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Background

          The clinical phenotype known as Pendred Syndrome (PS) was first observed in 1896 by a British physician, Vaughan Pendred.  He described an Irish family in which two of ten offspring were congenitally deaf and had goiters that could not be attributed to environmental factors (endemic goiter) (Pendred 1896).  The clinical features of PS include (1) sensorineural hearing loss (SNHL), typically bilateral, prelingual, and more severe in the high frequencies; and (2) goiter, usually not present until puberty at which time the thyroid becomes diffusely enlarged.  Affected individuals generally remain euthyroid despite the goiter.  The thyroid defect is associated with abnormal iodide processing, that often can be diagnosed using the perchlorate discharge test (Brain 1927, Fraser 1965, Morgans et al).  The prevalence of PS is estimated to be 1-8% of congenital deafness (Fraser et al 1960, Fraser 1965).

          Many years after the initial association of hearing loss and goiter, it was recognized that specific cochlear malformations are associated with PS.  Hvidberg-Hansen et al described dilation of the endolymphatic duct and sac, enlargement of the vestibular aqueduct and cochlear dysplasia in a histological study of temporal bones harvested from an affected person (Hvidberg-Hansen and Jorgensen 1968).  Utilizing axial pyramidal tomography, Johnsen et al studied 17 persons with the clinical diagnosis of PS and found Mondini dysplasia in all cases (Johnsen et al 1987).  Mondini dysplasia is defined as the presence of a dilated vestibular aqueduct associated with dilation of the apical turn of the cochlea resulting in an abnormal one-and-a-half turns replacing the normal two-and-a-half turns.  Mondini dysplasia, however, is not an invariable finding in PS, as documented by Andersen's study in which only eight of 13 patients with PS had this anomaly (Andersen 1974).  With improved resolution of computed tomography (CT) and magnetic resonance imaging (MRI), Phelps et al found bilateral dilated vestibular aqueduct (DVAs) in 31 of 40 affected persons and Mondini dysplasia in 8 (Phelps et al 1998).  Based on these data, a temporal bone assessment should be included in the diagnostic evaluation of PS.

                 

       Phenotypic heterogeneity can make the diagnosis of PS unclear and has made it difficult to reach a consensus on the best screening strategy for PS.  For example, in one two-sib family described by Johnsen et al, one sib demonstrated the classic features of PS (severe-to-profound SNHL, goiter and positive perchlorate discharge test) but the other sib had only mild SNHL and no goiter (Johnsen et al 1989).  This variability underscores the desire to have a genetic test for diagnosis of PS.

The Genetics of Pendred Syndrome

      In 1996 PS was mapped to a 9-cM region on the long arm of chromosome 7 (7q21034) (Sheffield et al 1996).  Other groups confirmed this linkage result and with fine mapping the candidate interval was reduced to 0.8 cM (Coyle et al 1996, Coucke et al 1996, Gausden et al 1997, Mustapha 1998).  In 1997, 100 years after the disease was first recognized, Everett et al cloned the causative gene and named it PDS (Everett et al 1997).  A form of non-syndromic deafness, DFNB4, localizes to the same genomic region and is allelic to PS.  Persons with DFNB4, as implied by the nomenclature, have SNHL and DVA but do not have any thyroid anomalies.  In 1998 Li et al demonstrated two mutations in PDS in a consanguineous Indian family with DFNB4 (Li et al 1998). Usami et al also demonstrated seven mutations in six families with DFNB4 (Usami et al 1999). Functional studies by Scott et al suggest that the observed phenotype correlates with the degree of residual function of the encoded protein, pendrin.  Thus, mutations that result in no residual transport function appear to be associated with the PS phenotype; minimal transport ability prevents thyroid dysfunction but not the SNHL and temporal bone anomalies that characterize DFNB4 (Scott et al 2000).

    Based on similarities to other solute carrier proteins, PDS has been renamed SLC26A4.  Mutations in this gene are the major genetic cause of PS and DFNB4.  In 2001 Campbell et al studied genotype-phenotype correlations in relation to temporal bone abnormalities.  The group found mutations in SLC26A4 in 82% of multiplex families (families with more than one affected offspring) with DVA or Monidini dysplasia but in only 30% of simplex families (Campbell et al 2001).  To date, 77 mutations have been found in a total of 155 families.  Most of these mutations have been reported in single families, however 28 mutations have been reported in more than one family and four (L236P, IVS8+1G>A, T416P, and H723R) account for approximately 60% of the total PS genetic load (SLC26A4 mutations). Free clinical testing is available through the Molecular Otolaryngology Laboratories (MORL) at University of Iowa Hospitals and Clinics, Department of Otolaryngology Head and Neck surgery.

Functional Analysis

     A mouse mutant with targeted deletion of Slc26a4 was created to perform functional analysis of pendrin, the translated protein.  Homozygous mouse mutants (Slc26a4-/-) are born deaf and show signs of vestibular dysfunction like head tilting and bobbing, circling and an abnormal reaching response.  Unexpectedly, inner ears develop normally until about embryonic day 15 (E15) at which time severe endolymphatic dilatation begins to occur.  Additionally, scanning electron microscopy revealed degeneration of hair cells by postnatal day fifteen (P15), with outer hair cells more severely affected than inner hair cells, as well as a complete lack of otoconia (Everett et al 2001).  By in situ hybridization, Slc26a4 expression was found to be greatest in the endolymphatic duct and sac, but expression in the non-sensory regions of the utricle and saccule and the external sulcus also was demonstrable (Everett et al 1999).  Since Slc26a4 is expressed in a limited number of cell types in the inner ear and since it functions as an anion transporter, it is presumed to play a role in inner ear fluid homeostasis.  Abnormal homeostasis presumably leads to altered cochlear morphology and hearing loss.  

    SLC26A4 is expressed not only in the inner ear, as described above, but also in the thyroid, kidney and placenta.  Many groups have investigated the function of pendrin in theses other tissues in order to gain a better understanding of the function of this protein.  Pendrin was found to be expressed in the apical membrane of thyrocytes, the intercalated cells of cortical collecting ducts in the kidney, as well as in the brush border membrane of cytotrophoblasts (Bidart and Mian et al 2000, Royaux et al 2000, Bidart and Lacroix et al 2000, Royaux et al 2001).  Further studies found that it functions as a chloride/iodide exchanger in the thyroid and similarly as a chloride/formate exchanger in the kidney (Scott et al 1999, Kraiem et al 1999, Scott et al 2000, Soleimani et al 2001, Bogazzi et al 2000).  The knowledge of how pendrin functions outside of the ear supports the hypothesis that it functions similarly in the inner ear controlling homeostasis of endolymph. 

Making the diagnosis of PS

    Reardon et al have advocated genetic testing to establish a diagnosis of PS since variability in onset and severity of goiter is an unreliable clinical indicator of disease (Reardon et al 1999),  The perchlorate test is also unreliable, as illustrated in two consanguineous Tunisian families with a genetic diagnosis of PS in which 11 of 23 affected individuals with goiter and mutations in SLC26A4 had negative perchlorate washouts (Masmoudi et al 2000).  These results, coupled with the data reported by Campbell et al (in which patients were ascertained based on temporal bone findings) make mutation screening of SLC26A4 the most reasonable diagnostic test in individuals with SNHL and cochlear malformations (DVA or Mondini).  Although a positive result does not currently impact on habilitation, it does permit a definitive diagnosis and makes accurate genetic counseling possible.

Looking ahead

    We have a rudimentary knowledge of PS at a molecular and functional level.  As much as 80% of PS may be attributed to point mutations and small insertions or deletions in SLC26A4, and it remains to be determined whether more complex alterations of the coding sequence contribute to the genetic load.  Mutations in the promoter regions of SLC26A4 have not been explored and the impact of SLC26A4 transcription modulators is unknown. We do not understand the basis for the observed phenotypic heterogeneity.  Variations in phenotype may reflect environmental or genetic factors. Unraveling these relationships will be important if we are to address the consequences of PS and DFNB4 like progressive hearing loss and progressive thyroid dysfunction.