Hearing Page Page last modified:
January 9, 2008
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Timothy C. Hain, MD
Hearing Page Page last modified:
January 9, 2008
While acquired deafness associated with age or noise exposure is more common than genetic deafness by roughly 2 orders of magnitude, congenital deafness occurs in 1 per every 1000-2000 births with autosomal recessive inheritance being the most common form (more than 75%). Another way to look at it is that about 50% of hearing loss in children is environmental.
Non-inherited abnormalities of the inner ear such as the Mondini malformation, account for roughly 20% of congenital sensorineural deafness. The bulk of the remaining genetic deafness is non-syndromic, meaning that it does not have any obvious distinguishing features.
Most of these disorders have been documented with genetic mapping. For this to work there must be more than 10 affected members in a family. Marker analysis enables identification of the region of the genome where the disease gene lies.
Before we start talking about individual syndromes, inherited deafness is usually symmetrical and bilateral, nearly always sensorineural, and usually more severe at high frequencies. However, a particular pattern of hearing loss called the "cookie bite", generally suggests a genetic pattern -- in other words, it is a fairly specific sign of a genetic deafness pattern. About 2/3 of persons with cookie bite patterns had hereditary hearing loss in a study of one academic practice (Shah and Blevins, 2005). It seems likely that outside of academic settings, cookie-bite hearing patterns are even more likely to be associated with inherited hearing loss.
Non-syndromic (80% of genetic deafness):
About 80% of genetic hearing loss is non-syndromic. Between 1992 and 2001, 38 loci for autosomal dominant nonsyndromic deafness have been mapped and 11 genes have been cloned. Autosomal dominant locii are called DFNA, autosomal recessive as DFNB, and X-linked as DFN. An update on current locii can be found on the hereditary hearing loss homepage, which is hosted by the University of Iowa. Non-syndromic deafness is highly heterogeneous but mutations in the connexin-26 molecule (gap junction protein, gene GJB2) account for about 49% of patients with non-syndromic deafness and about 37% of sporadic cases. Assays for connexin-26 are commercially available at several laboratories. About 1 in 31 individuals of European extraction are likely carriers. However, population analysis suggests that there are over 100 genes involved in non-syndromic hearing impairment (Morton, 1991). One mutation is particularly common, namely the 30delG.
There is a nomenclature for the nonsyndromic deafness:
Autosomal dominant deafness is passed directly through generations. It is often possible to identify an autosomal dominant pattern through simple inspection of the family tree. Examples of autosomal dominant deafness are missense mutation in COL11A2 (DFNA13) (Leenheer et al, 2001). COL11A2 encodes a chain of type XI collagen. As an example of a deafness phenotype, in DFNA10 results in a postlingual, initially progressive, and resulting, without the influence of presbycusis, in largely stable, flat sensorineural deafness (De Leenheer et al, 2001). DFNA9/COCH may initially resemble Meniere's disease, but it progresses and culminates in severe deafness and vestibular loss.(Lemaire et al. 2003)
The DFNA6/14-WFS1 mutation presents as a progressive low-frequency sensorineural hearing impairment (LFSNHL) caused by a heterozygous WFS1 mutation. (Pennings et al, 2003) . Mutations in the WFS1 gene are the most common form of dominant low frequency sensorineural hearing loss. The differential diagnosis of low frequency SNHL include sudden hearing loss, FDNA1, DFNA6/14, LFSNHL associated with Meniere's disease, and sporadic LFNSHL.
Autosomal recessive disorders require a gene from both the mother and father.
DFNB1 (connexin 26) is the most common form of genetic hearing loss. It presents as prelingual deafness, sometimes with mild-to-moderate hearing loss. There are no vestibular or radiographic abnormalities. It is caused by a mutation in the gap junction protein. There is a 3% carrier rate in the US.
Related mutations to DFNA6/14-WFS1 cause a recessive syndrome known as the Wolfram syndrome with diabetes insipidus, diabetes mellitus, optic atrophy and deafness (Lesperance et al, 2003).
These are an immensely complicated interlinked set of disorders. The descriptions here are only to give the general flavor of the diseases and are not meant to include all features of the disorders. In most cases an OMIM database link to the main type of the genetic disorder is provided.
Alport syndrome is caused by mutations in COL4A3, COL4A4 or COL4A5. The classic phenotype is renal failure and progressive sensorineural deafness.
Barakat syndrome, also known as HDR syndrome, is an inherited condition characterized by hypoparathyroidism, sensorineural deafness and renal disease (Barakat et al in 1977). Patients usually present with hypocalcaemia, tetany, or afebrile convulsions at any age. Hearing loss is usually bilateral and may range from mild to profound impairment. Renal disease includes nephrotic syndrome, renal dysplasia, hypoplasia or aplasia, chronic renal failure, hematuria, proteinuria and others. The frequency is unknown, but the disease is considered to be very rare.
The defect is on chromosome 10p (Gene Map Locus: 10p15, 10p15.1-p14), with haploinsufficiency or mutation of the GATA3 gene being the underlying cause. Inheritance is probably autosomal dominant. Management consists of treating the clinical abnormalities at the time of presentation. Prognosis depends on the severity of the renal disease.
Branchio-Oto-Renal Syndrome, and also see HERE
Branchio-oto-renal syndrome is caused by mutations in EYA1, a gene of 16 exons within a genomic interval of 156 kB. This syndrome is characterized by hearing disturbances and cataract, branchial cleft fistulae, and preauricular pits. Mondini malformations and related dysplasias may occur.
The dominantly iherited form of X-linked CMT is caused by a mutation in the connexin 32 gene mapped to the Xq13 locus. Usual clinical signs consist of a peripheral neuropathy combined with foot problems and "champagne bottle" calves. Sensorineural deafness occurs in some. (Stojkovic and others, 1999).
As noted above, the connexin gene is also associated with a large percentage of cases of non-syndromic deafness. There are several other associated neuropathies and deafness syndromes. Autosomal recessive demyelinating neuropathy, autosomal dominant hereditary neuropathies type I and II, and X-linked hereditary axonal neuropathies with mental retardation are all associated with deafness (Stojkovic and others, 1999).
Oculoauriculovertebral dysplasia (OAVD) or Goldenhar's syndrome was originally described in 1881. It includes a complex of features including hemifacial microtia, otomandibar dysostosis, epibulbar lipodermoids, coloboma, and vertebral anomalies that stem from developmental vascular and genetic field aberrations. It has diverse etiologies and is not attributed to a single genetic locus. The incidence is roughly 1 in 45,000. (Scholtz et al, 2001).
This hearing syndrome is associated with cardiac arrhythmias There is by prolongation of the QT interval, torsade de pointe arrhythmias (turning of the points, in reference to the apparent alternating positive and negative QRS complexes), sudden syncopal episodes, and severe-to-profound sensorineural hearing loss.
In the "Large Vestibular Aqueduct syndrome" there is enlargement of the endolymphatic duct (ED on figure above) that connects the endolymphatic compartment (blue above) to the endolymphatic sac (which lies just under the dura of the posterior fossa, ES above). Persons with LVAS may develop hearing loss as well as be unusually vulnerable to inner ear disease associated with head injury. Not all patients with LVAS have it as a hereditory condition (see later section on non-hereditory LVAS).
Many persons with LVAS also have Pendred syndrome (see below) (Berrettini et al, 2005). Presumably this vulnerability occurs because there is increased compliance (easier access) of pressure waves in the brain to the inner ear. Oddly though, this condition is basically the opposite of the situation in Meniere's disease, where it is classically hypothesized that the vestibular aqueduct (endolymphatic portion) is abnormally narrowed, but manifesting with similar hearing symptoms. It would seem likely that one of these mechanisms must be wrong. LVAS is also associated with renal tubular acidosis. (again, likely a genetic association).
Persons with LVAS may have a large air-bone gap (suggestive of conductive hearing loss) (Merchant et al, 2007). This is proposed to be due to an enhancement of the bone component, following logic similar to that applied in superior canal dehiscence syndrome.
Mohr-Tranebjaerg syndrome (DFN-1) is an X-linked recessive syndromic hearing loss characterized by postlingual sensorineural deafness in childhood followed by progressive dystonia, spasticity, dysphagia and optic atrophy. The syndrome is caused by a mutation thought to result in mitochondrial dysfunction. It resembles a spinocerebellar degeneration called Fredreich's ataxia which also may exhibit sensorineural hearing loss, ataxia and optic atrophy. The cardiomyopathy characteristic of Freidreichs is not seen in Mohr-Tranebjaerg.
Classic features include specific ocular symptoms (pseudotumor of the retina, retinal hyperplasia, hypoplasia and necrosis of the inner layer of the retina, cataracts, phthisis bulbi), progressive sensorineural hearing loss, and mental disturbance, although less than one-half of patients are hearing impaired or mentally retarded.
Pendred syndrome is one of the most common syndromic forms of deafness. In essence it is deafness associated with thyroid disease (euthyroid goiter). Vestibular testing, especially rotatory testing if available, should be obtained in cases with known mutations. This is due to a mutation in the sulfate ion transporter, 7q31. It is autosomal recessive. Pendred is associated with large vestibular aqueduct syndrome (see above) as well as Mondini (see below). Note that many persons with thyroid problems have Meniere's disease (Brenner et al, 2004), and thus LVAS, Meniere's and Pendred syndrome may all be interconnected.
About 60% of mutations in the SLC26A4 gene known to cause Pendred syndrome can be detected with genetic testing. This is an option in persons who have appropriate symptoms or radiology.
Mutations in COL11 are the cause in Stickler syndrome. This syndrome is characterized by hearing impairment, midface hypoplasia, progressive myopia in the first year of life and arthropathy.
Treacher Collins syndrome is characterized by coloboma of the lower eyelid (the upper eyelid is involved in Goldenhar syndrome), micrognathia, microtia, hypoplasia of the zygomatic arches, macrostomia, and inferior displacement of the lateral canthi with respect to the medial canthi.
Turner syndrome occurs in about 1/2000 female births. Most persons with Turner syndrome have but a single copy of the X chromosome and no Y. Roughly two thirds of the Turner's population has hearing loss, about evenly split between sensorineural and conductive types (Ingeborg et al, 2005).
The clinical symptoms of Waardenburg Syndrome (WS) include lateral displacement of the inner canthus of each eye, pigmentary abnormalities of hair, iris, and skin (often white forelock and heterochromia iridis), and sensorineural deafness. The combination of WS type I characteristics with upper limb abnormalities has been called Klein-Waardenburg syndrome or WS type III. The combination of recessively inherited WS type II characteristics with Hirschsprung disease has been called Waardenburg-Shah syndrome or WS type IV.
Usher syndrome is characterised by hearing impairment and retinitis pigmentosa. Usher syndrome can be classified into 3 different types on the basis of clinical findings. In type one, there is both hearing impairment and vestibular impairment. In type II, there is hearing impairment without vestibular impairment. In type three, there is variable amounts of vestibular impairment. Ushers patients may benefit from a cochlear implant. The electroretinogram is generally required to obtain a clear diagnosis (Loundon et al, 2003). Vestibular testing should be obtained if possible in Usher's.
This topic was recently reviewed (Edmonds et al, 2002). Mitochondrial disorders usually first manifest in tissues with high metabolic demands such as nerve and muscle. Similarly the complete auditory pathway is at risk from mitochondrial disorders. Hearing loss is common in mitochondrial disorders including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes), Kearns-Sayre syndrome (KSS) and MERRF (myoclonic epilepsy with ragged red fibers). Others include complex I deficiency, cytochrome-c oxidase (complex IV) deficiency or COX, pyruvate dehydrogenase deficiency (PDH). These disorders are caused by mutations in mitochondrial DNA, and are characterized by muscular weakness, an abnormal muscle biopsy with "ragged red" fibers, and a lactic acidosis. Edmonds et al found that 80% of persons with severe mitochondrial disease had hearing deficits. They suggested that these patients are more vulnerable than others to bacterial infection and should be managed more aggressively than the general population. This conclusion must be looked at with caution as some antibiotics may have their site of action on mitochondria, which resemble bacteria in many ways.
In MELAS, Sue et al recently reported that the hearing loss is caused by cochlear damage. It resembles presbyacusis in that it is generally symmetrical, gradual, and affects the higher frequencies first (Sue et al, 1998). Edmonds et al (2002) suggested that lesions might also occur elsewhere in the auditory pathway.
Others have also reported hearing loss associated with mitochondrial mutations (Yamasoba et al, 1999; Tsutsumi et al, 2001). Mitochondrial DNA mutations accumulate naturally during life and are presently implicated as an important cause of normal aging.
Patients with Kearns-Sayre syndrome were found to have a significantly prolonged I-V ABR latency in one study (Nakamura et al, 1995)
Mitochondrial defects including a deletion in A1555G have been reported to both cause unusual sensitivity to aminoglycosides as well as nonsyndromic sensorineural deafness (El-Schahawi et al, 1997 -- this paper reviews "mitochondrial deafness). These patients have a mild high-frequency sensorineural hearing loss without aminoglycoside exposure. Some indicate that as much as 15% of persons with aminoglycoside ototoxicity have this mutation. However, we are dubious that this is the case.
Mohr-Tranebjaerg syndrome (DFN-1) is also thought to cause deafness via a mitochondrial disturbance.
An update on current locii can be found on the hereditary hearing loss homepage, which is hosted by the University of Iowa. Labs that do testing for mitochondrial as well as other genetic disorders are listed here.
These types of abnormalities account for roughly 20% of congenital deafness, the remainder being genetic in origin. In general, these disorders can be associated with genetic disorders, but more often occur independently.
Congenital hearing loss is often attributed to prenatal infections with neurotrophic viruses such as measles or cytomegalovirus (CMV). A recent study suggested that "more than 40% of deafness of unknown cause, needing rehabilitation" is attributed to CMV. (Barbi et al, 2003). CMV is the most common intrauterine infection in the United States. Infants can be exposed through breast milk. Other bodily fluids can also transmit CMV (e.g. urine, saliva). In developed countries, older individuals become exposed through secondary mechanisms.
Delayed onset of hearing loss is common -- infants with CMV and normal hearing at birth should be monitored for 6 years. Newborn infants with CMV can be treated with ganciclovir. This treatment must be monitored very carefully as 2/3 of infants develop neutropenia.
Temporal Bone CT scans are done routinely in persons with childhood sensorineural hearing loss. About 25% of patients with congenital hearing loss will have bony inner ear malformations (Mafong et al, 2002)
The normal cochlea has two and one-half turns. A cochlear malformation consists of a membranous abnormality, a bony abnormality, or a combination of these two. If cochlear development is arrested in the embryo, a common cavity may occur instead of the snail like cochlea. A complete labyrinthine and cochlelar aplasia is called the Michel deformity. An incomplete partition is called the Mondini dysplasia or malformation. This furthermore consists of a cystic apex, a dilated vestibule and a large vestibular aqueduct (see below). An example of a high-resolution CT scan of a Mondini malformation is shown on the right (Strome et al, 1998). The black arrow shows a sac-like cochlea. The white arrow shows an amorphous vestibule without any defined semicircular canals. There are various other variant malformations including cochlear aplasia and hypoplasia, as well as others (Sennaroglu and Saatci, 2002)
Often accompanying the Mondini dysplasia is abnormal communication between the endolymphatic and perilymphatic spaces of the inner ear and subarachnoid space. It is usually caused by a defect in the cribiform area of the lateral end of the internal auditory canal. Presumably because of this abnormal channel, perilymphatic fistulae are more common in this disorder.
CT scans are not able to define abnormalities of the membranous labyrinth, but high-resolution MRI has been used to visualize these structures. Practically however, at this writing (2003), conventional 1.5 tesla MRI scanners do not provide enough detail to be of much clinical value.
Children with these malformations may also exhibit motor delay due to damage to the labyrinthine part of the inner ear (Bodensteiner et al, 2003).
A related anomaly and more severe syndrome, the CHARGE association consists of coloboma, heart disease, choanal atresia, retarded development, genital hypoplasia, ear anomalies including hypoplasia of the external ear and hearing loss. These individuals have a Mondini type deformity and absence of semicircular canals. A recent report documents that they have normal otolithic responses to off-vertical axis rotation (Wiener-Vacher et al, 1999).
First described by Valvassori, enlargement is defined on the CT scan as a diameter greater to or equal to 1.5 mm measured midway between the operculum and the common crus. According to Murray et al (2000), coronal CT scan is the best view for evaluating it in children. Enlarged vestibular aqueducts can also be seen on high-resolution MRI. It may cause a fluctuating sensorineural hearing loss. Conservative management, including avoidance of head trauma and contact sports, has been the mainstay of treatment. Surgery to close the enlarged structure frequently results in significant hearing loss (Welling et al, 1999). When genetic it is caused by the same gene associated with Pendred's syndrome.
See also: raisingdeafkids.org
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