Adapted from American Academy of Pediatrics, Joint Committee on Infant Hearing: Joint Committee on Infant Hearing 1994 position statement, Pediatrics 95:152, 1995.

Table 629-2 COMMON TYPES OF HEREDITARY NONSYNDROMIC SENSORINEURAL HEARING LOSS

LOCUS	GENE	AUDIO PHENOTYPE
DFN3	POU3F4	Conductive hearing loss due to stapes fixation mimicking otosclerosis; superimposed progressive SNHL
DFNA1	DIAPH1	Low-frequency loss beginning in the 1st decade and progressing to all frequencies to produce a flat audio profile with profound losses throughout the auditory range
DFNA2	KCNQ4	Symmetrical high-frequency sensorineural loss beginning in the 1st decade and progressing over all frequencies
DFNA2	GJB3	Symmetrical high-frequency sensorineural loss beginning in the 3rd decade
DFNA 6/14/38	WFS1	Early-onset low-frequency sensorinerual loss; about 75% of families dominantly segregating this audio profile carry missense mutations in the C-terminal domain of wolframin.
DFNA10	EYA4	Progressive loss beginning in the 2nd decade as a flat to gently sloping audio profile that becomes steeply sloping with age
DFNA13	COL11A2	Congenital mid-frequency sensorineural loss that shows age-related progression across the auditory range
DFNA15	POU4F3	Bilateral progressive sensorineural loss beginning in the 2nd decade
DFNA20/26	ACTG1	Bilateral progressive sensorineural loss beginning in the 2nd decade; with age, the loss increases with threshold shifts in all frequencies, although a sloping configuration is maintained in most cases
DFNB1	GJB2, GJB6	Hearing loss varies from mild to profound. The most common genotype, 35delG/35delG, is associated with severe to profound SNHL in about 90% of affected children; severe to profound deafness is observed in only 60% of children who are compound heterozygotes carrying 1 35delG allele and any other GJB2 SNHL-causing allele variant; in children carrying 2 GJB2 SNHL-causing missense mutations, severe to profound deafness is not observed.
DFNB4	SLC26A4	DFNB4 and Pendred syndrome (see Table 629-3) are allelic. DFNB4 hearing loss is associated with dilatation of the vestibular aqueduct and can be unilateral or bilateral. In the high frequencies, the loss is severe to profound; in the low frequencies, the degree of loss varies widely. Onset can be congenital (prelingual), but progressive postlingual loss also is common.
mtDNA 1555A > G	12S rRNA	Degree of hearing loss varies from mild to profound but usually is symmetrical; high frequencies are preferentially affected; precipitous loss in hearing can occur after aminoglycoside therapy.

From Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in children, Lancet 365:879–890, 2005.

SNHL, sensorineural hearing loss.

Table 629-3 COMMON TYPES OF SYNDROMIC SENSORINEURAL HEARING LOSS

SYNDROME	GENE	PHENOTYPE
DOMINANT
Waardenberg (WS1)	PAX3	Major diagnostic criteria include dystopia canthorum, congenital hearing loss, heterochromic irises, white forelock, and an affected first-degree relative. About 60% of affected children have congenital hearing loss; in 90%, the loss is bilateral.
Waardenberg (WS2)	MITF, others	Major diagnostic criteria are as for WS1 but without dystopia canthorum. About 80% of affected children have congenital hearing loss; in 90%, the loss is bilateral.
Branchio-otorenal	EYA1	Diagnostic criteria include hearing loss (98%), preauricular pits (85%), and branchial (70%), renal (40%), and external-ear (30%) abnormalities. The hearing loss can be conductive, sensorineural, or mixed, and mild to profound in degree.
RECESSIVE
Pendred syndrome	SLC26A4	Diagnostic criteria include sensorineural hearing loss that is congenital, nonprogressive, and severe to profound in many cases, but can be late-onset and progressive; bilateral dilation of the vestibular aqueduct with or without cochlear hypoplasia; and an abnormal perchlorate discharge test or goiter.
Usher syndrome type 1 (USH1)	USH1A, MYO7A, USH1C, CDH23, USH1E, PCDH15, USH1G	Diagnostic criteria include congenital, bilateral, and profound hearing loss, vestibular areflexia, and retinitis pigmentosa (commonly not diagnosed until tunnel vision and nyctalopia become severe enough to be noticeable).
Usher syndrome type 2 (USH2)	USH2A, USH2B, USH2C, others	Diagnostic criteria include mild to severe, congenital, bilateral hearing loss and retinitis pigmentosa; hearing loss may be perceived as progressing over time because speech perception decreases as diminishing vision interferes with subconscious lip reading.
Usher syndrome type 3 (USH3)	USH3	Diagnostic criteria include postlingual, progressive sensorineural hearing loss, late-onset retinitis pigmentosa, and variable impairment of vestibular function.

From Smith RJH, Bale JF Jr, White KR: Sensorineural hearing loss in children, Lancet 365:879–890, 2005.

Sudden SNHL in a previously healthy child is uncommon but may be due to otitis media or other middle ear pathologies. Usually these causes are obvious from the history and physical examination. Sudden loss of hearing in the absence of obvious causes often is the result of a vascular event affecting the cochlear apparatus or nerve, such as embolism or thrombosis (secondary to prothrombotic conditions). Additional causes include perilymph fistula, drugs, trauma, and the first episode of Ménière syndrome. In adults, sudden SNHL is often idiopathic and unilateral; it may be associated with tinnitus and vertigo. Identifiable causes of sudden SNHL include infections (Epstein-Barr virus, varicella zoster virus, herpes simplex virus), vascular injury to the cochlea, endolymphatic hydrops, and inflammatory diseases.

Infectious Causes

The most common infectious cause of congenital SNHL is cytomegalovirus (CMV), which infects 1/100 newborns in the USA (Chapters 247 and 630). Of these, 6,000-8,000 infants each year have clinical manifestations, including approximately 75% with SNHL. Congenital CMV warrants special attention because it is associated with hearing loss in its symptomatic and asymptomatic forms, and the hearing loss may be progressive. Some children with congenital CMV have suddenly lost residual hearing at 4-5 yr of age. Much less common congenital infectious causes of SNHL include toxoplasmosis and syphilis. Congenital CMV, toxoplasmosis, and syphilis also can manifest with delayed onset of SNHL months to years after birth. Rubella, once the most common viral cause of congenital SNHL, is very uncommon because of effective vaccination programs. In utero infection with herpes simplex virus is rare, and hearing loss is not an isolated manifestation.

Other postnatal infectious causes of SNHL include neonatal group B streptococcal sepsis and bacterial meningitis at any age. Streptococcus pneumoniae is the most common cause of bacterial meningitis that results in SNHL after the neonatal period and has become less common with the routine administration of pneumococcal conjugate vaccine. Haemophilus influenzae type b, once the most common cause of meningitis resulting in SNHL, is rare owing to the Hib conjugate vaccine. Uncommon infectious causes of SNHL include Lyme disease, parvovirus B19, and varicella. Mumps, rubella, and rubeola, all once common causes of SNHL in children, are rare owing to vaccination programs.

Genetic Causes

Genetic causes of SNHL probably are responsible for as many as 50% of SNHL cases (see Tables 629-2 and 629-3). These disorders may be associated with other abnormalities, may be part of a named syndrome, or can exist in isolation. SNHL often occurs with abnormalities of the ear and eye and with disorders of the metabolic, musculoskeletal, integumentary, renal, and nervous systems.

Autosomal dominant hearing losses account for about 10% of all cases of childhood SNHL. Waardenburg (types I and II) and branchio-otorenal syndromes represent 2 of the most common autosomal dominant syndromic types of SNHL. Types of SNHL are coded with a 4-letter code and a number, as follows: DFN = deafness, A = dominant, B = recessive, and number = order of discovery, for example DFNA 13. Autosomal dominant conditions in addition to those just discussed include DFNA 1-11, 13, 15, 17, 20, 22, 28, 36, 48 and mutations in the crystallin gene (CRYM).

Autosomal recessive genetic SNHL, both syndromic and nonsyndromic, accounts for about 80% of all childhood cases of SNHL. Usher syndrome (types 1, 2, and 3), Pendred syndrome, and the Jervell and Lange-Nielsen syndrome (one form of the long Q-T syndrome) are 3 of the most common syndromic recessive types of SNHL. Other autosomal recessive conditions include Alström syndrome, type 4 Bartter syndrome, biotinidase deficiency and DFNB1-4, 6-9, 12, 16, 18, 21-23, 28-31, 36, 37, 67.

Unlike children with an easily identified syndrome or with anomalies of the outer ear, who may be identified as being at risk for hearing loss and consequently monitored adequately, children with nonsyndromic hearing loss present greater diagnostic difficulty. Mutations of the connexin-26 and -30 genes have been identified in autosomal recessive (DNFB 1) and autosomal dominant (DNFA 3) SNHL and in sporadic patients with nonsyndromic SNHL; up to 50% of nonsyndromic SNHL may be related to a mutation of connexin-26. Mutations of the GJB2 gene co-localize with DFNA 3 and DFNB 1 loci on chromosome 13, are associated with autosomal nonsyndromic susceptibility to deafness, and are associated with as many as 30% of cases of sporadic severe to profound congenital deafness and 50% of cases of autosomal recessive nonsyndromic deafness. Sex-linked disorders associated with SNHL, thought to account for 1-2% of SNHL, include Norrie disease, the otopalatal digital syndrome, Nance deafness, and Alport syndrome. Chromosomal abnormalities such as trisomy 13-15, trisomy 18, and trisomy 21 also can be accompanied by hearing impairment. Patients with Turner syndrome have monosomy for all or part of 1 X chromosome and can have CHL, SNHL, or mixed hearing loss. The hearing loss may be progressive. Mitochondrial genetic abnormalities also can result in SNHL (see Table 629-2).

Many genetically determined causes of hearing impairment, both syndromic and nonsyndromic, do not express themselves until some time after birth. Alport, Alström, and Down syndromes, von Recklinghausen disease, and Hunter-Hurler syndrome are genetic diseases that can have SNHL as a late manifestation.