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Evaluation of Genotype–Phenotype Relationships in Patients Referred for Endocrine Assessment in Suspected Pendred Syndrome

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Evaluation of Genotype–Phenotype Relationships in Patients Referred for Endocrine Assessment in Suspected Pendred Syndrome L M Soh and others Perchlorate discharge test in 172:2 217–226 Clinical Study Pendred syndrome Evaluation of genotype–phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome Lip Min Soh1, Maralyn Druce1, Ashley B Grossman1,2, Ann-Marie Differ3, Liala Rajput4, Maria Bitner-Glindzicz5,6 and Ma´ rta Korbonits1 1Department of Endocrinology, Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK, 2Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK, 3North East Thames Regional Genetics Correspondence Service Laboratory and 4Department of Audiovestibular Medicine, Great Ormond Street Hospital for Children NHS should be addressed Foundation Trust, London WC1N 3JH, UK, 5Clinical and Molecular Genetics Unit, UCL Institute of Child Health, to M Druce London WC1N 1EH, UK and 6Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Foundation Email Trust, London WC1N 3JH, UK [email protected] Abstract Design: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit. Methods: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status. Results: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with O30% discharge developed hypothyroidism. In our cohort, c.626GOT and c.3-2AOG result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4–15%) compared with 40% European Journal of Endocrinology (interquartile range 21–60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT !30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (RZ0.61, PZ0.0009) and the age of onset of hypothyroidism (RZK0.62, PZ0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P!0.001). Conclusion: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge O30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring. European Journal of Endocrinology (2015) 172, 217–226 Introduction From the first description by Pendred in 1896 to the large protein pendrin. Over the last few decades, diagnostic series by Fraser in 1965 (1), the diagnosis of Pendred procedures have evolved considerably with the introduc- syndrome was based on the clinical triad of deafness, tion of the perchlorate discharge test (PDT) (3) and genetic goitre and thyroid dysfunction due to an iodide organifi- testing. Today, the vast majority of patients are identified cation defect. In 1997, the disease-causing gene was in infancy or childhood due to hearing impairment, and identified as SLC26A4 (2) (solute carrier family 26 (anion the detection of enlarged vestibular aqueducts (EVA) on exchanger), member 4), coding for the anion transporter CT scan leads to genetic testing for biallelic mutations www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0679 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 12:17:07AM via free access Clinical Study L M Soh and others Perchlorate discharge test in 172:2 218 Pendred syndrome of the SLC26A4 gene. Approximately, 180 mutations have of thyroid on the basis of phenotype, between 2004 and been reported (http://www.healthcare.uiowa.edu/labs/ 2012. The inclusion criteria were as follows. All patients had pendredandbor/slcMutations.htm), which include mis- pre-lingual deafness, or apparently postlingual, but sense, nonsense, splice site, and frameshift mutations, as progressive hearing impairment; 46 also had EVA/ well as partial gene deletions (4, 5). Mutations in FOXI1 (6) endolymphatic sacs on CT/MRI scanning. Of the remaining and KCNJ10 (7) mutations have also been implicated four subjects, all had other reasons for suspecting in some cases of Pendred syndrome, although their role, if Pendred syndrome: two were hypothyroid with hearing any, is likely to be minor (8, 9). loss, and the other two subjects were deaf siblings, one Clinically, thyroid hormone abnormalities and of whom had a goitre, whose parents were first cousins. As a development of goitre have incomplete penetrance and real-world study, all patients referred for evaluation of these may occur in later life, the variability may be partly criteria were included in the assessment and analysis of accounted for by fluctuations in iodine deficiency in the results. As part of routine clinical evaluation, all patients region (10, 11). Phenocopies (co-incidental hearing were assessed clinically, biochemically (free thyroxine4, impairment and thyroid dysfunction/goitre not due to thyrotrophin (TSH) and thyroid peroxidase (TPO) Pendred syndrome) have also been described (12, 13). antibodies), and also had undergone genetic analysis of Recently, atypical presentation with thyroid dysgenesis the SLC26A4 gene. Eighty percent of the patients (40 of 50 has also been associated with SLC26A4 mutations in a few patients) agreed to undergo a PDT. Patients found to have patients (14). A number of studies have investigated the biallelic mutations were monitored annually for thyroid correlation of the clinical phenotype and genetic back- hormone levels and goitre development, which was ground (15, 16, 17, 18, 19), but the necessity of PDT for classified as large, moderate, small or none, based on clinical diagnostic purposes remains unclear. examination by their regular endocrine physician. The With these uncertainties, individuals suspected to goitre size was noted in the clinical notes reviewed retro- have Pendred syndrome often undergo a combination of spectively for the purpose of this study. Ultrasound genetic analysis and PDT, and if either result is abnormal, scanning of the thyroid was not routinely used for they are subjected to lifelong monitoring for thyroid evaluation due to the lack of indications for this. dysfunction, which involves annual clinical assessment and examination as well as thyroid function tests. Genetic analysis Anecdotally, physicians looking after such patients note that these seemingly innocuous investigations may result All patients gave consent for genetic testing. Genomic European Journal of Endocrinology in significant psychological distress in this young DNA of patients was extracted from peripheral blood by population group. standard methods. Patients in whom a single mutation We conducted a retrospective analysis of patients was identified all had complete bidirectional exon referred to our institution for suspected Pendred syn- resequencing (see Supplementary Table 1 and Methods, drome. The aim of the study was to address a number of see section on supplementary data given at the end of this hypotheses. Namely that genetic analysis would be article) using the ABI PRISM Big Dye Terminator Cycle sufficient to confirm the diagnosis of Pendred syndrome Sequencing Ready Reaction Kit (Applied Biosystems, and that PDT may not be an essential evaluation for the Branchburg, NJ, USA). Exon resequencing was performed diagnosis of all individuals suspected of having Pendred on all samples with a total reaction volume of 20 ml, syndrome but that it may play a role in understanding consisting of 0.5 ml genomic DNA (ca. 250 mg/ml), 19 ml thyroid prognosis. We also aimed to evaluate any Megamix (Microzone Ltd, Hayward Heath, UK) and 0.5 ml genotype–phenotype correlation for thyroid dysfunction of primer mix containing 10 pmol/ml forward and reverse in Pendred syndrome. primers. All exons were amplified using the Peltier thermal cycler (Bio-Rad tetrad 2 DNA engine) and PCR was performed under the following conditions: denaturation Patients and methods at 95 8C for 3 min (95 8C!30 s, 65 8C!30 s, and 72 8C! 45 s) with decrease in annealing temperature by about 1 8C Patients for further 14 cycles (95 8C!30 s, 50 8C!30 s, and 72 8C! We conducted a retrospective analysis of 50 patients 45 s), for 20 cycles, followed by final extension at 72 8C for (27 females and 23 males) with suspected Pendred syn- 5 min. All forward and reverse primers had a tailed drome, referred to our university hospital for the evaluation sequence at the 50 of the primer for automated Sanger www.eje-online.org Downloaded from Bioscientifica.com at 09/25/2021 12:17:07AM via free access Clinical Study L M Soh and others Perchlorate discharge test in 172:2 219 Pendred syndrome sequencing. The sequence was analysed on an ABI3730 in SLC26A4, 11 had a monoallelic mutation, while six had Genetic Analyser (Applied Biosystems) using standard no detectable mutations. As all 50 patients had been protocols. The data were collated using Foundation
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