Endocrine Abstracts

Objective

Primary hyperparathyroidism (PHPT) is a common endocrine disorder affecting 2% of the population aged 55 years or older. Primary hyperparathyroidism is due to parathyroid adenoma in about 85% of cases, parathyroid hyperplasia in about 15% of cases, and parathyroid carcinoma in less than 1% of cases. Familial parathyroid disorders are responsible for 10% of the PHPT cases and include among other disorders caused by parafibromin malfunction. Parafibromin is a tumour-suppressor protein that regulates apoptosis, cell-cycle transition, grow factor gene expression and tumour-associated wingless-type (Wnt) pathway. The loss of parafibromin tumour-suppressor function is associated with parathyroid tumours. Parafibromin is coded by gene CDC73 (cell division cycle 73, previously HRPT2). Immunohistochemical assay of parafibromin has limited validity, therefore it is recommended molecular-genetic analysis of the gene CDC73. The spectrum of disorders associated with mutations of the gene CDC73 includes such phenotypes: HPT-JT syndrome (hyperparathyroidism-jaw tumor syndrome), isolated familial hyperparathyroidism and parathyroid carcinomas. Here, we are presenting a case of a family with primary hyperparathyroidism, which was manifested by adenomas of the parathyroid gland for most members of the family. Associated comorbidity in 4 members of the family was an essential tremor.

Methods

Molecular-genetic analysis of 17 genes from DNA obtained from peripheral blood leukocytes (Parathyroid NGS panel, Endocrinological institute): AIP; AIRE; AP2S1; CASR; CDC73; CDKN1A; CDKN1B; CDKN2B; CDKN2C; GATA3; GCM1; GCM2; GNA11; MEN1; PTH; RET; STX16 and then examination of segregation of causal mutation in 14 family members (3 generations).

Results

Causal mutation of the gene CDC73 was detected. It is a deletion of 4 nucleotides NM_02 4529.4:c.520_523delTCTG; p.(Ser174LysfsTer27) in 7th exon, which causes premature stop of parafibromin synthesis in 200th amino acid.

Conclusion

Disorders associated with CDC73 are autosomal dominant inherited. The mutation is inherited from the affected parent with a 50% probability or arises de novo. Patients with CDC73 associated disease should be observed by an endocrinologist in regular terms. It includes an annual examination of PTH and calcium levels, dental examination and periodic ultrasound of the pelvis and kidneys.