Molecular and genetic features of primary hyperparathyroidism in young patients

Abstract

When primary hyperparathyroidism (PHPT) is diagnosed in a young patient in the absence of other clinical manifestations differential diagnosis between a sporadic form of PHPT and PHPT as the first manifestation of one of hereditary syndromes may be challenging. Diagnosis of sporadic or hereditary PHPT determines the extent of surgical intervention, a strategy for further observation and treatment, and the need for examination and treatment of first-degree relatives. Aim of the study — to determine genetic characteristics of PHPT with manifestation at a young age (<40 years old) with clinically sporadic PHPT and familial isolated hyperparathyroidism (FIHP).Material and methods. 40 patients with manifestation of PHPT at the age younger than 40 years, 4 of which with FIHP, were included in the study. In 11 patients Sanger sequencing of MEN1 gene was performed (ABI 3130 Genetic Analyser, «Applied Biosystems», USA). 37 patients underwent next-generation sequencing (NGS) (Ion Torrent PGM, Thermo Fisher Scientific — Life Technologies, USA) using a panel of candidate genes (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). Results. In 3 (7,5%) patients (1 of which with FIHP) we revealed germline heterozygous mutations in MEN1 gene: in exon 9 p.D418N, exon 3 p.R176Q, intron 3 с.654+1G>A. In 4 (4/40, 10%) patients we revealed germline heterozygous mutations in CDC73 gene: 3 nonsense mutations in patients with parathyroid carcinoma — in exon 3 p.R91X, exon 6 p.Q166X, exon 7 p.R229X, and 1 missense mutation in a patient with parathyroid hyperplasia in exon 8 p.R263C. Conclusions. In the majority of cases (75%) PHPT in young patients without positive family history is sporadic. Search for germline mutations in the genes, leading to development of hereditary forms of PHPT (first of all in MEN1 and CDC73), is appropriate in young patients with positive family history, or when positive family history may be suspected, and in patients with parathyroid carcinoma. In the majority (75%) of FIHP cases search for other, probably yet unknown, genes is necessary.

Multiple Metastases of Parathyroid and Papillary Thyroid Carcinoma in a Female Patient Treated with Long-Term Hemodialysis

“…Parathyroid cancer is typically sporadic, and much less common in the framework of hereditary syndromes. It mainly develops as part of the hyperparathyroidism-jaw tumor syndrome (HPT-JT), in which the incidence of cancer is as high as 15–37.5% [ 29 , 30 , 31 ]. Isolated clinical cases of parathyroid cancer have been described in patients with MEN-2A [ 32 , 33 , 34 ] and familial isolated primary hyperparathyroidism (FIHP) [ 35 , 36 ].…”

Hereditary syndromal and nonsyndromal forms of primary hyperparathyroidism

“…во 2−4-й декадах жизни, чаще в возрасте 20−25 лет), хотя описаны как более ранние (с развитием клинической симптоматики в возрасте 8 лет и биохимической -до 6 лет жизни), так и значительно более поздние (в 81 год) манифестации; не имеет гендерных различий [4,19]. Результаты исследований российской популяции демонстрируют смещение дебюта заболевания на 3−4-ю декаду жизни [20,21]. Первичный гиперпаратиреоз при МЭН-1 характеризуется полигландулярным поражением, причем опухоли не всегда развиваются синхронно, что обусловливает высокую частоту послеоперационных рецидивов заболевания (до 50% в течение 12 лет после паратиреоидэктомии) [22].…”