Rare duplication of the CDC73 gene and atypical hyperparathyroidism-jaw tumor syndrome: A case report and review of the literature

Abstract

Background: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients.

Case report: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait.

Conclusion: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.

Keywords: CDC73; HPT-JT syndrome; adenomyosis; rare duplication.

FIGURE 1

Choline PET/CT of proband. PET VCAR found a hyperfixation of posteroinferior right thyroid, well separated from the thyroid lobe, which may correspond to a parathyroid adenoma P3 right (SU VMAX = 3.62). The arrow indicates the right parathyroid lesion in PET/CT (1) and CT (2).

FIGURE 2

Family tree. Apart from the index case and his mother, there is no other history of hyperparathyroidism or symptoms of the HPT‐JT spectrum. The arrow indicates the proband.

FIGURE 3

CDC73 gene germline variation. *A germline mutation was identified in CDC73 gene, which changed codon 230 in exon 7 from valine to glutamine and leads to a frameshift with the appearance of a stop codon. The identification of this mutation is in favor of a HPT‐JT.