ISSN Objective : To present a clinical case of Pendred syndrome, a rare pathology in children that includes congenital deafness and goiter. Clinical case : Preschool female 5 years and 4 months of age, whose mother refers disease of 3 months of evolution characterized by progressive increase in volume of the anterior neck, without redness, heat, or pain; concomitantly drowsiness, constipation and hypoactivity. Physical Examination: Weight
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Alternative titles; symbols. There is evidence that Pendred syndrome may also rarely be caused by digenic inheritance of a heterozygous mutation in the SLC26A4 gene and a heterozygous mutation in the FOXI1 gene 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. For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 A mild type of organification defect is associated with congenital deafness.
Their thyroids are moderately enlarged from childhood. Patients are usually euthyroid, although an exaggerated response to thyrotropin-releasing hormone TRH; suggests a compensated hypothyroidism Gomez-Pan et al. Massa et al. Thyroid carcinoma has been observed Thieme, ; Elman, ; Milutinovic et al.
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. Illum et al. 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, In 1 patient, histologic examination showed a Mondini type malformation of the cochlea i.
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. There appear to be different varieties of Pendred syndrome, because Hollander et al. Milutinovic et al.
On the other hand, Medeiros-Neto et al. Desai et al. Fraser raised the question of whether the organification defect without deafness, as described by Stanbury and Hedge and later by Furth et al. 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. 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; 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 Phelps et al. 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.
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 -deficient knockout mice had been reported to develop overt acid-base disturbances, such as metabolic alkalosis. Royaux et al. 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.
McKusick noted a possible relationship between progression of deafness and the occurrence of trauma. Lesions in the organ of Corti have been produced in the chick and rat by administration of propylthiouracil during embryogenesis. The lesion did not occur when thyroxine was given with the antithyroid drug Bargman and Gardner, Sheffield et al. Therefore, the possibility of a circulating inhibitor of organification had not been previously excluded.
By measuring the major steps of thyroid hormonogenesis simultaneously in cryopreserved cultured cells from Pendred patients, Sheffield et al. Furthermore, they found that the magnitude of the organification defects was similar to the decrease in T3 secretion, suggesting that in Pendred syndrome patients iodide organification may be the rate-limiting step in thyroid hormone secretion. Taylor et al. Transient expression of green fluorescent protein-tagged pendrin mutant constructs in mammalian cell lines demonstrated appropriate trafficking to the plasma membrane for only 2 mutants.
The remaining SLC26A4 mutants appeared to be retained within the endoplasmic reticulum following transfection. Iodide efflux assays were performed. The results indicated loss of pendrin iodide transport for all mislocalizing mutations.
However, SLC26A4 mutants are associated with variable thyroid dysfunction in affected subjects. 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. 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. One perchlorate discharge test was false-negative 2.
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. 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. 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. Fraser estimated the frequency in the British Isles to be about 0.
Pourova et al. Biallelic SLC26A4 mutations were found in 6 Monoallelic SLC26A4 mutations were found in 3 The most frequent mutations were VF No biallelic mutations were found in EVA-negative patients, but 4. Overall, biallelic mutations were found in only 2. The findings also suggested that a single SLC25A4 mutation may contribute to the phenotype, perhaps in concert with mutations in other genes.
Van Wouwe et al. The father carried a de novo balanced translocation between 8q and 10p: t 8;10 q24;p The authors raised the possibility that Pendred syndrome maps to 8qqter.
It should be noted that the structural gene for thyroglobulin is in this segment. Although the proposita had deafness and hypothyroidism consistent with Pendred syndrome, as well as a marked reduction of I uptake on perchlorate test, is it possible she has a thyroglobulin synthesis defect such as that discussed in and that the deafness has other cause?
By linkage studies, Gausden et al. This confirmed that at least 1 further step is required for complete organification of iodide within the thyroid.
Observations that when both parents are affected there was no complementation for the disease phenotype suggested homogeneity. Coyle et al. However, they did find significant linkage to the DFNB4 locus located on 7q Twelve families with 2 or more affected individuals with Pendred syndrome were studied. They mapped the locus to an approximately 9-cM interval on chromosome 7 in the 7qq34 region.
Gausden et al. Coucke et al. For a more complete discussion of the molecular genetics of Pendred syndrome, see the entry for the SLC26A4 gene Everett et al. In PDS families, Everett et al. They considered it likely that the DFNB4 individuals reported actually have Pendred syndrome, rather than mutations in another 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 delT mutation; 3 were heterozygous and 3 were homozygous for the wildtype allele, suggesting a probable distinct genetic cause for their deafness.
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. 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.
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.
Campbell et al. Park and Chatterjee 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. Tsukamoto et al. None of their patients had the Mondini malformation. Pryor et al.
Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. A syndromic genetic deafness clinically variable characterized by bilateral sensorineural hearing loss and euthyroid goiter. Pendred syndrome PDS is one of the most frequent forms of syndromic genetic deafness. Although precise prevalence is unknown, PDS may account for up to 7. Considerable phenotypic variability is found even within families.
Pendred syndrome is an autosomal recessively inherited disorder characterized by a euthyroid goiter associated with sensorineural hearing loss. There is an autosomal recessive pattern inheritance, although this appears complex with most patients being compound heterozygotes. Inner ear malformations are an invariable finding in Pendred syndrome. The most commonly described features are the following 1 :.