Syndromic Sensorineural Hearing Loss Clinical Presentation

Upon identification of hearing loss, a complete history should include gestational, perinatal, postnatal, and family histories. Medical problems or morphologic abnormalities of the ear, face, or other organ systems may, in association with hearing impairment, indicate a recognizable syndrome.

Because abnormalities of virtually every organ system have been associated with sensorineural hearing loss (SNHL), physicians must become familiar with the constellation of physical findings that may help determine the etiology of a patient's hearing impairment. The physical examination should incorporate an in-depth ears, nose, throat, head, and neck evaluation, along with an overall assessment of general physical and neurologic status.

Abnormalities of many systems have been associated with syndromic hearing loss, including the following:

• Craniofacial malformations

• Dental abnormalities

• Ocular abnormalities

• Renal defects

• Cardiac abnormalities

• Endocrine dysfunction

• Neurologic dysfunction

• Skeletal abnormalities

• Integumentary abnormalities

• Metabolic disease

• Chromosomal abnormalities

Clinical findings suggestive of syndromes associated with hearing loss include the following:

• Ear examination findings

  • Auricular deformity - Treacher-Collins syndrome, Goldenhar syndrome

  • External canal atresia or stenosis - Treacher-Collins syndrome, Goldenhar syndrome

  • Preauricular pits - Branchiootorenal syndrome

  • Preauricular skin tags - Goldenhar syndrome

  • Enlarged vestibular aqueduct - Pendred macrotia, Kabuki syndrome, Turner syndrome, Opitz-Frias syndrome

  • Lop ears - Trisomy 21, otopalatodigital syndrome

  • Cup ear - Pierre Robin sequence

  • Microtia - Treacher-Collins syndrome, Goldenhar syndrome, first branchial cleft syndrome, Möbius syndrome, Duane syndrome

• Eye examination findings

  • Cataracts - Congenital rubella

  • Coloboma - Coloboma of iris, heart deformities, choanal atresia, retarded growth, genital and ear deformities (CHARGE) association

  • Dystopia canthorum - Waardenburg syndrome (WS)

  • Heterochromia irides - WS

  • Keratitis - Cogan syndrome

  • Ocular palsy - Duane syndrome

  • Retinal atrophy - Cockayne syndrome

  • Retinitis pigmentosum - Usher syndrome

  • Retinal degeneration - Alström syndrome

  • Congenital blindness, pseudotumor retinae - Norrie syndrome

• Integumentary examination findings

  • Depigmentation - albinism, piebaldness, WS, Tietze syndrome

  • Ectodermal dysplasia - Ichthyosis

  • Hypopigmentation - Albinism

  • Lentigines - Lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (LEOPARD) syndrome

  • White forelock - WS syndrome

• Cardiac findings

  • Widened electrocardiographic wave (QRS) or bundle branch block (BBB), pulmonary stenosis - LEOPARD syndrome

  • Prolonged QT - Jervell and Lange-Nielsen syndrome

  • Mitral Insufficiency - Forney syndrome

• Renal findings

  • Dysfunction - Alport syndrome, Hermann syndrome, Fanconi anemia, branchiootorenal syndrome

  • Malformation - Goldenhar syndrome

• Dental findings

  • Abnormal dentin - Osteogenesis imperfecta

  • Pegged (Hutchinson) incisors - Congenital syphilis

• Endocrine/metabolic findings

  • Goiter - Pendred syndrome

  • Hypogonadism - Alström syndrome

  • Obesity - Laurence-Moon-Biedl syndrome

  • Mucopolysaccharidosis - Hunter, Hurler, Sanfilippo, and Morquio syndromes

  • Diabetes mellitus - Alström, Hermann syndromes

  • Ovarian dysgenesis - Perrault syndrome

  • Thymus agenesis - DiGeorge syndrome

• Chromosomal abnormalities

  • Trisomy 13 - Patau syndrome

  • Trisomy 18 - Edwards syndrome

  • Trisomy 21 - Down syndrome

  • Trisomy 22

• Neurologic abnormalities

  • Ataxia - Spinocerebellar degeneration

  • Epilepsy - Herman syndrome

  • Peripheral neuropathy - Flynn-Aird syndrome

  • Polyneuropathy - Refsum disease

• Skeletal examination findings

  • Dwarfism - Achondroplasia, Cockayne syndrome

  • Fusion of cervical vertebrae - Klippel-Feil syndrome

  • Limb deformities - Osteogenesis imperfecta, Hurler syndrome

  • Scoliosis, elongated limbs - Marfan syndrome

  • Syndactyly - Apert syndrome

• Craniofacial abnormalities ^[8]

  • Acrocephaly (tower skull) - Apert syndrome

  • Branchial fistulas - Branchiootorenal syndrome

  • Cleft palate, small mandible - Pierre Robin sequence

  • Cranial synostosis - Crouzon syndrome

  • Malar/facial bone anomalies - Treacher-Collins syndrome

  • Midface hypoplasia - Crouzon syndrome

  • Ocular/auricular anomalies - Goldenhar syndrome

Autosomal dominant syndromic hearing loss

These are less frequent causes of hearing loss than autosomal recessive disorders. Examples include Waardenburg, neurofibromatosis, Tietze, Hermann, Leopard, Kearns-Sayre, Crouzon, Forney, achondroplasia, Duane, Marfan, and branchiootorenal syndromes.

• Waardenburg syndrome ^[9]

  • Waardenburg syndrome (WS) is the most common cause of autosomal dominant syndromic hearing loss. It occurs in approximately 2 per 100,000 births and is estimated to account for 2% of all cases of congenital hearing loss in the United States. A literature review by Song et al found hearing loss in 71% of patients with WS, with such loss being primarily bilateral and sensorineural. ^[10]

  • WS is characterized by autosomal dominant inheritance with variable penetrance. WS has undergone intense gene mapping and has been localized at gene locus 2q35 or 2q37.3. Mutations in PAX3 cause WS type I and WS type III. Some cases of WS type II are caused by mutations in MITF. WS type IV has been linked to mutations in EDNRB, EDN3, and SOX10.

  • Temporal bone pathology includes atrophy of the organ of Corti and stria vascularis, with reduction in the number of spiral ganglion nerve cells. Hearing loss can be unilateral or bilateral, with severity that ranges from total loss to moderate loss with preservation of high frequencies.

  • Type I WS includes the following primary features:

    • Lateral displacement of the medial canthi and lacrimal puncta (100%)

    • Hyperplastic high nasal root (75%)

    • Hyperplasia of the medial portion of the eyebrows (50%)

    • Partial or total heterochromia irides (25%)

    • Circumscribed albinism of the frontal head hair or white forelock (20%)

    • Sensorineural deafness, unilateral or bilateral (25%)

  • Type II WS is differentiated by the absence of dystopia canthorum and a higher incidence of SNHL, up to 55%. Estimates indicate type II as 20 times more frequent than type I.

  • Type III WS includes upper-limb malformations.

  • Type IV WS includes Hirschsprung disease

• Branchiootorenal syndrome is the second most common type of autosomal dominant syndromic hearing loss. Branchial fistulas, renal anomalies, and anomalous development of the external, middle, and inner ear typify this disorder. Inheritance is via autosomal dominant transmission. Hearing loss may be conductive, sensorineural, or mixed and is characterized by preauricular pits and auricular malformations of the outer ear and by structural defects of the middle ear and inner ear. Mutations in the EYA1, SIX1 and SIX5 genes have been identified.

• Neurofibromatosis 2 is caused by a mutation in the NF2 gene on chromosome 22 and is characterized by the development of multiple tumors, including vestibular schwannomas, meningiomas, gliomas, and ependymomas. In some cases, tumors may manifest as early as 8-12 years of age. Fortunately, the hearing loss associated with vestibular schwannomas is potentially treatable with early surgical intervention.

Autosomal recessive disorders

See the list below:

• Usher syndrome ^[9]

  • The reported incidence for Usher syndrome is approximately 3 per 100,000 live births. (A study by Yoshimura et al estimated that the prevalence of Usher syndrome in Japan is at least 0.4 per 100,000 population. ^[11] ) The disorder is responsible for up to 10% of cases of congenital deafness, and it is inherited in an autosomal recessive fashion. It is the most common type of autosomal recessive syndromic hearing loss. Usher syndrome features progressive blindness due to retinitis pigmentosa, along with moderate-to-severe SNHL, and accounts for about 50% of the deaf blind in the United States.

  • Vision impairment is not easily identified in the first decade of life. Funduscopic examination before age 10 years is limited. Electroretinography can reveal early retinal abnormalities in young children but is not routinely available. Night blindness and visual field deficits may mark developing retinitis pigmentosa. Loss of vision is progressive, and 50% of individuals develop complete blindness before age 50 years.

  • Hearing loss is generally present at birth, and 85% of affected individuals eventually become totally deaf. Histopathologic findings include degeneration of sensory epithelium within the cochlea. Absence of cochlear microphonic potentials indicates hair cell dysfunction as a cause for noted hearing impairment. Vestibulocerebellar ataxia is present in a high percentage of individuals with severe deafness.

  • The following 3 types of Usher syndrome are found:

    • Type I is characterized by bilateral congenital severe to profound hearing loss and poor vestibular function.

    • Type II is characterized by mild-to-moderate hearing loss at birth and normal vestibular function.

    • Type III Usher syndrome is characterized by progressive hearing loss and vestibular dysfunction.

  • The genetic basis of Usher’s syndrome is complex with mutations at 10 loci and 8 genes identified including MYO7A, USH2A, CDH23, PCDH15 and others. ^[12]

• Pendred syndrome is transmitted in an autosomal-recessive fashion and encompasses a clinical triad of congenital hearing loss, multinodular goiter, and pathologically decreased perchlorate test result. ^[9]

  • Goiter is not present at birth but rather develops in early puberty or adulthood and is due to abnormal organification of iodine. Pendred syndrome accounts for up to 5-10% of recessive hereditary hearing loss cases. Hearing loss is typically bilateral and most prominent in higher frequencies, often with positive recruitment suggestive of a cochlear site of lesion. A Mondini cochlear malformation and enlarged vestibular aqueduct are often identified.

  • Mutations in SLC26A4 are commonly identified. The SLC26A4 gene codes of pendrin, a protein that transports chorine, iodide and bicarbonate in and out of cells. The protein is important for the function of the inner ear and thyroid. ^[13] Genetic testing is available for mutations in this gene and is indicated in patients with Mondini malformation or enlarged vestibular aqueduct.

• Jervell and Lange-Nielsen syndrome is thought to be the third most common cause of autosomal syndromic hearing loss and accounts for 1% of all cases of recessive hearing loss. This disorder is characterized by electrocardiographic changes of a prolonged QT interval, Stokes-Adams attacks, congenital bilateral severe hearing loss, and sudden death. Syncopal attacks begin in early childhood, with sudden death often occurring in later years. Postmortem examinations have revealed abnormal cardiac defects, including degeneration of fibers of the sinoatrial node, fibrosis, hemorrhage, and infarction.

  • Temporal bone findings include atrophy of the organ of Corti and spiral ganglion, along with large periodic acid-Schiff (PAS)–positive hyaline deposits throughout the membranous labyrinth. Atrophy of sensory cells within the utricle and saccule is also evident.

  • A screening ECG may show prolonged QT interval, but the sensitivity is not high. Children with a family history of sudden death, sudden infant death syndrome (SIDS), syncopal episodes, or prolonged QT interval should be closely examined.

  • The genetic basis of Jervell and Lange-Nielsen syndrome is thought to be mutations in the KCNQ1, and less commonly, the KCNE1 gene, that are responsible for coding proteins that form potassium transport channels. These channels are critical in the function of the inner ear and heart muscle. The KCNE1 and KCNQ1 genes provide instructions for making proteins that work together to form a channel across cell membranes. These channels transport positively charged potassium atoms (ions) out of cells. The movement of potassium ions through these channels is critical for maintaining the normal functions of inner ear structures and cardiac muscle. ^[14]

• Cockayne described a syndrome of dwarfism with retinal atrophy and deafness. Classic onset occurs during the second year of life. Inheritance is in an autosomal-recessive pattern. Characteristics include dwarfism with kyphosis and ankylosis, prognathism, sunken eyes, mental retardation, retinal atrophy, thickened skull, carious teeth, and hearing loss. Hearing loss is bilateral, sensorineural, and progressive. Evidence points to degenerative changes of the spiral ganglion, cochlear nucleus, and olivary nucleus. According to the Genetics Home Reference, mutations in ERCC6 and CRCC8 cause Cockayne syndrome. These genes code for proteins that are involved in repairing damaged DNA. If damaged DNA accumulates, cell function is compromised and cell death occurs, likely contributing to growth failure and premature aging. ^[15]

• Alström syndrome is characterized by features such as retinitis pigmentosa, diabetes mellitus, cardiomyopathy, short stature, obesity, and progressive hearing loss. The disease can lead to liver failure, kidney failure and pulmonary problems, although the presentation is variable. Hearing loss, generally of the sensorineural variety, typically occurs by age 10 years. Inheritance is by autosomal recessive transmission. Mutations in ALMS1 are linked to Alström, but the function of the protein it codes is unknown. ^[16]  In a study of the histopathology of the inner ear in patients with Alström syndrome, Nadol et al reported an association between sensorineural hearing loss and degeneration of the organ of Corti’s inner and outer hair cells and of the spiral ganglion cells, as well as atrophy of the stria vascularis and spiral ligament; the report was based on two genetically confirmed cases. ^[17]

• Refsum disease is a recessive-inherited disorder characterized by retinitis pigmentosa, ichthyosis, polyneuritis, cerebellar ataxia, and hearing loss. Affected individuals often survive through the second decade of life. Visual loss typically occurs in patients older than 20 years. Progressive SNHL occurs in more than 50% of patients. Degeneration of the organ of Corti and stria vascularis have been reported in histopathologic studies.

• Disorders with X-linked, variable, or unknown inheritance have been identified.

Disorders with X-linked, variable, or unknown inheritance

See the list below:

• Alport syndrome represents the most common form of hereditary nephritis, with an incidence of 1 case per 200,000 individuals. Hematuria, posterior cataracts, corneal dystrophy, and dislocation of the lens characterize the condition. Although the disease is more common in females, boys are affected more severely than girls, commonly progressing to end-stage renal failure during their second or third decade of life. Untreated males die by age 30 years. Symptoms typically appear during the first decade of life.

  • Hearing loss is usually bilateral and symmetric, but progressive SNHL, with higher frequencies most prominently affected, has also been noted. Autosomal dominant, autosomal recessive and X-linked forms have been identified. X-linked inheritance is thought to cause about 85% of cases. Mutations in the COL4A3, COL4A4, and COL4A5 genes have been linked to Alport syndrome.

  • These genes code for Type IV collagen, a protein important in the structure and function of the basement membrane of the glomerular membrane and basilar membrane of the stria vascularis. In the glomerulus, the basement membrane eventually fails and leads to end-stage renal disease. The pathophysiologic mechanisms of hearing loss are unknown but Merchant et al identified separation of the basilar membrane and the basement membrane and cellular dysmorphology within the organ of corti. ^[18]

• Norrie Disease is a rare disorder caused by a mutation in the NDP gene located on the X chromosome that codes for a large protein, designated norrin, the seems to play a role in signaling developmental activities, including cell division, adhesion, and migration. As a result, problems may include vision impairment, motor developmental delay, retardation, and hearing loss. ^[19]

• Lysosomal storage diseases: Inborn errors of metabolism, including mucopolysaccharidoses (Hurler syndrome, Hunter syndrome) and sphingolipidoses (Fabry disease), often manifest with SNHL as part of the clinical presentation.

  • Hurler syndrome, inherited as an autosomal recessive trait, is a lysosomal storage disease caused by an enzymatic deficiency that results in accumulation of the mucopolysaccharides heparin sulfate and dermatan sulfate. Hurler syndrome is characterized by mental retardation, dwarfism, kyphosis, hepatosplenomegaly, and hearing loss. Hearing loss is generally mixed with prominence of sensory loss in the higher frequencies. Temporal bone studies have demonstrated PAS-positive material within the substance of the mesenchyme with degeneration of the organ of Corti. Generally, survival is rare past the 14th year of life. Hunter syndrome, inherited as an X-linked trait, is similar to Hurler syndrome in its clinical presentation.

  • Hunter syndrome is a milder form, with those enduring the condition commonly surviving into the early third decade of life. Hearing loss may be conductive, sensorineural, or mixed.

  • Fabry disease is also inherited in an X-linked fashion, leading to accumulation of sphingolipid within endothelial, smooth muscle, and ganglion cells. Hearing loss is typically bilateral with a predominant sensorineural high-frequency loss. Histopathologic studies of affected temporal bones include atrophy of the spiral ligament and accumulation of sphingolipid in vascular endothelial and ganglion cells of the auditory system.

• Trisomy 13 occurs in 1 per 6000 births. Congenital malformations are so severe that most affected infants do not survive beyond their first year of life. Clinical features include microcephaly, cleft lip and palate, polydactyly, rocker-bottom feet, low-set malformed pinna, cardiac dextroposition, scalp defects, and mental retardation. Temporal bone analysis reveals cystic changes within the stria vascularis, shortened length of the cochlea, saccular degeneration, and anomalies of the semicircular canals.

• Trisomy 18 reportedly occurs in 1 per 10,000 live births, although some reports place the incidence as high as 1 per 5,000 live births. Most affected infants do not survive past their third month of life, although up to 13% live past age 1 year. Clinical features include malformed pinna, micrognathia, prominent occiput, intestinal defects, and mental retardation. Temporal bone histopathology demonstrates incomplete development of the stria vascularis, semicircular canal anomalies, and decreased spiral ganglion cells.

• Trisomy 21, or Down syndrome, is the most common chromosomal disorder in the world. Incidence of Down syndrome is 1 per 1000 births overall, with an increasing incidence based on maternal age (1 per 25 births in women > 45 y). Clinical features include a broad short trunk, epicanthal folds, muscular hypotonia, congenital heart disease, and mental retardation. Hearing loss occurs in up to 78% of cases, with conductive, sensorineural, and mixed losses evident. Histopathologic temporal bone findings include residual mesenchyme in the middle ear, endolymphatic hydrops, and a wide angle of the facial nerve genu.

• Klippel-Feil syndrome was described in 1912. This syndrome is characterized by congenital fusion of 2 or more cervical vertebrae, high scapula, spina bifida, facial asymmetry, spasticity, and congenital heart defects. When associated with bilateral abducens palsy and hearing loss, it is referred to as Wildervanck syndrome. Hearing loss is of the profound sensorineural type, but conductive and mixed losses have also been reported. Hypoplasia of the inner ear, with both bony and membranous labyrinth underdevelopment, has been reported. Inheritance pattern is heterogeneous.

• Wildervanck syndrome (cervico-oculo-acoustic dysplasia) includes fusion of cervical vertebrae, short neck, low hairline posteriorly (Klippel-Feil) plus enophthalmos, mixed hearing loss, and lateral gaze weakness. A female predominance for Wildervanck syndrome is found. Inheritance is X-linked dominant.

• Albinism is due to defects in the biosynthesis and distribution of melanin. Oculocutaneous albinism is an autosomal recessive disorder; patients demonstrate lack of pigmentation in the skin, eyes, and hair. Most cases associated with SNHL are of the oculocutaneous form with hearing loss that varies in degree of severity.

• Otopalatodigital syndrome is thought to be X-linked recessive and includes cleft palate, fishmouth, clinodactyly, prominent forehead, hypertelorism, and antimongoloid palpebral fissures. Hearing loss is conductive because of ossicular malformations.

• X-linked disorders associated with syndromic hearing loss include Kearns-Sayre syndrome, myoclonic epilepsy and ragged red fibers, mitochondrial encephalopathy, lactic acidosis, and strokelike episodes, and maternally inherited diabetes and deafness.