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

Context: Heterozygous pathogenic germlinevariants in CDC73 predispose to the development of primary hyperparathyroidism(pHPT) and, less frequently, ossifying fibromaof the jaw and renal and uterine tumors. Clinical information on CDC73- related disordershas so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73- related disordersand 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 germlineCDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: GermlineCDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germlineCDC73 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 disorderswas 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: GermlineCDC73 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 germlineCDC73 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.