Disease summary:

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  Hearing loss (HL) is the most common sensory deficit in humans, occurring in 1 in 500 births and affecting 278 million people worldwide.

  
  
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  Conductive HL (CHL) is characterized by abnormalities of the external and/or middle ear, while sensorineural hearing loss (SNHL) is caused by malfunction of the inner ear, and mixed HL is a combination of both CHL and SNHL.

  
  
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  Nonsyndromic HL (NSHL) is not associated with any abnormalities of the external ear or any other organs and comprises the majority (70%) of hereditary HL (Fig. 151-1).

Hereditary basis:

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  Most cases of NSHL have a genetic etiology.

  
  
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  NSHL is genetically heterogeneous with 64 genes currently implicated in the disorder (Table 151-1).

  
  
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  Mutations in the gene encoding the gap junction protein connexin 26 (GJB2) are the most common genetic cause of NSHL, occurring in an estimated 25% of autosomal recessive cases in the US population.

Differential diagnosis:

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  Environmental causes of hearing impairment (acquired HL) account for approximately 30% of NSHL in developed countries

  
  
  
  
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    Acquired HL in children may be caused by

    
    
    
    
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      Prenatal infections from TORCH organisms (Toxoplasmosis, Rubella, Cytomegalovirus [CMV], and Herpes) with infection comprising the majority of environmental HL in children

      
      
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      Postnatal infections, particularly bacterial meningitis caused by Neisseria meningitides, Haemophilus influenzae, or Streptococcus pneumoniae

  
  
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  Acquired HL in adults is most often due to environmental noise exposure, though there is evidence for gene-environment interactions in “age-related” HL.

Syndromic hearing impairment is characterized by hearing loss and abnormal findings of at least one other organ system. There are more than 400 genetic syndromes that include hearing impairment and only the most common are briefly outlined here.

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  Autosomal dominant syndromic hearing impairment

  
  
  
  
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    Waardenburg syndrome: variable SNHL, pigmentary abnormalities including white forelock, and heterochromia iridis

    
    
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    Branchiootorenal syndrome (BOR syndrome): CHL, SNHL, or mixed HL, branchial cleft cysts, malformations of the external ear, and renal anomalies

    
    
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    Stickler syndrome: progressive SNHL, cleft palate, and spondyloepiphyseal dysplasia leading to arthritis

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  Autosomal recessive syndromic hearing impairment

  
  
  
  
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    Usher syndrome (USH): the most common cause of deaf-blindness is characterized by congenital SNHL, retinitis pigmentosa, and vestibular dysfunction. There are three types of USH differentiated by hearing and vestibular phenotypes:

    
    
    
    
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      USH type I: severe-to-profound SNHL, vestibular deficits

      
      
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      USH type II: mild-to-severe SNHL, normal vestibular function

      
      
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      USH type III: progressive SNHL and progressive loss of vestibular function

    
    
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    Pendred syndrome: severe-to-profound SNHL and euthyroid goiter associated with an abnormality of the bony labyrinth on CT examination (Mondini dysplasia or enlarged vestibular aqueduct [EVA])

    
    
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    Jervell and Lange-Nielsen syndrome: congenital deafness and prolongation of the QT interval leading to syncopal episodes

  
  
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  X-linked syndromic impairment

  
  
  
  
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    Alport syndrome: progressive SNHL and progressive glomerulonephritis which can lead to end-stage renal disease along with variable ophthalmologic findings (eg, anterior lenticonus)

  
  
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  NSHL is distinguished by a lack of visible abnormalities of the external ear or other organ systems, however, it can be associated with abnormalities of the middle and/or inner ear (Table 151-1). NSHL is categorized by mode of inheritance and the different gene loci are designated DFN (for DeaFNess) and then given a letter according to inheritance pattern.

  
  
  
  
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    Autosomal dominant NSHL (DFNA): generally progressive and moderate to severe. Significant genotype-phenotype correlations exist (eg, WFS1, DFNA6/14, causes low-frequency SNHL).

    
    
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    Autosomal recessive NSHL (DFNB): generally congenital severe to profound, with exceptions (eg, TECTA, DFNB21, causes moderate NSHL).

    
    
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    X-linked NSHL (DFNX): there are two identified X-linked NSHL genes with variable phenotypes.

    
    
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    Mitochondrial NSHL: mutations in two mitochondrial genes cause NSHL by a mechanism that is not understood and some cases (eg, MT-RNR1 mutations) susceptibility to developing deafness is conferred by aminoglycoside administration.