Genetic Sensorineural Hearing Loss Clinical Presentation

Genetic hearing loss may be congenital, prelingual, or postlingual in onset and may present with progressive, fluctuating, or stable patterns. Congenital hearing loss is potentially identifiable with newborn screening. High-risk indicators should be used to identify children who are at risk for developing hearing loss after birth. Attention to high-risk indicators, to achievement of speech and language milestones, and to the family history are essential in evaluating a child for hearing loss.

Failure to achieve the following speech and language milestones may indicate hearing loss and necessitate a hearing evaluation:^[13]

• Birth to 3 months

  • Startles to loud noise
  • Awakens to sounds
  • Blinks or widens eyes in response to noises
• 3-4 months

  • Quiets to mother's voice
  • Stops playing, listens to new sounds
  • Looks for source of new sounds that are not in sight
• 6-9 months

  • Enjoys musical toys
  • Coos and gurgles with inflection
  • Says "mama"
• 12-15 months

  • Responds to his or her name and the word "no"
  • Follows simple requests
  • Uses expressive vocabulary of 3-5 words
  • Imitates some sounds
• 18-24 months

  • Knows body parts
  • Uses expressive vocabulary with 2-word phrases (minimum of 20-50 words)
  • 50% of speech intelligible to strangers
• By 36 months

  • Uses expressive vocabulary of 4- to 5-word sentences (approximately 500 words)
  • 80% of speech intelligible to strangers
  • Understands some verbs

Potential sources of acquired hearing loss should be considered including the following: in utero infection associated with genetic sensorineural hearing loss (SNHL; eg, toxoplasmosis, rubella, CMV infection, herpes, syphilis), hyperbilirubinemia at levels that require exchange transfusion, birth weight of less than 1500 g, bacterial meningitis, low Apgar scores (0-3 at 5 minutes, 0-6 at 10 minutes), respiratory distress (eg, due to meconium aspiration), mechanical ventilation for more than 10 days, and exposure to ototoxic medication (eg, gentamicin) administered for more than 5 days or used in combination with loop diuretics.

In older children, additional confounding factors include otitis media, mumps, measles, and head trauma. A history of visual impairment, syncope spells, kidney disease, or other system issues should be identified as potential indicators of a syndromic etiology. A detailed family history to identify affected parents, siblings, and relatives is imperative in the evaluation of the patient with hearing impairment.

Because genetic sensorineural hearing loss (SNHL) is associated with effects on virtually every organ, the physician must be familiar with the constellation of physical findings that may elucidate the etiology of a patient's hearing impairment.

Physical examination should include a complete evaluation of the ears, nose, throat, head, and neck, along with an overall assessment of the child's general physical and neurologic status.

Findings associated with hearing loss include microtia or atresia of the ear canal, cleft lip or palate, craniofacial abnormalities (eg, micrognathia, facial asymmetry, microcephaly, or craniosynostosis), cranial nerve weakness, heterochromia of the iris or other abnormalities of the ocular structures, vision impairment, goiter, and skeletal abnormalities.

Approximately 50% of all cases of congenital deafness are genetic. Approximately 70% of cases of hereditary deafness are nonsyndromic, and the remaining 30% are syndromic, associated with specific deformities or medical problems. Of nonsyndromic hearing losses, 75-85% are inherited in an autosomal recessive pattern, 15-20% are inherited in an autosomal dominant pattern, and 1-3% are inherited in an X-linked pattern. Genetic hearing loss is differentiated from acquired hearing loss with identification of a perinatal infection, such as toxoplasmosis, rubella, cytomegalovirus and herpes (TORCH), or another source such as trauma or noise. Although generally thought of as a childhood condition, genetic hearing loss can result in adult-onset hearing loss. A genetic basis or a genetic-environmental interaction appears to predispose some patients to noise or age-related hearing loss.

Syndromic hearing impairment

More than 400 genetic syndromes are associated with hearing impairment. These disorders are categorized as autosomal dominant, recessive, or X-linked.

Syndromic hearing impairment, autosomal dominant

• Waardenburg syndrome is the most common cause of autosomal dominant syndromic hearing loss. The syndrome includes dystopia canthorum, a broad nasal root, confluence of the medial eyebrows, heterochromia irides, a white forelock, and bilateral or unilateral SNHL. Expressivity is extremely variable.

  • Four subtypes of Waardenburg syndrome are defined, as follows:
    • Type I includes dystopia canthorum (ie, lateral displacement of the inner canthus of the eye) and is caused by mutations in PAX3.
    • Type II is characterized by the absence of dystopia canthorum and is caused by mutations in MITF.
    • Type III has associated upper-limb abnormalities and is caused by mutations in PAX3.
    • Type IV is thought to be caused by mutations in EDNRB, EDN3, and SOX10, and patients with type IV have Hirschsprung disease.
• Branchio-oto-renal syndrome is the second most common cause of autosomal dominant syndromic HL. This condition manifests as renal abnormalities, preauricular pits, deformed auricles, and lateral branchial cysts. The hearing loss may be conductive, SNHL, or mixed. Some patients have Mondini anomalies of the cochlea. Penetrance is high, but expressivity is extremely variable. Mutations in the EYA1, SIX1, and SIX5 genes have been identified.
• Neurofibromatosis type 2 (NF2) is associated with vestibular schwannomas, meningiomas, ependymomas, juvenile cataracts, and other intracranial and spinal tumors. The gene for NF2 has been mapped to chromosome 22q12.2 and is thought to be a tumor-suppressor gene. It has about 50% penetrance. In the Wishart type of NF2, the disease manifests in childhood or early adulthood. As vestibular schwannomas and other tumors develop, this subtype becomes rapidly progressive and often severely disabling. In the Gardner type of NF2, disease is more limited, less disabling, and presents later (in the third or fourth decades) that it is in the Wishart type.
• Sticker syndrome is defined by the association of cleft palate, progressive genetic sensorineural hearing loss (SNHL), and spondyloepiphyseal dysplasia (SED). Defects in COL result in 3 different types STL1 (COL2A1), STL2 (COL11A1), and STL3 (COL11A2). Related morbidity of SED includes atlantoaxial instability, scoliosis, osteoarthritis, myopia, and retinal detachment.
• Otosclerosis is a genetic disorder generally associated with adult-onset conductive hearing loss. However, advanced otosclerosis may cause SNHL. The genes responsible for otosclerosis have not been found, but foci on chromosomes 6, 7, and 15 have been implicated.
• Achondroplasia may be associated with mixed hearing loss.
• Paget disease may result in progressive, adult-onset conductive hearing loss, genetic sensorineural hearing loss (SNHL), or both. Other common findings of this bone disorder are enlargement of the skull, kyphosis, and shortening of stature. The hearing loss is thought to be due to a cochlear process. Genetic and environmental factors are likely to be contributing factors.

Syndromic hearing impairment, autosomal recessive

• Usher syndrome is the most common cause of autosomal recessive syndromic SNHL. Usher syndrome results in both hearing and visual impairments, and it is the etiology in at least 50% of persons with deafness and blindness. It may represent 3-6% of children born deaf and an additional 3-6% of children with milder hearing loss. The incidence is 4 in 100,000 births.

  • Three main types of Usher syndrome are described, as follows:
    • Type I is characterized by congenital severe-profound hearing loss and vestibular dysfunction. Retinitis pigmentosa (RP) develops in childhood and progresses from night blindness and loss of peripheral vision to blindness, through progressive degeneration of the retina. Vestibular dysfunction results in delayed motor milestones and may not walk until after 18 months.
    • Type II Usher syndrome is characterized by congenital mild-to-severe SNHL but normal vestibular function. Associate RP develops during the later teen years and tends to progress slower than in type I.
    • Children with Type III Ushers have normal hearing at birth that progresses during the teen years, requiring hearing aids by adulthood. Vestibular function is usually fairly normal, but may decline over time. RP begins at puberty and progresses into adulthood.
  • Early diagnosis is important in Usher syndrome and will impact management. Patients with Type I Usher syndrome who rely on manual communication may be more significantly impacted with development of visual impairment, at which time auditory rehabilitation will be less complete than if initiated earlier. Electroretinogram can be performed after the age of 2 years and may aid in identifying retinal problems earlier than fundoscopic examination and visual field tests. Genetic testing is now available and should be considered. Early identification and early cochlear implantation may mitigate the effect of dual sensory impairment if auditory-oral skills are developed prior to the onset of visual impairment.^[14]
  • Twelve loci have been found to cause Usher syndrome. Genes and the proteins that they encode have been identified for 7 of the 12 loci. The genes that cause Usher syndrome are MY07A, USH1C, CDH23, PCDH15, and SANS, which cause USH1, USH2A (which causes USH2), and USH3A (which causes USH3). A mutation, named R245X, of the PCDH15 gene may account for a large percentage of USH1 cases in today's Ashkenazi Jewish population.
• Pendred syndrome is the second most common type of AR syndromic hearing loss. It is characterized by congenital severe-to-profound sensorineural hearing impairment and euthyroid goiter. Goiter develops in early puberty or adulthood. Affected individuals have an abnormal perchlorate test indicating delayed organification of iodine by the thyroid. Mondini dysplasia and dilated vestibular aqueduct are commonly found during radiographic evaluation. Mutations in SLC26A4, which codes for pendrin, have been identified. Genetic testing is available and can be suggested if a Mondini malformation is found during evaluation.
• Jervell and Lange-Nielsen syndrome results in congenital genetic sensorineural hearing loss (SNHL) and a prolonged QT interval. Affected individuals have syncopal episodes and may have sudden death. High-risk children (ie, those with a family history that is positive for sudden death, SIDS, syncopal episodes, or long QT syndrome) should have a thorough cardiac evaluation. EKG is commonly included in screening protocols for congenital hearing loss.

  • Mutations in the KCNE1 and KCNQ1 genes cause Jervell and Lange-Nielsen syndrome. About 90% of cases of Jervell and Lange-Nielsen syndrome are caused by mutations in the KCNQ1 gene; KCNE1 mutations are responsible for the remaining 10% of cases.
  • These genes are responsible for coding potassium channel proteins critical for maintaining the normal functions of the inner ear and cardiac muscle. Mutations in these genes alter the usual structure and function of potassium channels or prevent the assembly of normal channels. These changes disrupt the flow of potassium ions in the inner ear and in cardiac muscle, leading to the hearing loss and irregular heart rhythm characteristic of Jervell and Lange-Nielsen syndrome.
• Refsum disease is a rare condition manifested by severe progressive genetic sensorineural hearing loss (SNHL) and retinitis pigmentosa due to abnormal phytanic acid metabolism. Because it can be treated with dietary modification and plasmapheresis, identification may be helpful

X-linked syndromic hearing loss

• Alport syndrome is a result of mutations in type IV collagen genes that result in faulty basement membranes of the kidney and cochlea. The incidence is thought to be 1 in 5000 persons and is more common in males. The HL is bilateral and slowly progressive often starting in late childhood in the high frequencies. Deafness is common by age 25 years. In males, proteinuria progresses to end-stage renal disease before age 40 years.

  • In females, end-stage renal disease is less frequent until later decades. Diagnostic criteria include family history of hematuria progressing to end-stage renal disease, progressive high frequency genetic sensorineural hearing loss (SNHL), thickening of the renal basement membrane by electron microscopy, and anterior lenticonus and perimacular flecks.
  • In 80% of patients with Alport syndrome, the inheritance is X-linked dominant. Patients with Alport syndrome have mutations in COL4A3, COL4A4, or COL4A5 near Xq22. Other forms are autosomal dominant or recessive and, in these cases, the severity is equal between the sexes.

Nonsyndromic genetic sensorineural hearing loss

An estimated 70-80% of hereditary hearing loss is nonsyndromic. Approximately 75% of nonsyndromic genetic sensorineural hearing loss (SNHL) is autosomal recessive, 15-20% is autosomal dominant, and 1-3% is X-linked. As highlighted by Van Laer et al, some genes may be associated with both autosomal dominant and recessive hearing loss. Some variability may be seen in the phenotype, based on the location and type of mutation of a gene and effects of modifying genes and environmental factors.^[15]

When a gene locus for hearing loss is identified, it is named for the inheritance pattern and a consecutive number. DFNA indicates autosomal dominant gene loci, DFNB indicates autosomal recessive loci, and DFN indicates X-linked loci.^[16] Mitochondrial disorders also exist. New gene loci are discovered every year.

Autosomal recessive nonsyndromic hearing loss is usually prelingual, nonprogressive, and severe to profound. Mutations in the connexin 26 gene at locus DFNB1 on chromosome 13 are thought to account for about 50% of recessive nonsyndromic hearing loss. 35delG is the most common mutation, but at least 90 different GJB2 mutations have been described.^[17]

The gene GJB2 codes for connexin 26, a gap junction beta2 protein. These proteins form intercellular channels in the plasma membrane and facilitate the exchange of molecules between cells. Connexin 26 is expressed in the stria vascularis, spiral ligament, spiral limbus, and in supporting cells of the cochlea. It appears to have a role in recycling of potassium. The hearing loss is usually prelingual and varies from mild to profound. It is usually predominantly high frequency and sloping but may also present with a flat audiometric curve. It is most often bilateral and symmetric, but unilateral cases have been identified. The ear is usually radiologically normal. Connexin 26-related hearing loss can be inherited by autosomal recessive or dominant patterns.

Autosomal dominant nonsyndromic hearing loss is more likely to be postlingual than autosomal recessive nonsyndromic hearing loss and is more variable in frequency distribution and severity. A common X-linked nonsyndromic mutation at gene locus DFN3 causes a mixed hearing loss. These patients are prone to perilymph gushers during stapedectomy that will result in profound postoperative SNHL. The related gene is POU3F4.

An interesting mitochondrial gene mutation is that for aminoglycoside-induced genetic sensorineural hearing loss (SNHL). The mutation A1555G in the 12s rRNA gene makes a person susceptible to hearing loss after treatment with gentamicin, neomycin, or other aminoglycosides.

Several websites are devoted to cataloging gene mutations, including The Hereditary Hearing Loss Homepage and those of the Harvard Medical School Center for Hereditary Deafness and GeneTests.