural hearing loss, without other associated features, and with normal vestibular function. The severity of the hearing loss is variable and may differ between siblings and other close relatives sharing the same mutation.

CT scans of the temporal bone show a normal otic capsule.

Six connexin 26 molecules oligomerize into hexamers called connexons, and two connexons, one from each cell, join in the extracellular gap to form a transmembrane gap junction channel that allows intercellular flow of ions and molecules between cells. In the inner ear, gap junctions allow synchronization of electrical activity in excitable tissues and the maintenance of the endolymphatic potential.

DFNB1 accounts for 50% of congenital autosomal recessive deafness in the United States, Europe, and Australia. Its approximate prevalence in the general population is 14 per 100,000. Numerous deafness-caus- ing mutations have been identified, but by far the most common one is 35delG. The 35delG mutation is estimated to be responsible for 10% of all childhood deafness, and 20% of all childhood hereditary hearing loss. Other recessive mutations are common in some ethnic groups. The 167delT mutation, rare in most groups, is prevalent in Ashkenazi Jewish families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the carrier rate for these two connexin 26 deletion mutations (35delG and l67delT) is nearly 5%. This carrier frequency predicts a prevalence of one deaf individual in 1800 and appears to account for most cases of nonsyndromic recessive deafness in patients with a Jewish background.

Molecular genetic testing of DFNB1 has become widely available and can identify 95% of deafnesscausing mutations. However, 10% of patients with connexin 26 gene mutations have only one mutated allele, and some families in whom the diagnosis of DFNB1 was established by linkage studies have no connexin 26 mutation; thus failure to detect a connexin 26 mutation does not exclude the diagnosis of DFNB1. The DFNB1 chromosomal locus contains two functionally related connexin genes, GJB2 (connexin 26) and GJB6 (connexin 30), and DFNB1 may result from a monogenic or digenic pattern of inheritance.

DFNA9

Gene map locus: 14q12–q13

Gene: COCH

Autosomal dominant

DFNA9 patients show onset of hearing loss in young adulthood (20–30 years of age). Impairment is initially worse at high frequencies, and then variably progresses to anacusis by 40 to 50 years of age. Clinical vestibular symptoms mimicking Meniere’s disease occur.

The COCH gene protein cochlin was detected in cells accompanying neurons at the habenula perforata. Acidophilic deposits, consistent with mucopolysaccharide ground substance, have been noted at that anatomical site in temporal bones from DFNA9 patients

DFNB3

Gene map locus: l7p11.2

Gene: MYO15A

Autosomal recessive

•DFNB3 is a profound, congenital, nonsyndromic SNHL.

•Animal model: mouse mutant shaker-2’, showing mutations of MYO15, another unconventional myosin gene

DFNB4 (See Also Pendred Syndrome)

Gene map locus: 7q31

Gene: PDS

Autosomal recessive

The DFN4 gene is apparently the same gene that causes Pendred’s syndrome, but in this nonsyndromic recessive deafness there are no associated thyroid abnormalities on physical exam or thyroid function tests. SNHL is usually progressive, and CT scan of the temporal bone shows dilated vestibular aqueduct/Mondini deformity.

Nonsyndromic Deafness and Abnormal Myosin 7A Gene (See Also Usher Syndrome)

Gene map locus: 11q13.5

Gene: MYO7A

Both recessive (DFNB2) and dominant (DFNA11) forms of nonsyndromic deafness have been found in different parts of the world in families with myosin 7A gene mutations. These nonsyndromic families do not have impairment in vision (recall that myosin 7A is abnormal in Usher’s syndrome type 1, the single most common cause of deaf/blindness).

DFNA2

Gene map locus: 1p34

Gene: KCNQ4

Autosomal dominant

Families with DFNA2 are characterized by progressive deafness involving preferentially the high frequencies. KCNQ4 encodes a subunit of a potassium channel of the outer hair cells that play a role in the maintenance of the electrical properties of these cells. KCNQ4 is the second member of the KCNQ gene family to be involved in SNHL, the first being the KCNQ1 gene responsible for JLNS.

DFNA8/DFNA12

Gene map locus: 11q22–q24

Gene: TECTA

Autosomal dominant

Alpha-tectorin is one of the major noncollagen components of the tectorial membrane in the organ of Corti. Mutations in the -tectorin gene, TECTA, are responsible for at least two autosomal nonsyndromic deafness forms.

MITOCHONDRIAL DNA DEAFNESS

Hearing loss accompanies many mtDNA disorders, perhaps reflecting the highly metabolic state of the hearing process. Initially, mtDNA defects were described in some systemic neuromuscular disorders, such as Kearns-Sayre syndrome, MERRF, and MELAS, as well as in families with diabetes mellitus and SNHL. More recently, nonsyndromic deafness has been shown to occur with mtDNA mutations, with remarkable heterogeneity of phenotypic expression even with the same genetic defect, suggesting the possibility of a nuclear gene in modifying the effect of the mutation.

The A1555G mutation is one of the genes encoding mitochondrial ribosomal RNA (12S rRNA) and has been recognized as the most common cause of aminoglycoside-induced deafness. Although sufficiently high doses of aminoglycosides will cause SNHL in any person, deafness will occur after even small dosages of aminoglycoside antibiotics in patients who carry this mutation.The mitochondrial ribosome in the cochlea is the most likely target of aminoglycoside ototoxicity, because the “natural target” of aminoglycosides is the bacterial ribosome. The mechanism of ototoxicity of aminoglycosides is thought to be reduced production of adenosine triphosphate (ATP) in the mitochondria

of hair cells. The A1555G mutation also has been described in families with SNHL without aminoglycoside exposure.

Other families with nonsyndromic SNHL and maternal inheritance have been described to carry a mutation at nucleotide 7445 in the mitochondrial transfer RNA (tRNA)Ser(UCN) gene. Furthermore, acquired mtDNA defects have been implicated in the aging process and in the development of presbycusis, in combination with other environmental factors.

GENETIC SCREENING AND MOLECULAR

DIAGNOSIS OF DEAFNESS

Genetic screening is defined as the analysis of human DNA to detect heritable-related mutations. A genetic test is one to detect a heritable disease; we will primarily refer to DNA tests for SNHL, but keep in mind that other means to diagnose genetic disease are available, such as RNA, chromosomes, proteins, and certain metabolites.

The recent availability of DNA tests to diagnose genetic hearing loss has revolutionized the way we approach these cases. In some cases, the DNA test has supplanted other, more invasive and less accurate tests. The goal of genetic testing is to establish an etiologic basis for hearing loss in the most efficient manner possible. Based on the results of the clinical evaluation, the following should be considered.

Syndromic forms of hearing loss have a genetic origin, except for congenital rubella, toxoplasmosis, and cytomegalovirus embryopathies. When syndromic hearing loss is suspected, gene-specific testing should be performed. Available DNA tests for diagnosis of syndromic deafness exist for Waardenburg, Usher, Jerwell and Lange Nielsen, and Pendred syndromes. For a complete list of syndromes and corresponding DNA tests, see Geneclinics (http://www.geneclinics.org). The evaluation can be complemented with specific viral titers and cultures (Table 19-1).

Nonsyndromic hearing loss (NSHL) is the most common type of genetic deafness, and among these the most common type of NSHL inheritance is autosomal recessive (ARNSHL). A family history is not usually evident in ARNSHL because sporadic cases predominate, but the hearing loss is usually severe and occurs at birth. Autosomal dominant NSHL tends to occur later in life, is progressive, and usually not severe. It is interesting that in some populations, particularly in Europe and the midwestern section of the United States, one gene alone accounts for just over half of all cases of ARNSHL; that is, the connexin 26 gene

(Cx26). Thus the following are recommendations for genetic screening of NSHL:

•In neonates with congenital hearing loss and no obvious family history: Cx26 mutation screening by gene sequencing and cytomegalovirus immunoglobulin M (IgM) titers

•The patient has a family history and other first-degree hearing-impaired relative(s): Cx26 mutation screening and gene-specific mutation screening if the pedigree shows autosomal dominant inheritance

•The pedigree suggests mitochondrial DNA inheritance (maternal inheritance): testing for the A1555G mutation (associated with aminoglycoside ototoxicity) and the A7445G mutation, after excluding Cx26 mutations

•If nonsyndromic deafness is suspected and both parents are deaf, Cx26-related deafness is strongly suspected; because Cx26 deafness is the most common in the United States, the vast majority of marriages between deaf individuals who produce deaf offspring are between individuals with Cx26- related deafness

•In patients with progressive SNHL, imaging studies are recommended to identify inner ear malformations. If a cochlear dysplasia is found (Mondini deformity, dilated vestibular aqueduct): screening for SLC26A4 mutations for Pendred syndrome/DFNB4.

After genetic testing it will be possible to ascribe a genetic etiology to the hearing loss in many persons. For example, a child may be diagnosed with Cx26 deafness if two mutated alleles are found.We then know the cause of the child’s deafness with certainty and can accurately predict the chance of recurrence in a subsequent child. Alternatively, the test may be negative. A negative screening test does not mean that the deafness is not genetic.This distinction is subtle but very important and must be conveyed to parents prior to testing. In patients with a negative family history and a negative test for Cx26, the probability that the deafness is genetic can be given, and this probability is based on the number of hearing siblings and the ethnic group.

The benefits of genetic testing in single-gene diseases when the genetic loci are known are obvious, such as in DFNB1, and include determination of the cause of hearing loss, avoidance of unnecessary and costly tests, determination of the chance of recurrence of deafness in the family, and identification of relatives at risk. Prenatal diagnosis is possible by obtaining fetal DNA through

amniocentesis or chorionic villi sampling, but there are important pitfalls.

Often, there are several loci that cause syndromes or diseases; ruling out one or two may be possible, but it will not comprehensively rule out the possibility of a trait. Prenatal diagnosis is therefore not available for every disease associated with a known mutant gene.

Merely having the mutant gene does not necessarily mean developing the disease. In most known oncogenes, carrying the mutation places an individual at increased risk but does not predict that cancer will actually occur. Therefore,prenatal testing is currently limited for selected conditions where the clinical usefulness of the screening test has been proven;for example,tests with high predictive value in disorders with specific therapeutic interventions to reduce risk in genetically susceptible individuals.

GENETIC COUNSELING

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The purpose of genetic counseling is to ensure that the parents/patients understand the findings and limitations inherent in any genetic test. Parents are usually given detailed counseling before undergoing genetic testing to ensure that they make informed decisions about the use of tests with complex personal implications. Genetic counseling is usually nondirective; that is, counseling provides sufficient information to empower families or individuals to determine the best course of action for them but avoids making recommendations.

Optimally, counseling includes both preand post-test sessions.A pretest session focuses on factual information, including an explanation of the disorder, modes of inheritance, and genetic testing options including their risks, benefits, and limitations. A post-test session includes an explanation of test results, an assessment of the psychological impact that the results may have on the parents and child, and a description of treatment and supportive resources that are available for the family needs.

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 716.

1.The p53 gene encodes for a protein that

A.Enhances hearing acuity

B.Increases tumor metastases

SUMMARY

The otolaryngologist in the era of genomic medicine will have the opportunity to use the patient’s own unique genome to determine the optimal management approach (i.e., preventive, diagnostic, and/or therapeutic). Future challenges include the constantly changing knowledge base on concepts such as genetic variability, interaction of an individual’s inherited genetic traits with the environment, and clinical usefulness and reliability of available DNA tests, as well as patient privacy and confidentially issues related to genetic testing.

SUGGESTED READINGS

Casselbrant ML, Mandel EM, Fall PA, et al. The heritability of otitis media: a twin and triplet study. JAMA 1999;282: 2125–2130

Del Castillo I, Villamar M, Moreno-Pelayo MA, et al. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 2002;346(4):243–249

Fischel-Ghodsian N, Bykhovskaya Y, Taylor K, et al. Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations. Hear Res 1997;110: 147–154

Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Screening. Genet Med 2002;4(3): 162–171

Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860–921 [errata, Nature 2001;411:720, 412:565]

Manolidis S, Alford RL, Smith RJH, et al. Do the genes that cause otosclerosis reduce susceptibility to otitis media? Otol Neurotol 2003;24:868–871

McKusick VA. Online Mendelian Inheritance in Man (OMIM). Available at: http://www.ncbi.nlm.nih.gov/Omim/. Accessed March 15, 2004

Petit C, Levilliers J, Hardelin JP. Molecular genetics of hearing loss. Annu Rev Genet 2001;35:589–646

Van Camp G, Smith RJH. Hereditary Hearing Impairment Homepage. Available at: http://www.uia.ac.be/dnalab/hhh/. Accessed March 16, 2004

C.Arrests the cell cycle at G1 in a cell with damaged DNA

D.All of the above

2.Usher’s syndrome type 1 affects

A.The visual system only

B.The auditory system only

C.The vestibular system only

D.All of the above

3.Mutations in which gap junction protein gene account for the highest percentage of nonsyndromic congenital sensorineural hearing loss?

A.Connexin 43

B.Connexin 30

C.Connexin 26

D.Connexin 32

4.The following are features of hereditary tumors except

A.Bilateral and multicentric tumors

B.More aggressive course than nonhereditary tumors

C.DNA mutations are found in the tumor cells only.

D.May occur in patients without risk factors

5.The following are examples of the benefits of genetic screening except

A.A negative screening test for connexin 26 mutations in a child with congenital deafness is proof that the hearing impairment is not genetic.

B.In relatives of patients with MEN2A and medullary thyroid carcinoma, blood DNA screening for RET gene mutations is available to evaluate the need for prophylactic thyroidectomy.

C.In adult relatives of patients with neurofibromatosis II, magnetic resonance imaging with gadolinium of the brain is indicated even if the patient is asymptomatic.

D.DNA tests are being used for the diagnosis of some genetic diseases instead of other invasive, costly tests.

6.Autosomal recessive inheritance is characterized by all of the following except

A.Skipped generations

B.The chance of disease recurrence increases with each affected child in the family.

C.25% chance of disease recurrence in successive children

D.No sex predilection

E.Consanguinity