Pendred syndrome, the most common syndromal form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter) (Everett et al., 1997).
For a general ... Pendred syndrome, the most common syndromal form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter) (Everett et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (274400).
The perchlorate discharge test, the gold-standard investigation for Pendred syndrome, is nonspecific, and in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown. Reardon et al. (1997) used the mapping of the Pendred syndrome ... The perchlorate discharge test, the gold-standard investigation for Pendred syndrome, is nonspecific, and in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown. Reardon et al. (1997) used the mapping of the Pendred syndrome gene to 7q to identify pedigrees, and assessed the prevalence of clinical parameters of disease in affected individuals. Cosegregation between disease and the locus on 7q was found in 36 familial cases. Clinical and investigative findings were compared in 18 index cases versus 18 affected sibs. The overall prevalence of goiter was 73%, higher in index cases (94%) than in sibs (56%), many of whom had not previously been considered to have the condition. One perchlorate discharge test was false-negative (2.9%). Radiologic malformations of the cochlea were identified in 86% of cases. Reardon et al. (1997) concluded that securing a diagnosis of Pendred syndrome may be difficult, especially in the single case. They noted that the perchlorate discharge test, although valuable, is difficult to undertake in the younger patient, and radiology may assist in diagnosing such patients. Reardon et al. (1999) performed perchlorate discharge tests in 57 individuals with Pendred syndrome. In 52 (21 males and 31 females, age range 9 to 54 years) a discharge of greater than 10% of radioiodide was observed (less than 10% is regarded as normal in control subjects). Goiter was present in 43 (83%) of the cohort and generally developed after the age of 10 years. Fifty-six percent remained euthyroid, and 19 (44%) had objective evidence of hypothyroidism. Reardon et al. (1999) concluded that thyroid dysfunction in Pendred syndrome is variable, and that inclusion of goiter as a diagnostic requirement will lead to underascertainment. Reardon et al. (2000) stated that enlargement of the vestibular aqueduct, a radiologic marker, should be considered as the most likely presentation of Pendred syndrome. They found that 49 of 57 cases of deafness with enlarged vestibular aqueducts had signs of Pendred syndrome. They suggested that Pendred syndrome might be recharacterized as deafness with enlargement of the vestibular aqueduct that is sometimes associated with goiter. Masmoudi et al. (2000) found that of 23 members of a family with Pendred syndrome, all who underwent CT scan of the inner ear had a widened vestibular aqueduct. However, only 11 of the patients had goiter; 8 of these patients who were tested had a normal result on perchlorate discharge test. This finding called into question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome. Masmoudi et al. (2000) suggested the use of molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphologic anomaly even in the absence of thyroid goiter.
A mild type of organification defect is associated with congenital deafness. Patients show only partial discharge of iodide (25 to 50%) when thiocyanate or perchlorate is given (Fraser et al., 1960). Their thyroids are moderately enlarged from childhood. ... A mild type of organification defect is associated with congenital deafness. Patients show only partial discharge of iodide (25 to 50%) when thiocyanate or perchlorate is given (Fraser et al., 1960). Their thyroids are moderately enlarged from childhood. Patients are usually euthyroid, although an exaggerated response to thyrotropin-releasing hormone (TRH; 613879) suggests a compensated hypothyroidism (Gomez-Pan et al., 1974); mental retardation has been reported (Thompson et al., 1970). Massa et al. (2003) found that a solitary thyroid nodule may be the presenting feature. Thyroid carcinoma has been observed (Thieme, 1957; Elman, 1958; Milutinovic et al., 1969); because of the characteristically 'wild' histology, malignancy may be incorrectly diagnosed. The deafness is neurosensory in type and sometimes associated with defective vestibular function. The deafness may be present at birth or develop in early childhood. Batsakis and Nishiyama (1962) estimated that Pendred syndrome accounts for 1 to 10% of hereditary deafness. Illum et al. (1972) reported 15 cases. They showed a pedigree in which 8 proven cases and several presumed cases occurred in 3 generations of a family in a pseudodominant pattern (same family as that of Johnsen, 1958). In 1 patient, histologic examination showed a Mondini type malformation of the cochlea (i.e., only the basal cochlear turn was retained while the apical turns formed a common cavity). In 6 and perhaps 7 of the other 14 cases, the same defect was demonstrated by tomography of the temporal bones in the axial-pyramidal projection. The authors suggested that peroxidase deficiency may be responsible for the cochlear lesion as well as the thyroid defect. Peroxidase activity is normal in Pendred syndrome (Burrow et al., 1973; Ljunggren et al., 1973; Cave and Dunn, 1975). There appear to be different varieties of Pendred syndrome, because Hollander et al. (1964) found a defect involving, apparently, an abnormal condensation of iodotyrosines to form iodothyronines, rather than an inadequate iodination of tyrosine. Milutinovic et al. (1969) found about 80% of the protein-bound radioiodine in the normal 19S human thyroglobulin fraction from a Pendred gland. On the other hand, Medeiros-Neto et al. (1968) found less than 15% in the 19S fraction. Desai et al. (1974) found a 15.2-16.8S radioiodinated thyroidal protein with immunologic properties of normal thyroglobulin. Fraser (1967) raised the question of whether the organification defect without deafness, as described by Stanbury and Hedge (1950) and later by Furth et al. (1967), was different from the organification defect with deafness as described by Pendred. He proposed that variability in severity of the same defect may be involved and supported this contention with a description of a patient with unilateral deafness whose sister had Pendred syndrome and bilateral deafness. Also, cases of the full syndrome and cases with near-normal hearing occurred in the same family. Cremers et al. (1998) described a boy whose bilateral sensorineural hearing loss progressed rapidly from about 50 to 60 decibels at the age of 3 years and 3 months to more than 100 decibels at the age of 4 years and 4 months. A search for the cause of the progressive hearing loss led to discovery of dysplasia of the cochlea and a widened vestibular aqueduct. Thyroid function tests were normal, but thyroglobulin (TG; 188450) was elevated. The diagnosis of Pendred syndrome was confirmed by the positive results of a potassium perchlorate test, indicating defective organic binding of the iodine in the thyroid gland. A widened vestibular aqueduct occurs also in branchiootorenal dysplasia (113650). Phelps et al. (1998) presented data on the radiologic malformations of the ear in 40 patients, all complying with strict diagnostic criteria for Pendred syndrome. Deficiency of the interscalar septum in the distal coils of the cochlea (Mondini deformity) was found to be common but probably not a constant feature of Pendred syndrome. On the other hand, enlargement of the endolymphatic sac and duct in association with a large vestibular aqueduct was present in all 20 patients examined by MRI. Phelps et al. (1998) concluded that thin section high resolution MRI on a T2 protocol in the axial and sagittal planes is the imaging investigation of choice in this disorder. They concluded that 'if there is uncertainty about cochlear malformation being a constant feature of Pendred syndrome, there can be little doubt as to the importance of enlarged vestibular aqueduct, endolymphatic sac, and endolymphatic duct, which were almost constant features' in their series. Neither Pendred syndrome patients nor pendrin (605646)-deficient knockout mice had been reported to develop overt acid-base disturbances, such as metabolic alkalosis. Royaux et al. (2001) demonstrated that pendrin is an apical anion transporter in intercalated cells of the cortical collecting ducts of the kidney and has an essential role in renal bicarbonate secretion. The fact that patients have not shown abnormalities with reference to the kidney probably reflects the fact that the kidney has other means of regulating bicarbonate excretion. Overt abnormalities in acid-base balance in pendrin-deficient humans may be induced under conditions of extensive alkali loading or severe metabolic alkalosis.
Tsukamoto et al. (2003) screened 10 Japanese families with Pendred syndrome, 32 Japanese families with bilateral sensorineural hearing loss associated with enlarged vestibular aqueduct (EVA), and 96 unrelated Japanese controls for mutations in the SLC26A4 gene. They identified ... Tsukamoto et al. (2003) screened 10 Japanese families with Pendred syndrome, 32 Japanese families with bilateral sensorineural hearing loss associated with enlarged vestibular aqueduct (EVA), and 96 unrelated Japanese controls for mutations in the SLC26A4 gene. They identified causative mutations in 90% of the typical Pendred syndrome families and in 78.1% of those with sensorineural hearing loss with EVA. None of their patients had the Mondini malformation. Tsukamoto et al. (2003) noted that the same combination of mutations resulted in variable phenotypic expression, suggesting that these 2 conditions are part of a continuous spectrum of disease. Pryor et al. (2005) evaluated the clinical phenotype and SLC26A4 genotype of 39 patients with EVA from 31 families, definitively classifying 29 individuals. All 11 PDS patients had 2 mutant SLC26A4 alleles, whereas all 18 nonsyndromic EVA patients had either 1 or no SLC26A4 mutant alleles. Pryor et al. (2005) concluded that PDS and nonsyndromic EVA are distinct clinical and genetic entities, with PDS being a genetically homogeneous disorder caused by biallelic SLC26A4 mutations, and at least some cases of nonsyndromic EVA being associated with a single SLC26A4 mutation. They noted that the detection of a single mutant SLC26A4 allele is incompletely diagnostic without additional clinical evaluation to differentiate PDS from nonsyndromic EVA. Recessive mutations in the anion transporter gene SLC26A4 are responsible for Pendred syndrome and for nonsyndromic hearing loss associated with EVA. However, a large percentage of patients with these phenotypes lack mutations in the SLC26A4 coding region in one or both alleles. Yang et al. (2007) identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1 (601093), which is a transcriptional activator of SLC26A4. They found 9 patients with Pendred syndrome or nonsyndromic EVA who were heterozygous for a novel -103T-C mutation (605646.0027) in this regulatory element, which interfered with FOXI1 binding and completely abolished FOXI1-mediated transcriptional activation. They also identified 2 Pendred and 4 EVA patients with heterozygous mutations in FOXI1 that compromised its ability to activate SLC26A4 transcription; 1 of the latter EVA patients was a double heterozygote who also carried a heterozygous mutation in the SLC26A4 gene (see 605646.0028 and 601093.0001). This finding was consistent with their observation that EVA occurs in the mouse mutant doubly heterozygous for mutations in these 2 genes, and the results supported a dosage-dependent model for the molecular pathogenesis of Pendred syndrome and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery. Yang et al. (2007) stated the this was the first example of digenic inheritance to be verified as a cause of human deafness.
For a more complete discussion of the molecular genetics of Pendred syndrome, see the entry for the SLC26A4 gene (605646).
Everett et al. (1997) used a positional cloning strategy to identify the gene (SLC26A4) mutated in ... For a more complete discussion of the molecular genetics of Pendred syndrome, see the entry for the SLC26A4 gene (605646). Everett et al. (1997) used a positional cloning strategy to identify the gene (SLC26A4) mutated in Pendred syndrome. In PDS families, Everett et al. (1997) found 3 apparently deleterious mutations, each segregating with the disease in the respective families in which they occurred (e.g., 605646.0001). Everett et al. (1997) speculated that Pendred syndrome may be more common than previously thought. They pointed out that another recessive locus for deafness, designated DFNB4 (see EVA, 600791), maps to 7q31, the same region as the PDS gene. They considered it likely that the DFNB4 individuals reported actually have Pendred syndrome, rather than mutations in another gene. In the index patient with PDS from a consanguineous kindred from northeastern Brazil, Kopp et al. (1999) found homozygosity for a 279delT mutation (605646.0016) in exon 3 of the PDS gene. The index patient showed the classic triad of deafness, positive perchlorate test, and goiter. Two other patients with deafness were homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wildtype allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the 279delT mutation; 3 were heterozygous and 3 were homozygous for the wildtype allele, suggesting a probable distinct genetic cause for their deafness. The authors concluded from comparison of phenotypes and genotypes that phenocopies generated by distinct environmental and/or genetic causes were present in this kindred and that the diagnosis of PDS may be difficult without molecular analysis. The identification of the disease gene for Pendred syndrome prompted the need to reevaluate the syndrome to identify possible clues for the diagnosis. To this purpose, Fugazzola et al. (2000) conducted a molecular analysis and full clinical, biochemical, and radiologic examination in 3 Italian families presenting with clinical features of Pendred syndrome. A correlation between genotype and phenotype was found in 1 patient with enlargement of vestibular aqueduct and endolymphatic duct and sac at magnetic resonance imaging. This subject was a compound heterozygote for a deletion in SLC26A4 exon 10 (1197delT; 605646.0020) and a novel insertion in exon 19 (2182-2183insG; 605646.0021). The authors concluded that their study demonstrates the value of the combination of clinical/radiologic and genetic studies in the diagnosis of Pendred syndrome. The hearing loss that occurs in Pendred syndrome or in isolation as DFNB4 is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2.5 turns is replaced by a hypoplastic coil of 1.5 turns. Campbell et al. (2001) found mutations in 5 of 6 multiplex families with EVA (83%) and in 4 of 5 multiplex families with Mondini dysplasia (80%), implying that mutations in the SLC26A4 gene are the major genetic cause of these temporal abnormalities. In their analyses of Pendred syndrome and DFNB4, they found that the 2 most common mutations, T416P (605646.0006) and IVS8+1G-A (605646.0007), were present in 22% and 30% of families, respectively. Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder.
Fraser (1965) estimated the frequency in the British Isles to be about 0.000075.
Pourova et al. (2010) screened the SLC26A4 gene in 303 Czech patients with early-onset hearing loss. The patients were divided into 3 groups: ... Fraser (1965) estimated the frequency in the British Isles to be about 0.000075. Pourova et al. (2010) screened the SLC26A4 gene in 303 Czech patients with early-onset hearing loss. The patients were divided into 3 groups: 22 with EVA and/or Mondini malformation on imaging, 220 patients without imaging available, and 61 patients with EVA/Mondini-negative imaging studies. Biallelic SCL26A4 mutations were found in 6 (27.3%) patients in the first group, 2 (0.9%) patients in the second group, and none (0%) in the third group; 4 of the 8 patients with biallelic mutations had goiter, consistent with Pendred syndrome. Monoallelic SLC26A4 mutations were found in 3 (13.6%) patients in the first group, 12 (5.5%) patients in the second group, and 3 (4.9%) patients in the third group. The most frequent mutations were V138F (605646.0024) and L445W (605646.0018), in 18% and 8.9% alleles, respectively. Among 13 patients with bilateral EVA, 6 (46%) carried biallelic mutations. No biallelic mutations were found in EVA-negative patients, but 4.9% had monoallelic mutations. Overall, biallelic mutations were found in only 2.7% of all patients, but were more common in familial cases. The findings also suggested that a single SLC25A4 mutation may contribute to the phenotype, perhaps in concert with mutations in other genes.