Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL) that is usually congenital and often severe to profound (although mild-to-moderate progressive hearing impairment also occurs), vestibular dysfunction, and temporal bone abnormalities (bilateral enlarged vestibular aqueduct with or without cochlear hypoplasia). PDS also includes development of euthyroid goiter in late childhood to early adulthood whereas NSEVA does not.

Maternally inherited diabetes-deafness syndrome (MIDD) is a mitochondrial disorder characterized by onset of sensorineural hearing loss and diabetes in adulthood. Some patients may have additional features observed in mitochondrial disorders, including pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, renal problems, and neuropsychiatric symptoms (Ballinger et al., 1992; Reardon et al., 1992; Guillausseau et al., 2001). The association of diabetes and deafness is observed with Wolfram syndrome (see 222300), Rogers syndrome (249270), and Herrmann syndrome (172500), but all 3 of these disorders have other clinical manifestations.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the GRXCR1 gene.

Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Intact or variable vestibular responses. Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families.

Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (Jen et al., 2007). For a discussion of genetic heterogeneity of episodic ataxia, see EA1 (160120).

Autosomal recessive deafness-70 (DFNB70) is a neurologic disorder with a variable disease course. All individuals present with isolated congenital sensorineural hearing loss in infancy that appears to be stable for the first decades of life. Affected members of 1 family with longer follow-up developed a neurodegenerative disease in their forties, including ataxia with loss of ambulation, optic atrophy, dystonia or spasticity, and cognitive decline with psychiatric features. The later onset of additional symptoms in this family suggests that others with DFNB70 may be at risk of developing multisystem disease in mid-to-late adulthood. These reports indicate that there is a phenotypic spectrum of PNPT1-related disease manifestations (Von Ameln et al., 2012; Eaton et al., 2018).

An autosomal recessive nonsyndromic deafness that is characterized by prelingual onset with severe to profound, stable hearing loss and has material basis in mutation in the CDH23 gene on chromosome 10q22.

Autosomal dominant deafness-11 is a nonsyndromic form of progressive neurosensory hearing loss with postlingual onset. Some affected individuals have mild vestibular symptoms (summary by Sun et al., 2011).

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the TMC1 gene.

DFNB48 is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies (summary by Riazuddin et al., 2012).

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the MYO7A gene.

Hyperostosis cranialis interna is a bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII (Waterval et al., 2010).

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the MYO6 gene.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").

Any autosomal dominant nonsyndromic deafness in which the cause of the disease is a mutation in the CCDC50 gene.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the LHFPL5 gene.

Any autosomal dominant nonsyndromic deafness in which the cause of the disease is a mutation in the SLC17A8 gene.

An autosomal dominant nonsyndromic deafness that has material basis in variation in the chromosome region 14q11.2-q12.

An autosomal recessive nonsyndromic deafness that has material basis in variation in the chromosome region 4q12-q13.2.

An autosomal recessive nonsyndromic deafness that has material basis in variation in the chromosome region 2p25.1-p24.3.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

This form of autosomal recessive deafness is sensorineural and nonsyndromic, and shows prelingual onset (summary by Charizopoulou et al., 2011).

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the LRTOMT gene.

CATSPER-related male infertility results from abnormalities in sperm and can be either CATSPER-related nonsyndromic male infertility (NSMI) or the deafness-infertility syndrome (DIS) when associated with non-progressive prelingual sensorineural hearing loss. Males with NSMI have infertility while females have no symptoms. Males with DIS have both infertility and hearing loss, while females have only hearing loss. Routine semen analysis typically identifies abnormalities in sperm number, morphology, and motility. Otologic examination and audiologic assessment can identify hearing loss.

Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the GJB6 gene.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the LOXHD1 gene.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the PTPRQ gene.

Autosomal dominant deafness-4B is a form of nonsyndromic progressive sensorineural hearing loss with postlingual onset (summary by Wang et al., 2015)

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Autosomal dominant deafness-56 is a form of nonsyndromic sensorineural hearing loss. Hearing impairment shows postlingual onset and is progressive (summary by Zhao et al., 2013).

An autosomal recessive nonsyndromic deafness that has material basis in variation in the chromosome region 1q43-q44.

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures. Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability. Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function. Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the GRXCR2 gene.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the CLIC5 gene.

Any autosomal dominant nonsyndromic deafness in which the cause of the disease is a mutation in the CRYM gene.

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the RIPOR2 gene.

Autosomal dominant deafness-66 is a form of nonsyndromic sensorineural hearing impairment with widely variable age at onset (Nyegaard et al., 2015).

Autosomal dominant deafness-70 is a form of nonsyndromic sensorineural hearing loss. Hearing impairment shows postlingual onset and is slowly progressive (Gao et al., 2015).

Autosomal recessive deafness-57 (DFNB57) is characterized by symmetric bilateral moderate to severe hearing loss, represented by gently downward-sloping audiograms. The hearing loss may be mildly progressive (Guan et al., 2018).

Autosomal dominant deafness-74 (DFNA74) is characterized by nonsyndromic postlingual progressive hearing loss, with onset in the third decade of life in most affected individuals (Wang et al., 2018).

An atypical form of Usher syndrome, here designated type IV (USH4), is an autosomal recessive disorder characterized by late onset of retinitis pigmentosa and usually late-onset of progressive sensorineural hearing loss without vestibular involvement (summary by Khateb et al., 2018). For a discussion of genetic heterogeneity of Usher syndrome, see 276900.

DFNB99 is characterized by prelingual, severe to profound sensorineural hearing loss without vestibular dysfunction (Cheng et al., 2003).

DFNB113 is characterized by postlingual progressive hearing impairment (Booth et al., 2018).

DFNB100 is characterized by prelingual onset of profound sensorineural deafness without vestibular involvement (Yousaf et al., 2018).

DFNB94 is characterized by prelingual profound sensorineural hearing loss (Simon et al., 2015).

Usher syndrome type 1M (USH1M) is characterized by prelingual sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa (Ahmed et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of Usher syndrome, see USH1 (276900).

Autosomal dominant deafness-76 (DFNA76) is characterized by progressive or nonprogressive hearing loss with variable age at onset. Hearing loss is more severe at higher frequencies in most patients (Schrauwen et al., 2019; Morgan et al., 2019; Diaz-Horta et al., 2019).

Tolchin-Le Caignec syndrome (TOLCAS) is a developmental disorder characterized by mildly to moderately impaired intellectual development and behavioral problems, such as autism, ADHD, labile mood, and aggressive episodes. Many patients have bony abnormalities, including osteochondroma, craniosynostosis, dysmorphic facies, arachnodactyly, and large head circumference. Rarely, additional congenital anomalies may also be observed. These additional features and the bony defects are highly variable (summary by Tolchin et al., 2020).

Autosomal dominant deafness-79 (DFNA79) is a nonsyndromic form of progressive sensorineural hearing loss with age of onset ranging from 20 years to 65 years. Affected females appear to have milder hearing loss than males (Lu et al., 2020).

Autosomal recessive deafness-117 (DFNB117) is characterized by nonsyndromic bilateral moderate-to-profound sensorineural deafness, with onset in early childhood (Vona et al., 2021).

DFNA81 is characterized by postlingual onset of slowly progressive sensorineural hearing loss (Li et al., 2018).

DFNB118 is characterized by congenital profound sensorineural hearing loss and cochlear aplasia (Bademci et al., 2020).

Any Usher syndrome in which the cause of the disease is a mutation in the CLRN1 gene.

Autosomal dominant deafness-86 (DFNA86) is characterized by late-onset progressive hearing loss through p53 (TP53; 191170)-mediated hair cell apoptosis (Zhang et al., 2020).