Timothy C. Hain, MD Hearing Page Page last modified: February 2, 2018
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. In other words, although there are many many more papers about genetic syndromes than non-syndrome deafness, and lots more text on this page, these conditions that are the subject of so much discussion, are just a little piece to the big genetic hearing loss puzzle.
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 bilateral vestibular loss.(Lemaire et al. 2003)
DFNA11 can also cause vestibular problems (Jen, 2009)
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.
- De Leenheer EM, Huygen PL, Wayne S, Smith RJ, Cremers CW. The DFNA10 phenotype.Ann Otol Rhinol Laryngol 2001 Sep;110(9):861-6
- Pennings RJE and others. Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1). Arch OtoHNS 2003:129;421-42
- Lesperance MM and others. Mutations in the Wolfram syndrome type-I gene (WFS1) define a clinical entity of dominant low-frequency sensorineural hearing loss. Arch Oto HNS 2003:129:411-420
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).
This unusual type of genetic problem means that there is a mutation (not necessarily the same) in both copies of a particular gene (paternal and paternal).
The MEGDEL (3-methylglutaconic aciduria, dystonia-deafness, encephalopathy, Leigh-like) syndrome is due to motations in the SERAC1 gene, which encodes a protein with a serine-lipase domain. Maas et al (2017) reported on this rare syndrome in 2017. It should be thought of as a progressive deafness-dystonia syndrome with frequent liver involvement. Spasticity and dystonia are common. The MRI shows a patognomonic "putaminal eye". Survival to adulthood is common.
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. These are genes that affect collagen. The classic phenotype is renal failure and progressive sensorineural deafness. The hearing loss is bilateral and correlated with age (Moon et al, 2009). There is no association of Alports and vertigo.
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 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 inherited 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). Some of these patients have auditory neuropathy.
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).
Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. According to Koping et al (2017), "Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%."
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.
- Yildirim N, Arslanoğlu A, Mahiroğullari M, Sahan M, Ozkan H. Klippel-Feil syndrome and associated ear anomalies.Am J Otolaryngol. 2008 Sep-Oct;29(5):319-25.
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.
Classic features include Duane's syndrome (resembles a 6th nerve palsy), congenital optic nerve hypoplasia, bilateral deafness, and "radial ray" malformation. It is related to other SALL4 disorders including acro-renal-ocular syndrome and Holt-Oram syndome. According to Chun et al, sensorineural deafness occurred in only 17% of their 41 subjects (2001).
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.
Although the SMA's are not generally associated with hearing symptoms, a recent report suggests that the disorder caused by a mutation in TRPV4 can induce a neuropathy as well as hearing loss (Oonk et al, 2014).
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).
Waardenburg syndrome (WS) is a largely autosomal dominant disorder characterised by pigmentary anomalies of the skin, hairs, eyes and various defects of other neural crest derived tissues (Read and Newton, 1997). It accounts for over 2% of congenital hearing impairment. At least four types are recognized on the basis of clinical and genetic criteria. (Apaydin et al, 2004). The disorder is not very homogeneous, even within the same families. About 1/30 persons in schools for the deaf have Waardenburg syndrome.
There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups(Chen et al, 2010). The SOX10 mutation is also involved in the Kallman syndrome with deafness (Pingault et al, 2015). The MITF (microphthalmia transcription factor) is related to the melanogenesis process (i.e. pigment), and mutations can also lead to Tietz syndrome (Otreba et al, 2012).
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; or light blue eyes), and sensorineural deafness. Some patients also have dizziness (Black et al, 2001). The displacement of the canthus, dystropia cantorum, is the distinguishing feature between WS1 (has it) and WS2 (doesn't have it). 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. Mutations of EDNRB, EDN3 and SOX10 genes are responsible for Waardenburg syndrome type IV (Otreba et al, 2013) .
Usher syndrome is characterised by hearing impairment and retinitis pigmentosa (Young, Mets and Hain; 1996). 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. However, there is some controversy about this as some well documented USH-2 paients have abnormal testing including VHIT, and reduced or absent VEMP testing (Magliulo et al, 2017). We are a bit dubious about this as the tests where abnormalities were reported are often abnormal in the normal population. Still, it seems worth more study.
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.
See this page for a separate discussion.
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)|
These malformations cause conductive hearing loss. The Teunissen and Cremers class III malformations are examples in which there is a mobile stapes footplate. As is the case with most middle ear disturbances, these can often be treated with surgery. (Vincent et al, 2016)
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.
Unusually sized openings between the inner ear and the brain (internal auditory meatus) are usually associated with other bone abnormalities (surprise !). Li et al (2014).
See also: raisingdeafkids.org