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

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


J Clin Endocrinol Metab. 2017;102(12):4534-4540. 

In This Article

Abstract and Introduction


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.


Primary hyperparathyroidism (pHPT) is a common endocrine disease with a prevalence of 1 to 4 per 1000 persons and with a peak incidence in the sixth decade of life.[1] In the majority of cases, pHPT is caused by a single parathyroid adenoma (PA) and in <1% by a parathyroid carcinoma (PC).[2] A genetic predisposition for pHPT can be found in ~10% of pHPT cases. This might be an underestimation because of unavailable, incomplete, or misdiagnosed family history; variable penetrance; or unknown genetic causes. To date, pathogenic variants in at least 11 genes have been found to be associated with hereditary pHPT. The most commonly identified hereditary syndromes associated with pHPT include multiple endocrine neoplasia type 1, 2a, or 4; and CaSR-, GCM2-, and CDC73-related disorders.[3,4] Inactivation of the CDC73 tumor suppressor gene (formerly known as HRPT2 and encoding parafibromin) predisposes heterozygous carriers to a spectrum of conditions: hyperparathyroidism–jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism (FIHP), and PC.

The penetrance of pHPT in CDC73-related disorders has been reported to be as high as 80% to 95%.[5] The onset is typically in late adolescence or early adulthood, although patients younger than 10 years of age have also been reported.[6,7] PC may be found in >20% of patients with germline pathogenic CDC73 variants, which is higher than in other hereditary pHPT syndromes.[5] Distinguishing between PA, atypical adenoma, and PC remains a challenge given the lack of specific differentiating clinical, biochemical, and histological features among these pathologies. However, the latter is of the utmost importance because it determines the extent and radical nature of initial surgery, which is in turn the major determinant of prognosis.[5]

In addition to pHPT, patients with CDC73-related disorders are predisposed to developing ossifying fibromas of the mandible and/or maxilla, uterine tumors (e.g., adenofibromas, leiomyomas, adenomyosis, hyperplasia, adenosarcomas) and less frequently, a variety of malignant and nonmalignant renal lesions [e.g., Wilms tumor, clear cell renal carcinoma (RCC), papillary renal cell tumor, renal cysts].[5]

In total, about 100 index CDC73 mutation carriers have been reported to date, with no clearly identified phenotype-genotype relationship.[5] The majority of germline (and somatic) pathogenic CDC73 variants are frameshift and nonsense variants, although missense variants as well as (small) deletions and insertions have been reported.[7–9]

Limited data are available on the germline CDC73 mutation detection yield in patients with HPT-JT syndrome, FIHP, and PC. In this study, we performed a nationwide evaluation of germline CDC73 analyses undertaken in pHPT patients in the Netherlands and characterized the clinical manifestations and penetrance of 12 families with CDC73-related disorders.