Учебники / Genetic Hearing Loss Willems 2004

ification defect. Computed tomography (CT) scanning of the temporal bones was performed on 3 a ected family members and one una ected member; the a ected individuals all were found to have enlarged vestibular aqueducts and normal cochleae, while the una ected member had no anatomical abnormalities. A ected family members were homozygous for two missense mutations in PDS exon 13, G497S and I490L. Scott et al. found PDS mutations in 3 of 20 (15%) patients with enlarged vestibular aqueducts and nonsyndromic deafness (17).

VIII. PERCHLORATE TEST

Owing to the lack of sensitivity and specificity of goiter or thyroid function tests as diagnostic criteria for Pendred syndrome, the perchlorate discharge test has emerged as the evaluation of choice to detect the underlying iodine organification defect (3,58). The thyroid glands of a ected individuals show normal uptake of orally administered radioiodine from the bloodstream, but fail to organify iodine at a normal rate. The perchlorate discharge test is used to measure this defect (3). A dose of radiolabeled iodine is administered and the radioactivity over the thyroid is measured and used as a baseline. Potassium perchlorate is then administered. This allows unincorporated iodide to di use back into the circulatory system. Serial measurements of thyroid radioactivity are used to calculate the percentage of iodine that is discharged from the gland. In a normal thyroid, organification is rapid and less than 10–15% of the radioiodine is washed out, whereas a greater amount (usually more than 20–30%) of radioiodine is released from the glands of Pendred syndrome patients.

Although the perchlorate test has been a useful adjunct to the clinical and molecular diagnosis of Pendred syndrome, there are problems with its use. First, there are no well-established normative data and the criterion for a positive discharge result varies among investigators. Most investigators consider any discharge above 10% as abnormal (32,42,55,59,60), but other studies have used 15% (17,30,39,61,62) or even 20% (37) as the upper limit of normal. Another problem is that a positive discharge result is not specific for Pendred syndrome: abnormally high discharge is also observed in Hashimoto’s thyroiditis, thyrotoxicosis treated with 131I, cretinism, and peroxidase deficiency (3,39,61,63). Rigorous medical histories, physical examinations, and the appropriate laboratory evaluations must rule out these potential causes of an abnormally high discharge result. Furthermore, false negative results may occur when initial thyroid uptake is low (61). Finally, potential e ects of di erences in perchlorate dosage or the size of patients (especially children) on the discharge response have not been

systematically analyzed. In toto, these caveats and potential pitfalls dictate that perchlorate discharge studies be interpreted cautiously.

It is not clear that deafness and goiter associated with PDS mutations are always associated with a positive perchlorate test result. Masmoudi et al. reported two large families cosegregating Pendred syndrome and the L445W mutation, but all of the a ected homozygotes that were tested had negative (<3%) perchlorate tests, while goiter varied (56). Other studies have concluded that the perchlorate discharge phenotype does not correlate with the size or presence of goiter, underlying PDS genotype, or temporal bone anatomy. The results may also vary with time; Stinckens et al. reported two perchlorate discharge tests performed 5 years apart on the same patient (at ages 9 and 14) in which the results were 27% and 63% discharge (64). This apparent variability of the perchlorate discharge test may reflect one or more of the confounding factors discussed above, especially since few medical centers routinely administer the test (5) and variations in technique and interpretation are almost certainly a problem. Other obstacles to performing the perchlorate test include the di culty of administration in young children and the necessity to discontinue any thyroid medications 4–6 weeks before testing (3).

IX. PHENOTYPIC VARIABILITY

Thyroid phenotypic variability in Pendred syndrome is significant and might be due to any one or a combination of environmental factors (e.g., longterm thyroid hormone replacement therapy, dietary iodine intake), concomitant thyroid disorders, genetic background, stochastic variation, underlying PDS mutant genotypes, or di erences in ascertainment. The last factor is especially problematic in evaluating and comparing the results of di erent studies of goiter or perchlorate discharge test results for the reasons previously discussed. The literature indicates that there is wide intraand interfamilial variability of the thyroid phenotype, whether the phenotype is defined as goiter or as an abnormal perchlorate discharge result. Some of this variability may be attributed to undetected phenocopies or di erences in the administration and interpretation of the perchlorate discharge test. If the criterion of 10 or 15% for an abnormal discharge is too low (which is very likely), many of the individuals with a reported abnormal perchlorate discharge will be false positives. Unfortunately, few published studies report actual percent discharge, thus prohibiting a critical retrospective analysis of their results.

Some splice site mutations or mutations that create cryptic splice sites have been reported to be associated with wide variability in both the thyroid

and auditory phenotypes, suggesting that the observed variability is not simply due to di erences in ascertainment of the thyroid phenotype. LopezBigas et al. hypothesized that variability in processing of mutant PDS mRNA transcripts among di erent individuals may account for the observed phenotypic variability (44).

While numerous authors have suggested the possibility of a genotypephenotype correlation in Pendred syndrome (10,30,45,65), the significant interand intrafamilial variability of the thyroid phenotype among individuals segregating the same mutations (including those that do not a ect splice sites) indicates that any such correlation will be extremely di cult to demonstrate (30,37,39,44,48). As alluded to earlier, correlation of PDS genotype with the auditory phenotype may be more straightforward since auditory status is not as complicated by phenocopies and a lack of normative data. However, there are still no data to suggest that the hearing loss phenotype is correlated with the underlying PDS mutation, as any potential correlation may be obscured by intrafamilial variation of both auditory functional and radiological phenotypes.

A functional study of anion transport by PDS mutant allele products has been valuable toward confirming the pathogenic nature of a few PDS mutations. These investigators extrapolated their data to hypothesize a correlation of the anion transport phenotype with the thyroid phenotype (17). Scott et al. used a Xenopus oocyte expression system to evaluate the iodide and chloride transport function of various mutant pendrin products modeled on known human mutations. T416P, L236P, and E384G were considered to be mutations associated with classic Pendred syndrome (with goiter), while I490L, G497S, V480D, and V653A were considered to be associated with nonsyndromic deafness. The authors observed that the former group of mutations abolished anion transport, whereas the latter group of mutations reduced, but did not eliminate, activity. They concluded that functional null alleles cause deafness plus goiter, whereas hypomorphic alleles cause deafness without goiter.

However, the pathogenic nature of at least one of the putative nonsyndromic alleles (e.g., V653A) is unclear since it is a nonconservative substitution observed in a single heterozygote, and may simply be a benign polymorphism. Furthermore, reduced but detectable transport activity is not proof of pathogenicity and may reflect normal polymorphic variation of functional activity (66). The high degree of variation of thyroid phenotype and the problems associated with its ascertainment currently prevent any conclusions to be drawn about its correlation with the underlying PDS genotype and anion transport function. Attempts to correlate thyroid phenotype with PDS genotype should only be made if and when specific

mutant alleles are rigorously shown to be uniformly and commonly associated with either Pendred syndrome or nonsyndromic deafness.

X.PHENOTYPE: INNER EAR ANATOMY

Gross malformations of the inner ear have long been known to be associated with Pendred syndrome. Hvidberg-Hansen and Jorgensen, in their 1968 case report of a patient with Pendred syndrome (67) described the histological findings of enlarged vestibular aqueduct, enlarged endolymphatic duct and sac, incomplete partition of the apical turn of the cochlea, deficient modiolus, and vestibular malformation in a patient with Pendred syndrome. This constellation of abnormalities is often referred to as a ‘‘Mondini deformity,’’ and it is essentially identical to the combination of malformations originally described by Mondini in 1791. Some authors use the Mondini eponym to describe any inner ear with an incomplete partition of the cochlea. A larger series of histological findings in five Pendred patients was published by Johnsen et al. in 1986; all were found to have Mondini malformations (68). Similarly, Illum et al. found that seven of 15 Pendred syndrome patients had cochlear partition defects on conventional tomographic examination (61). In 1989, Johnsen et al. demonstrated that CT scanning is more sensitive than conventional tomography at detecting the Mondini malformation, and found Mondini malformations in all of five Pendred syndrome patients imaged by CT scan (69).

While the full Mondini defect is observed in the ears of many Pendred syndrome patients, it is not universally present. Enlargement of the vestibular aqueducts (EVA) is a much more sensitive radiological marker for Pendred syndrome that can be detected by CT scanning or MRI scanning (38,41,47,48), although it is actually the soft tissue and fluid contents of the vestibular aqueduct (the endolymphatic duct and sac) that are visualized by MRI (Fig. 1). The vestibular aqueduct is considered enlarged when its diameter exceeds 1.5 mm at the midpoint between the posterior cranial fossa and the vestibule of the inner ear (49). Of a series of 40 Pendred syndrome patients examined by CT and MRI, Phelps et al. identified enlarged vestibular aqueducts in 31 of 40 imaged by CT and enlarged endolymphatic sacs and ducts in all of 20 imaged by MRI (48). The identification of EVA as a highly penetrant radiological marker for Pendred syndrome was an important observation since it identified temporal bone imaging as a much more sensitive modality for the ascertainment of Pendred syndrome.

Reardon et al. evaluated a series of 57 patients with enlarged vestibular aqueducts and found PDS mutations in 86% (38). Although EVA is a reliable

Figure 1 Images of right temporal bone demonstrating enlarged vestibular aqueduct (arrows). (left panel) MRI scan showing enlarged endolymphatic sac and duct. Fluid-filled spaces are light and bone and soft tissues dark. (right panel) CT scan showing enlarged vestibular aqueduct. Bone is white and fluid and air-filled spaces are black.

marker for PDS-related deafness, it is not pathognomonic. In addition to its occurrence in nonsyndromic deafness and Pendred syndrome, EVA has been reported for a few patients with branchio-oto-renal syndrome (70) caused by mutations in the EYA1 locus, deafness-oligodontia syndrome (71), and deafness associated with the recessive form of distal renal tubular acidosis (72). Although there are no reports of nonsyndromic deafness phenotypes allelic with any of these three syndromes (36), it is possible that mutant alleles at these loci may contribute to some cases of nonsyndromic hearing loss associated with EVA.

A causal relationship of EVA to hearing impairment has not been established; initially it was believed that the enlarged endolymphatic system transmits otherwise benign pressure fluctuations with reflux of endolymphatic sac contents from the posterior fossa to the inner ear (73). However, there is little evidence to support this theory, as obliteration of the endolymphatic sac and duct do not reverse or even prevent further hearing loss in patients with EVA (74). It is more likely that hearing loss is due to a defect in endolymph homeostasis or, in some cases associated with classical Mondini deformities, perilymph fistulae. Sudden drops and fluctuation of hearing may also be caused by intrascalar fistulae with mixing of endolymph and perilymph, a hypothesis that is suggested by the high degree of endo-

lymphatic hydrops observed in pds / mice (24). Finally, some have suggested that EVA may represent an arrest in normal development at about 7 weeks of human gestation (61) but this is not likely to be the case. The size of the vestibular aqueduct in EVA is larger than a normal VA at any stage of its development. Anatomical evidence from the pds / mice further argues against the theory of arrested development, as pds / mice initially have a normal inner ear anatomy, and then develop dilatation (24). This indicates that other causes of EVA may also be due to perturbations of endolymph pH, ionic, or osmotic homeostasis. Identification of these other etiologies, especially mutant genetic loci, may further elucidate the molecular pathways of homeostasis in the auditory system.

XI. DIAGNOSIS AND MANAGEMENT

The diagnosis of Pendred syndrome is not always straightforward. History and physical examination can be very suggestive, but not diagnostic. When a patient presents with prelingual sensorineural hearing loss with or without goiter, CT or MRI scanning should be included whenever possible as part of the initial evaluation. The presence of EVA or a Mondini malformation should trigger further investigation into the possibility of Pendred syndrome.

Ultrasound measurement of thyroid volume can be helpful in the detection of subtle goiters. Although problems exist with its interpretation, the perchlorate discharge test, when positive, can be a useful adjunct in detecting a thyroid organification defect before goiter appears. Molecular testing of PDS is currently available; any PDS screening should ideally include all coding regions, given the lack of a single predominant mutation or mutated exon and the ethnic variability of PDS mutations. Vestibular testing should be performed when clinically indicated, but is not often useful in distinguishing Pendred syndrome from other entities.

Management of patients with Pendred syndrome should focus first on rehabilitation. Amplification can be helpful when deafness is not profound. Patients should be cautioned to avoid minor head injuries and barotrauma, which may cause additional hearing loss. Those with Mondini malformations should also be informed of the possible increased susceptibility to meningitis. Patients with EVA have undergone cochlear implantation with good results (75). Ears with EVA may have a higher risk of mild CSF leaks upon cochleostomy, but these seem to be easily controlled without longterm sequelae (75). Endolymphatic sac obliteration and shunting have led to worsened hearing and are contraindicated in these patients (73,74).

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