Epidemiology and Prevalence Hearing loss is the most common sensorineural deficit. Bilateral hearing loss ≥ 40 dB HL is present in 1.33 per 1,000 newborns. When unilateral hearing loss is included, the incidence figures raise to 1.86 per 1,000 at birth. 2 In developing countries, the prevalence of congenital hearing loss may be as high as 6 neonates per 1,000 live births. 3, 4 The risk for PCHI is 10 times higher in infants from the neonatal intensive care unit (NICU), with a prevalence of 2 to 4%. Bilateral severe hearing loss (> 70 dB HL) was documented in 1.9% of NICU graduates at 3 years of age. 5 Nearly 20 to 30% of affected children have profound hearing loss (> 90 dB HL). Approximately 30% of children with bilateral hearing loss have additional disabilities, most frequently generalized learning difficulty or intellectual disability. 6 Hearing loss may become manifest postnatally. The child passes the neonatal hearing-screening test and hearing loss becomes apparent later in childhood. It can be categorized as delayed onset, progressive, or acquired. Delayed-onset hearing loss results from adverse medical conditions that are present during the pre- or perinatal period (intrauterine infections, asphyxia). Their effects become manifest over time. Progressive hearing loss is usually caused by viral infections, hereditary factors, or neurodegenerative disorders. Acquired hearing loss results from external factors occurring in the postnatal period, such as meningitis, use of ototoxic drugs, trauma, and noise exposure. Consequently, the prevalence of PCHI increases during childhood with values of 2.7 per 1,000 children around 5 years (prelingual hearing loss) and up to 3.5 per 1,000 during adolescence. 2 Postnatal impairment may account for 25% of all bilateral PCHI at the age of 9 years. 7 Hearing loss present at birth is termed congenital hearing loss. In approximately 50% of the cases with congenital hearing loss, a genetic or inherited cause can be identified; the remaining are related to environmental factors ( ▶ Fig. 13.1). 8 Fig. 13.1 Relative contribution of environmental and genetic causes to congenital hearing loss. (Modified after Smith RJ, Bale JF, Jr, White KR. Sensorineural hearing loss in children. Lancet 2005; 365(9462):879–890, with permission.) The hearing loss may be an isolated defect, may occur in association with one or more congenital defects that do not constitute a defined syndrome, or may be one feature of a group of congenital anomalies that form a defined and recognized pattern (syndromic hearing loss). More than 450 genetic syndromes that include hearing loss have been described. 9 Nonsyndromic inherited hearing loss is often difficult to differentiate from environmental or multifactorial causes of hearing loss. Ototoxic medication, especially aminoglycosides, may cause hearing loss in newborns. Patients carrying an A1555G mutation in the mitochondrial 12S ribosomal gene are more sensitive to aminoglycoside ototoxicity. 10 Inherited deafness is extremely heterogeneous genetically and shows considerable phenotypic variability. More than 175 different loci/genes have been identified over the last decades. For a full summary of loci and genes associated with inherited hearing loss, the reader is advised to consult the Hereditary Hearing Loss homepage at http://hereditaryhearingloss.org/. The pattern of inheritance is autosomal recessive in approximately 75% of cases, autosomal dominant in approximately 20%, X-linked in approximately 5%, and mitochondrial in less than 1%. 11 In general, prelingual, profound, nonprogressive deafness is inherited as an autosomal recessive trait. The genetic causes may be subdivided into syndromic and nonsyndromic forms. Syndromal hearing loss accounts for 30% of all cases of genetic hearing impairment. 12 A list of the most common syndromic causes for PCHI is presented in ▶ Table 13.1. In the following sections, we briefly describe three syndromic forms of PCHI. A basic knowledge of these syndromes is required to understand the rationale of the standard diagnostic protocol for infants/children with PCHI as described further in this chapter. For more detailed information and more rare syndromes, refer to the Hereditary Hearing Loss Homepage. Syndrome Gene Inheritance pattern Phenotype Waardenburg Type 1 (most common) PAX3 AD Unilateral (10%) or bilateral (90%) hearing loss, patches of hypopigmentation in skin, eye, hair, dystopia canthorum, synophrys, pinched nares Type 2 MITF, SNAI2 AD As type 1 but without dystopia canthorum Klein-Waardenburg syndrome (Type 3) PAX3 AD and AR As type 1 but with limb abnormalities Waardenburg-Shah syndrome (Type 4) EDNRB, EDN3, and SOX10 AD and AR As type 2 but with Hirschprung disease Branchio-otorenal EYA1, SIX1, and SIX5 AD Hearing loss, preauricular pits, dysplastic ears, branchial fistulae, renal abnormalities Treacher Collins TCOF1, POLR1C, and POLR1D AD Conductive hearing loss, ossicular anomalies, microtia, cleft palate, micrognathia, downward slanting eyes, coloboma Pendred SLC26A4, FOXI1, and KCNJ10 AR Sensorineural hearing loss, enlargement of the vestibular aqueduct, thyromegaly Usher Type 1 MYO7A, USH1C, CDH23, PCDH15, CIB2, and SANS AR Profound HL, vestibular symptoms, RP from first decade Type 2 USH2A, VLGR1, and WHRN AR Nonprogressive, moderate-to-severe HL, RP from first to second decade Type 3 CLRN1 and PDZD7 AR Progressive HL, variable vestibular symptoms, variable onset of RP Jervell and Lange-Nielsen KVLQ1 and KCNE1 AR Profound bilateral hearing loss, QTc prolongation, syncope, sudden death Abbreviations: AD, autosomal dominant; AR, autosomal recessive; HL, hearing loss; QTc, corrected QT; RP, retinitis pigmentosa. The most common syndromic form is Pendred’s syndrome ( ▶ Fig. 13.2). This syndrome combines inner ear malformations, in particular a bilateral enlargement of the endolymphatic duct and sac (LEDS) with or without cochlear hypoplasia with thyroid dysfunction as manifested by an abnormal perchlorate test or a goiter. Most frequently, Pendred’s syndrome is linked to mutations in the SLC26A4 gene (Pendrin) on chromosome 7. A finding of bilateral LEDS should prompt thorough investigations for Pendred’s syndrome. Children with nonsyndromic LEDS carry a single SLC26A4 mutation in 61% of the cases. 2 Children with LEDS are at risk for sudden hearing loss following head injury or sudden changes in intracranial pressure. Parents of these children should be advised about minimizing the risk of head injury, for example, by avoiding contact sports and diving. Fig. 13.2 A 12-year-old boy with severe high-frequency sensorineural hearing loss on the left side and moderate on the right side. Axial 0.3 mm thick heavily T2-weighted driven equilibrium (DRIVE) images at the level of the labyrinth (a) and lower in the posterior fossa (b). (a) A prominent endolymphatic duct can be seen on the right side (white arrow) with a width similar to the cross-section through the posterior semicircular canal (white arrowhead). On the left side the endolymphatic duct (black arrow) is clearly larger than the cross-section of the posterior semicircular canal (white arrowhead) and hence clearly widened. The widened endolymphatic duct continues posteriorly in an enlarged endolymphatic sac. (b) The extension of the enlarged endolymphatic sac in the posterior fossa on the left side can be seen and although the dimensions of the right endolymphatic duct were borderline, the endolymphatic sac is clearly enlarged and its extension in the posterior fossa can also be seen (gray arrow). The more extensive enlargement on the left side explains also the more dominant hearing loss on this side. Note that both high-signal clear fluid and low-signal proteinaceous fluid and/or fibrous areas can be seen in the enlarged endolymphatic sacs (gray arrows). Courtesy of Jan Casselman, AZ St. Jan Hospital, Department of Radiology, Bruges, Belgium. Usher’s syndrome is a heterogeneous autosomal recessive inherited disorder with a prevalence of 3.5 per 100,000 children. It is characterized by sensorineural hearing loss (SNHL) of varying severity associated with progressive pigmentary retinal degeneration. Approximately 3 to 6% of all children who are deaf and another 3 to 6% of children who are hard of hearing have Usher’s syndrome. Usher’s syndrome type I (USH1) is distinguished from the other infantile form (USH2) on the basis of severity of hearing loss and the extent of vestibular involvement: USH1 is characterized by profound congenital deafness, absent vestibular function, and progressive visual loss starting in the first decade of life. 13 Jervell and Lange-Nielsen’s syndrome, also known as long QT syndrome (LQTS), is a rare autosomal recessive disorder with an estimated incidence of 1.6 to 6 cases per million, thought to result from mutations in genes that encode proteins forming the delayed rectifier potassium channel. The responsible genes have been identified as KVLQ1 and KCNE1, located on chromosomes 11 and 21, respectively. 14 Mutations in these genes encoding cardiac ion channels result in delayed myocellular repolarization. The syndrome consists of congenital bilateral profound deafness and prolongation of the QT interval as detected by electrocardiography (ECG; abnormal corrected QT [QTc] > 440 ms). Affected individuals have syncopal episodes and may have sudden death. Nonsyndromal inherited hearing loss accounts for 70% of genetic causes. 12 Despite the tremendous heterogeneity of deafness, mutations in one gene, encoding the gap junction β2 protein, connexin 26 (GJB2), are responsible for more than half of hereditary prelingual SNHL in the white population. 8 Particularly when both parents have normal hearing, connexin-related deafness will be strongly suspected. Connexin 26 is a gap junction protein expressed in supporting cells and connective tissue of the inner ear. These gap junctions are critical for recycling of potassium ions and maintenance of a normal endocochlear potential. More than 100 mutations involving GJB2 have been identified. They often cause a profound and nonprogressive hearing loss, although phenotypic variations and milder variants are known. A single variant known as 35delG accounts for up to 70% of all pathogenic mutations. Homozygous* 35delG mutations result in profound hearing loss. Heterozygous mutations in connexin 26 may contribute to hearing loss when there is a simultaneous mutation in connexin 30 (GJB6) (compound heterozygosity). *Homozygous: having two identical alleles at a given gene locus; heterozygous: having two different alleles at a given gene locus; compound heterozygous: having two different mutant alleles at the same gene locus. Various infectious pathogens may result in SNHL when they infect the mother during pregnancy. These agents are quoted as TORCHES (toxoplasmosis, others, rubella [ ▶ Fig. 13.3], cytomegalovirus [CMV], and herpes simplex virus [HSV]). Fig. 13.3 Newborn baby with congenital rubella. The skin lesions are characteristic. Other features include profound sensorineural hearing loss, cataracts, microcephaly, and hepatosplenomegaly. Vaccination has virtually eliminated this condition in the developed world. In countries without universal rubella vaccination, congenital rubella infection is the most common environmental cause. The earlier the infection is acquired during pregnancy, the more severe the effect on the fetus. Nearly 90% of the infants with the congenital rubella syndrome have SNHL. Hearing loss is usually bilateral, severe to profound, affecting all frequencies, and may be progressive and/or asymmetric. Other findings include pigmentary retinitis (most common and consistent finding), cataract, microcephaly, intellectual disability, cardiovascular abnormalities, intrauterine growth retardation, and hyperbilirubinemia. 15 This infection represents the most important cause of SNHL in the developed countries where universal rubella vaccination is available, having an incidence of approximately 1 in 100 births. At birth, 3.9% of infants with congenital CMV infection have hearing loss. 2 Intrauterine transmission of primary CMV infection, especially during 4th to 22nd week of gestation, has the most potential to cause significant fetal damage. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy is 30 to 40% and 1.4%, respectively ( ▶ Fig. 13.4). The risk of congenital CMV with recurrent infection (i.e., in a mother who had a previous CMV infection) is lower. Transmission of CMV People who are infected with CMV shed the virus from infected body fluids such as saliva, urine, blood, and semen. For pregnant women, the most common exposures to CMV are through sexual contact and through contact with the urine or saliva of young children with CMV infection. A pregnant woman may pass the virus to her baby as the virus can cross the placenta and infect the fetus’s blood. CMV can also be shed in breast milk but infections that occur from breast-feeding usually do not cause symptoms or disease in the infant. Pregnant women should be counseled to take preventive measures with the aim to avoid getting urine or saliva of children on the hands or in the nose, eyes, and mouth. Primary intrauterine CMV infections are a leading cause of SNHL and second only to Down’s syndrome as a known cause of intellectual disability. Approximately 10 to 15% of infants with congenital CMV infection are symptomatic at birth. These infants may present with jaundice (conjugated hyperbilirubinemia), hepatosplenomegaly, petechiae (thrombocytopenia), microcephaly, lethargy, hypotonia, and seizures. 16 Symptomatic children are at particularly increased risk for SNHL with a cumulative prevalence of 36% at 6 years. 17 In a recently published systematic review, it was concluded that 1 out of 3 symptomatic children and 1 out of 10 asymptomatic children, will experience hearing loss ( ▶ Fig. 13.4). 18 There is no pathognomonic configuration for the hearing loss caused by congenital CMV infection. Unilateral and bilateral hearing losses at any frequency may occur in children with congenital CMV infection, with loss varying from mild to profound, the latter being more common in symptomatic infants. In addition, progressive and fluctuating hearing loss has been observed in 29.4% of symptomatic and 54.1% of asymptomatic babies with congenital CMV infection. In fact, approximately half of the cases of hearing loss due to congenital CMV infection are late onset and/or progressive and, therefore, will not be detected at birth through newborn hearing screening. 19 Fig. 13.4 Frequency of maternal and fetal cytomegalovirus infections and morbidity of infected children. (After Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, et al. Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA 1986;256(14):1904–1908; and Ludwig A, Hengel H. Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. Euro Surveillance European Communicable Disease Bulletin 2009;14(9):26–32.) Toxoplasma Gondii Infection of the mother may be detected by serological testing during pregnancy. Rates of congenital infection range from less than 0.1 to 1 per 1,000 live births. At birth, 90% of toxoplasmosis babies will have no clinical features at birth, although many will develop visual or learning disabilities later in life. 20, 21 The prevalence of toxoplasmosis associated hearing loss in affected babies ranges from 0 to 28% and seems to depend on prior treatment. 22 Early identification and treatment are the key to minimizing morbidity. In children who received 12 months of antiparasitic treatment initiated prior to 2.5 months of age and with serologically confirmed compliance, the prevalence of SNHL was 0%. This is in strong contrast with those children receiving no or limited treatment and in whom a prevalence figure for SNHL of 28% was documented. Other findings caused by congenital toxoplasmosis include chorioretinitis, hydrocephalus, intracranial calcifications, lymphadenopathy, and pulmonary lesions. 15 Transmission of Toxoplasma Toxoplasma can be transmitted to a pregnant woman by ingestion of raw or inadequately cooked infected meat or by exposure to cat litter, dog feces, or soil containing oocysts. Toxoplasma infection can be prevented by cooking meat at temperatures high enough to kill the protozoan parasite, by avoiding contact with raw meat, poultry or seafood, unwashed vegetables or fruit, and pet excrement. An annual incidence of 0.1 per 1,000 live births is reported. Congenital syphilis can be found in two entities: an infantile form (early), which is usually fatal in outcome, and a tardive form (late). The late form expresses itself with sudden SNHL in childhood that tends to be profound and symmetric and associated with vestibular symptoms. A recently published literature search on the prevalence of SNHL following congenital syphilis infection concluded that there are no reports of confirmed congenital SNHL secondary to in utero syphilis infection. 23 This conclusion was largely based upon a prospective study in 75 neonates born with serological evidence of congenital syphilis who all had normal auditory brainstem responses (ABRs) in the newborn period. 24 Neonatal HSV infection has an annual incidence of less than 0.01 to 0.33 cases per 1,000 live births. 15 Infections are very rarely caused by in utero exposure. They present as disseminated infection, encephalitis, or localized infection. 25 SNHL related to congenital HSV infection has, however, only been described in disseminated disease in which other obvious clinical sequelae of HSV infection and comorbid conditions were present. Ototoxic medication, especially aminoglycosides, may cause hearing loss in newborns. Patients carrying an A1555G mutation in the mitochondrial 12S ribosomal gene are more sensitive to aminoglycoside ototoxicity. 10 Perinatal factors associated with PCHI include peripartum hypoxia, hyperbilirubinemia with kernicterus, or the need for exchange transfusion and extracorporeal membrane oxygenation (ECMO). These risk factors are typically found in infants staying in the special care baby unit or the NICU. Alcohol abuse during pregnancy may result in fetal alcohol syndrome and associated hearing loss. Use of chemotherapy during pregnancy may also cause hearing loss in the newborn. 26 The Joint Committee on Infant Hearing (JCIH) from the American Academy of Pediatrics identified several risk factors for congenital or late-onset childhood hearing loss (Box 13.1). 27 Three of these are considered as major risk factors for congenital hearing impairment: NICU stay > 48 hours. Family history of permanent hearing impairment. Craniofacial anomalies. One or more of these three risk factors were found in only 58.9% of children with bilateral congenital hearing impairment. 28 This means that a large number of babies with PCHI will not be identified if screening is confined to those at high risk. Box 13.1 Risk Factors for Permanent Congenital, Delayed, or Progressive Hearing Loss in Childhood 27 Caregiver concern regarding hearing, speech, language, or developmental delay. Family history of hearing loss. Neonatal intensive care > 5 days or any of the following regardless of length of stay: ECMO, assisted ventilation, use of ototoxic drugs (gentamycin, tobramycin) or loop diuretics, or hyperbilirubinemia requiring exchange transfusion. In utero infections (TORCHES). Craniofacial anomalies including those that involve the outer ear, ear canal, ear tags, ear pits, and temporal bone anomalies. Physical findings associated with a syndrome known to include permanent hearing loss (e.g., white forelock). Syndromes associated with hearing loss or progressive or late-onset hearing loss. Neurodegenerative disorders or sensorimotor neuropathies. Confirmed bacterial or viral (especially herpes and varicella) meningitis. Head trauma, especially basal skull or temporal bone fractures that require hospitalization. Chemotherapy. Robertson et al 5 found a 3.1% prevalence of permanent hearing loss in a cohort of 1,279 NICU survivors (≤ 28 weeks of gestation and < 1,250 g of birth weight) at the age of 3 years. In this study, all children with delayed-onset hearing loss and 82% of those with progressive hearing loss had required prolonged supplemental neonatal oxygen use. An association was suggested between prolonged need for oxygen/respiratory failure and permanent hearing loss through ototoxicity. Recent investigations of risk factors for SNHL in NICU infants found that dysmorphic features, low APGAR* scores at 1 minute, sepsis, meningitis, cerebral bleeding, and cerebral infarction should be considered as risk factors for SNHL, independent of postconceptional age, gender, and NICU admittance. 29 In addition, recent data from a large epidemiological study in 103,835 screened non-NICU babies showed that sociodemographic factors such as gender (boys), increasing birth order, birth length, feeding type (higher risk with formula), low level of education, and Eastern European origin of the mother are independent risk factors for permanent hearing impairment. 30 Many of these risk factors are associated with poverty and deprivation. *APGAR: score used for evaluation of the newborn based upon five items: A (appearance), P (pulse), G (grimace), A (activity), and R (respiration). More than 50% of cases of PCHI may be detected shortly after birth through a program of neonatal hearing screening. However, as mentioned earlier, a pass on the neonatal hearing test does not preclude late-onset hearing loss. Less severe congenital hearing loss (<30–40 dB) is not detected in most screening programs. Progressive or late-onset hearing impairment, as seen with congenital CMV infection or in some inherited conditions, is also not detected by a newborn screening program. Up to now, postnatal identification will remain dependent upon the interaction between parents and professionals and on pathways that allow ready access to audiology services. Continued surveillance, screening, and referral of infants and toddlers are needed. Health care providers, educators, and parents must remain attentive to the developmental progress of children, especially in expressive and receptive language domains. A hearing (re)assessment is recommended for all children experiencing developmental or learning difficulties. To be successful, a neonatal hearing-screening program should endeavor to be universal since selective screening based on high-risk criteria fails to detect at least half of all infants with congenital hearing loss. According to Declau et al, in a retrospective study of 170 referred neonates after universal neonatal hearing screening (UNHS), risk factors were also statistically not different between the normal-hearing and hearing loss groups. On the other hand, the presence of a high-risk factor predicts hearing loss in 68%. 31 In UNHS programs, two types of tests are commonly used: otoacoustic emissions (OAEs) and automated ABR (A-ABR). A detailed description of these tests may be found in Chapter 13.6.1. In the past, many centers used the Ewing test. This test is based upon an orientation reflex where the baby turns his/her head in the direction of a presented sound stimulus. This reflex is most evident at 9 to 12 months of age and disappears later on. In comparison with the Ewing test, both A-ABR and OAEs (transient OAE [TEOAE] or distortion product OAE) yield far better sensitivity and specificity, are easy to use, and are cost-effective. OAEs are highly sensitive but show less specificity. There is a higher rate of false-positive results due to middle ear pathology. Detection of OAEs implies a normal function of the auditory system up to the level of the outer hair cells. Hearing loss caused by auditory neuropathy/auditory dyssynchrony (Box 13.2) will be missed with this technology. A-ABR has a higher specificity. False-positives may result from an immature central nervous system. 32 Automated algorithms eliminate the need for individual test interpretation, reduce the effects of screener bias and errors on test outcome, and ensure test consistency across all infants, test conditions, and screening personnel. The JCIH recommends ABR technology as the only appropriate screening technique for use in the NICU. For infants who do not pass A-ABR testing in the NICU, referral should be made directly to an audiologist for rescreening and, when indicated, comprehensive evaluation including standard ABR. For rescreening, a complete screening on both ears is recommended, even if only one ear failed the initial screening. For readmissions in the first month of life for all infants (NICU or well infant), when there are conditions associated with potential hearing loss (e.g., hyperbilirubinemia that requires exchange transfusion or culture-positive sepsis), a repeat hearing screening is recommended before discharge. Box 13.2 Auditory Neuropathy/Dyssynchrony Some children will have normal OAEs but absent or abnormal ABR readings. This condition is referred to as “auditory neuropathy/auditory dyssynchrony” (AN/AD). Rapin and Gravel suggested that the term AN/AD should be limited to cases in which the pathology is located at the spiral ganglion cells, their processes, or the eighth cranial nerve. 33 This condition may be related to structural abnormalities of the auditory nerve such as cochlear nerve aplasia/hypoplasia, and in bilateral cases, mutations in the OTOF gene should be excluded. Some infants with an initial diagnosis of AN/AD may demonstrate improved auditory function and even “recovery” on ABR testing. 34 Particularly in high-risk neonates, a repeat ABR testing is recommended at the age of 6 months. For those infants who “recover” from AN/AD, regular surveillance of developmental milestones, auditory skills, parental concerns, and middle ear status is recommended consistent with the JCIH 2007 Position Statement. 27 Because the residual effects of transient AN/AD are unknown, ongoing monitoring of the infant’s auditory, speech, and language development, as well as global (e.g., motor, cognitive, and social) development is critical. Those infants and young children whose speech and language development is not commensurate with their general development should be referred for speech and language evaluation and audiological assessment.
13.3 Etiology
13.3.1 Genetic Causes of Permanent Childhood Hearing Impairment
Syndromal Hearing Loss
Pendred’s Syndrome
Usher’s Syndrome
Jervell and Lange-Nielsen’s Syndrome
Nonsyndromal Inherited Hearing Loss
13.3.2 Environmental Causes of Permanent Childhood Hearing Impairment
Congenital Rubella Infection
Congenital Cytomegalovirus Infection
Toxoplasma Gondii
Syphilis
Herpes Simplex Virus
Noninfectious Environmental Causes Of PCHI
13.4 Risk Factors for Hearing Loss
13.5 Identification of Hearing Loss
13.5.1 Neonatal Hearing Screening
Screening Methods
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