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CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism

van der Tuin, K., Tops, C. M. J., Adank, M. A., Cobben, J-M., Hamdy, N. A. T., Jongmans, M. C., Menko, F. H., van Nesselrooij, B. P. M., Netea-Maier, R. T., Oosterwijk, J. C., Valk, G. D., Wolffenbuttel, B. H. R., Hes, F. J. & Morreau, H., 1-Dec-2017, In : Journal of Clinical Endocrinology and Metabolism. 102, 12, p. 4534-4540 7 p.

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  • CDC73-Related Disorders

    Final publisher's version, 607 KB, PDF document

DOI

  • Karin van der Tuin
  • Carli M. J. Tops
  • Muriel A. Adank
  • Jan-Maarten Cobben
  • Neveen A. T. Hamdy
  • Marjolijn C. Jongmans
  • Fred H. Menko
  • Bernadette P. M. van Nesselrooij
  • Romana T. Netea-Maier
  • Jan C. Oosterwijk
  • Gerlof D. Valk
  • Bruce H. R. Wolffenbuttel
  • Frederik J. Hes
  • Hans Morreau

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.

Original languageEnglish
Pages (from-to)4534-4540
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number12
Publication statusPublished - 1-Dec-2017

    Keywords

  • FAMILIAL ISOLATED HYPERPARATHYROIDISM, JAW TUMOR SYNDROME, PARATHYROID CARCINOMA, GENETIC ANALYSES, HRPT2 GENE, PARAFIBROMIN, MUTATIONS, GERMLINE, CANCER, MANAGEMENT

ID: 51950630