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  Disease summary:

  
  
  
  
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    Usher syndrome is characterized by sensorineural hearing loss and retinitis pigmentosa (RP) with or without vestibular dysfunction.

    
    
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    Pendred syndrome is characterized by nonsyndromic hearing loss with enlarged vestibular aqueducts (EVA) and/or Mondini dysplasia (incomplete partition or common cavity malformation of the inner ear) in combination with euthyroid goiter or thyroid dysfunction. DFNB4 hearing loss is characterized by the same features of Pendred syndrome without thyroid abnormalities.

  
  
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  Hereditary basis:

  
  
  
  
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    Usher syndrome is inherited in an autosomal recessive manner.

    
    
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    Pendred syndrome or DFNB4 hearing loss is inherited in an autosomal recessive manner. However, there are rare reports of possible digenic inheritance involving the FOXI1 and KCNJ10 genes.

  
  
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  Differential diagnosis:

  
  
  
  
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    Usher syndrome

    
    
    
    
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      Nonsyndromic hearing loss or nonsyndromic RP

      
      
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      Deafness-dystonia-optic neuronopathy (DDON)

      
      
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      Mitochondrial disorders

      
      
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      Diabetic neuropathy

      
      
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      Viral infections

      
      
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      Alstrom syndrome

      
      
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      Bardet-Biedl syndrome

  
  
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  Pendred syndrome

  
  
  
  
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    Branchiootorenal syndrome (BOR)

    
    
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    Brachiooto syndrome (BO)

    
    
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    Waardenburg syndrome

    
    
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    Deafness associated with the recessive form of distal renal tubular acidosis

Diagnostic Criteria

A clinical diagnosis of Usher syndrome can be made based on the following features:

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  Sensorineural hearing loss with typical presentations as follows

  
  
  
  
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    Congenital severe to profound for type 1

    
    
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    Congenital moderate-to-severe sloping for type 2

    
    
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    Variable age of onset and severity for type 3, often progressive

  
  
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  RP

  
  
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  Vestibular dysfunction for type 1, which may also occur in type 3

  
  
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  Family history suggestive of autosomal recessive inheritance (though many cases are singletons)

  
  
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  Absence of other physical abnormalities such as dystonia/ataxia (DDON), obesity/cardiomyopathy/insulin resistance (Alstrom syndrome), obesity/postaxial polydactyly/cognitive impairment/genital abnormalities/renal abnormalities (Bardet-Biedl syndrome), or features suggestive of a mitochondrial disorder.

A genetic diagnosis of Usher syndrome can also be made based on the presence of two pathogenic variants in a gene that has been associated with Usher syndrome (Table 152-1). However, some pathogenic variants in USH1C, CDH23, PCDH15, and DFNB31 have also been associated with recessive nonsyndromic hearing loss. This is further addressed under the section on genetic counseling.

A clinical diagnosis of Pendred syndrome and DFNB4 hearing loss can be made based on the following features:

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  Sensorineural hearing loss that is typically congenital.

  
  
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  Bilateral enlarged vestibular aqueducts with or without incomplete partition (Mondini deformity). Goiter, hypothyroidism, or abnormal perchlorate discharge test result (this feature is absent in DFNB4).

  
  
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  Family history suggestive of autosomal recessive inheritance (though many cases are singletons).

A genetic diagnosis of Pendred syndrome or DFNB4 hearing loss can be made based on the presence of two pathogenic variants in the SLC26A4 gene (Table 152-1). These mutations in combination with a goiter or an abnormal perchlorate discharge test would confirm a diagnosis of Pendred syndrome.

Clinical Characteristics

Usher Syndrome: Usher syndrome is one of the most common types of autosomal recessive syndromic hearing loss and is the most common genetic cause of combined deafness and blindness. Its prevalence is at least 4/100,000, with an estimated carrier frequency of 1/70. Recent data suggest that 10% of hearing loss cases, negative for GJB2 mutations, will develop Usher syndrome.

Usher syndrome is subdivided into three clinical types depending on the severity and onset of hearing impairment and RP, as well as the presence of vestibular dysfunction (Table 152-2). Types 1 and 2 are equally frequent in the general population, while type 3 is considerably less common in the general population although it has a higher prevalence in the Finnish and Ashkenazi Jewish populations.

RP, a type of retinal dystrophy, is a group of hereditary retinal diseases in which there is degeneration of the rod and cone photoreceptors. RP can occur as an isolated condition or be part of at least 30 different syndromes. Usher syndrome is the most common syndromic form of RP, accounting for 10% to 20% of all individuals with RP. RP is a highly variable disorder with respect to age of onset, severity, and progression. Individuals often present with difficulties with dark adaptation and night blindness followed by reduction in peripheral (tunnel vision) then central vision loss.

The vestibular problems associated with Usher syndrome often present as delayed walking (>18 months), especially in Usher syndrome type 1. The presence of vestibular dysfunction in an individual with significant hearing loss increases the possibility for Usher syndrome.

Usher syndrome type 1 is the most severe form of the condition and is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular dysfunction, and the onset of RP in childhood. Individuals with Usher Syndrome type 2 also have congenital hearing loss (usually milder and worse in the higher frequencies), but vestibular problems are typically absent. In type 2, RP presents later, typically in teens—early 20s. The hearing loss associated with Usher syndrome type 3 may not be present at birth. Vestibular dysfunction may or may not be present, and RP usually develops later than it does in types 1 and 2.

There are atypical forms of Usher syndrome and overlap between the three types, which can make it difficult to make a clinical distinction between the three different types. In addition, CDH23, DFNB31, PCDH15, and USH1C have also been associated with recessive nonsyndromic hearing loss and USH2A can also cause nonsyndromic RP.

Pendred Syndrome

The incidence of Pendred syndrome is 7.5/100,000, which accounts for approximately 5% to 10% of childhood-onset hereditary hearing loss. Hearing loss associated with Pendred syndrome or DFNB4 is typically bilateral severe-to-profound sensorineural hearing loss that can be progressive or fluctuating. In some cases progression can be associated with head injury, infection, and delayed secondary hydrops. The most common abnormalities are enlarged vestibular aqueduct and incomplete partition (Mondini deformity).