Karin van der Tuin1, Carli M J Tops2, Muriel A Adank3, Jan-Maarten Cobben4, Neveen A T Hamdy5, Marjolijn C Jongmans6,7,8, Fred H Menko9, Bernadette P M van Nesselrooij7, Romana T Netea-Maier10, Jan C Oosterwijk11, Gerlof D Valk12, Bruce H R Wolffenbuttel13, Frederik J Hes1, Hans Morreau14. 1. Department of Clinical Genetics, Leiden University Medical Center, the Netherlands. 2. Department of Clinical Genetics, Laboratory for Diagnostic Genetic Analysis, Leiden University Medical Center, the Netherlands. 3. Department of Clinical Genetics, VU Medical Center, the Netherlands. 4. Department of Pediatrics, Academic Medical Center, the Netherlands. 5. Center for Endocrine Tumors Leiden, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, the Netherlands. 6. Department of Clinical Genetics, Radboud University Medical Center, the Netherlands. 7. Department of Medical Genetics, Utrecht University Medical Center, the Netherlands. 8. Princess Maxima Center for Pediatric Oncology, the Netherlands. 9. Family Cancer Clinic, Netherlands Cancer Institute, the Netherlands. 10. Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, the Netherlands. 11. Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands. 12. Department of Endocrine Oncology, University Medical Center Utrecht, the Netherlands. 13. Department of Endocrinology, University Medical Center Groningen, the Netherlands. 14. Department of Pathology, Leiden University Medical Center, the Netherlands.
Abstract
Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT. Design: Nationwide retrospective Dutch cohort study. Setting: Tertiary referral center. Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: Germline CDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.
Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT. Design: Nationwide retrospective Dutch cohort study. Setting: Tertiary referral center. Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: Germline CDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.
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