Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated H
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ORIGINAL PAPER
Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia Shafaq Khairi 1 & Jenae Osborne 2 & Michelle F Jacobs 2 & Gregory T Clines 1 & Barbra S Miller 3 & David T Hughes 3 & Tobias Else 1 Received: 13 May 2020 / Accepted: 27 July 2020 / Published online: 5 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Primary hyperparathyroidism (pHPT) is associated with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), 2A (MEN2A), MEN-like syndromes (CDKN1B), and CDC73-related disorder (hyperparathyroidism – jaw tumor syndrome (HPJT)). Familial hypocalciuric hypercalcemia (FHH) caused by CASR variants is an important differential diagnosis for pHPT. In order to evaluate the contribution of hereditary causes to pHPT in patients encountered in a specialized clinic, we conducted a retrospective study on patients with pHPT that underwent germline genetic testing. We evaluated 46 patients referred to a Cancer Genetics Clinic. Reasons for referral were young age (age < 40) for 29 patients (63%), multi-gland disease for 23 patients (50%), and a positive family history of pHPT for 11 patients (24%). All 46 patients underwent genetic evaluation. A total of 11 rare variants were found (CASR (4), CDC73 (2), MEN1 (2) CDKN1B (1), and RET (2)). One MEN1 variant was classified as pathogenic, and all others were variants of uncertain significance (VUS). All patients with CASR variants had clinical features of FHH and were counselled against parathyroidectomy. Both patients with CDC73 variants were counselled about recurrence of pHPT and parathyroid cancer. Neither of the RET variants were MEN2-associated. The CDKN1B variant was regarded as a true VUS and no action was taken. In this study, genetic testing impacted clinical care in 7 (15%) patients. We suggest that all patients < 40 years of age, with multi-gland disease, single gland disease refractory to treatment, and a positive family history for pHPT or associated tumors should be considered for genetic evaluation. Keywords Primary hyperparathyroidism . Genetic predisposition syndromes . Familial hypocalciuric hypercalcemia . Germline variants
Introduction Primary hyperparathyroidism (pHPT) is a common endocrine disorder characterized by elevated or inappropriately normal Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12672-020-00394-2) contains supplementary material, which is available to authorized users. * Tobias Else [email protected] 1
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
2
Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI, USA
3
Department of Surgery, Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA
parathyroid hormone levels and hypercalcemia. Symptomatic pHPT is clinically cha
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