Timothy C. Hain, MD Hearing Page Page last modified: August 29, 2012
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%). Approximately 50% of this hearing loss is genetic, 25% acquired, and 25% of unknown cause.
Abnormalities of the inner ear such as the Mondini malformation, with variable inheritance patterns, 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.
Of children with sensorineural hearing loss of any type, between 11-41% of them have inner abnormalities seen on CT. In children who are deemed likely to have an inner ear abnormality and who are sent for MRI scan, about 40% have abnormalities (McClay et al, 2008). Of course, this does not mean that 40% of all deaf children will have MRI abnormalties, but rather 40% of those who are thought by their doctors to have an MRI abnormality, and who are sent for an MRI, have MRI abnormalities. In other words, it means that the abnormal rate for clinicians at the location where this study was done (Dallas), is about 40%.
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 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.
Klippel-Feil (KFS) is a congenital anomaly of the cervical (neck) vertebrae. It manifests as a short neck, low hair line and limited neck mobility. It is associated with congenital anomalies of all three parts of the ear (external, middle and inner ear) as well as the IAC and vestibular aqueduct (see below). According to Yildirim et al (2008), about 60% of KFS patients have ear anomalies. There was no correlation between ear pathology and skeletal or extraskeletal anomalies.
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). See the page EVA on this condition.
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 signs 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 -- see above), 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 recent years it has been found that Usher's genes are somewhat common - -about 1/70 people have a single mutation. 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.
Wolfram Syndrome, first described in 1938, is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness). According to Plantinga et al (2008), all patients had similar sensorineural hearing loss with a gently downsloping pattern. It does not progress with age.
Plantinga et al (2008). Hearing impairment in genotyped Wolfram syndrome pateints. Ann ORL 117(7) 474-500
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.
|With Malformed Cochlea||Hearing Loss|
||Moderate to severe (higher frequencies perserved)|
|With Normal Cochlea|
||Moderate to severe (stepwise)|
|(Modified from Jackler et al)|
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 (see figure on right, from Strome).
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.
Patients with the common Down's syndrome (Trisomy 21), often have inner ear malformations.
There are also some deformities of the membranous labyrinth -- as for example the very common Schiebe deformity (pars inferior -- cochlea and saccule).
Alexander aplasia is characterized by aplasia of the cochlear duct. The organ of Corti, particularly the basal turn of the cochlea and adjacent ganglion cells, is affected most prominently. Hearing loss is most notable with higher frequencies, while low-frequency hearing is relatively preserved.
The frequency of these disorders mainly comes from temporal bone autopsies. Ther reason is that these deformities cannot be diagnosed on CT scan, as CT scans are not able to define abnormalities of the membranous labyrinth. High-resolution MRI has been used to visualize these structures. Practically however, conventional 1.5 tesla MRI scanners do not provide enough detail to be of much clinical value. The newer 3.0 tesla scanners may be of greater value.
One would think that the VEMP test would be a good method of detecting the Schiebe deformity, as the VEMP is sensitive to saccule disturbances.
See also: raisingdeafkids.org
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