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Pendred syndrome (PDS) is a clinically variable genetic disorder characterized by bilateral sensorineural hearing loss and euthyroid goiter.
PDS is one of the most frequent forms of syndromic genetic deafness. Although prevalence is unknown, PDS may account for up to 7.5% of cases of congenital hearing loss.
Considerable phenotypic variability is found even within families. The main presenting clinical sign is prelingual sensorineural deafness, although occasionally the hearing loss develops later in childhood. The degree of hearing loss is variable: it can be mild-to-moderate and progressive in some patients, and severe-to-profound in others. Fluctuations in hearing are also common and may be associated with or preceded by vertigo. The onset and presentation of euthyroid goiter (75%) is highly variable within and between families, with thyroid enlargement usually developing in late childhood or early adulthood. The thyromegaly reflects a defect in iodide transport from the thyrocyte to the colloid, although organification itself is not impaired. Hypothyroidism may develop if nutritional iodide intake is low. Genetic deafness at the DFNB4 locus is part of the phenotypic spectrum that includes PDS at one extreme and autosomal recessive non-syndromic sensorineural deafness type DFNB (see this term) at the other. In patients with the latter disease, thyroid function is normal.
Biallelic or double heterozygous genetic mutations are identified in about half of patients: biallelic mutations in SLC26A4 (7q31), or double heterozygous mutations in SLC26A4 and FOXI1 (5q34), or in SLC26A4and KCNJ10 (1q23.2). Nearly all mutations identified in SLC26A4 are biallelic encoding pendrin, a 780 amino acid multifunctional anion exchanger. Less than 1% of affected persons present with double heterozygous mutations.
The diagnosis is based on the presence of hearing impairment, temporal bone anomalies of the inner ear, and an abnormal perchlorate discharge test (if available) or goiter. Inner ear anomalies range from enlargement of the vestibular aqueduct (EVA, which is very common in DFNB4) to cochlear hypoplasia (a decrease in the number of cochlear turns in addition to EVA, which is very rare in DFNB4 but common in PDS). These anomalies can be diagnosed by computed tomography (CT) and/or magnetic resonance imaging (MRI), although the former provides better resolution of bony changes. Diagnosis is confirmed by molecular genetic testing which is available clinically.
The differential diagnosis of congenital non-syndromic hearing loss is extremely long, with over 80 genetic causes identified to date. If temporal bone imaging has been obtained to evaluate fluctuating hearing loss and EVA or cochlear hypoplasia is noted, the differential diagnosis is shorter and includes congenital cytomegaloviral infections, BOR syndrome (see this term), and deafness at the DFNX2 locus (POU3F4).
Prenatal testing for at-risk pregnancies is possible when mutations in a family are known.
PDS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.
Management and treatment
Management includes annual audiograms with suitable amplification (hearing aids) as soon as hearing impairment is diagnosed. Patients with severe-to-profound hearing loss should be evaluated for cochlear implantation, and when appropriate, specific educational programs for the hearing impaired should be considered. Abnormal thyroid function should be treated with standard therapy.
Patients with PDS may have progressive hearing loss, although it is not yet possible to identify these patients in advance. As a general rule, however, progression of hearing loss is more common in patients with more severe inner ear anomalies.
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