Clinical And Genetic Analysis Of Familial/syndromic Primary Hyperparathyroidism In Chinese

ObjectivePrimary hyperparathyroidism (PHPT) is mostly sporadic, and10%of cases are related to familial or syndromic forms (fPHPT/synPHPT). Clinically, it is important to identify the genetic background, because the management of each syndrome may differ. The aim of the present study was to analyze the clinical, genetic and protein expression characteristics of fPHPT/synPHPT.Subjects and Methods1. Eleven fPHPT families and27sporadic multiple endocrine neonplasia typel (MEN1) patients were retrospectively analyzed in this study.2. Genetic analysis:(1) Direct sequence of the MEN1, RET, CDKN1B, CDC73or CaSR gene was conducted selectively.(2) Reverse transcription PCR (RT-PCR) was used to study the effect of splice site mutations.(3) Quantitative real-time PCR (qRT-PCR) and multiplex ligation-dependent probe amplification (MLPA) were used to detect gross deletion mutations of CDC73and MEN1gene respectively.3. Immunohistochemistry (IHC) was performed to analyze Parafibromin or Menin expression in parathyroid tumors.4. Genotype-phenotype correlations were assessed through clinical characteristics and long-term follow-up data.Results1. Genetic analysis revealed that three familial isolated primary hyperparathyroidism (FIHPT) families and one hyperparathyroidism-jaw tumors syndrome (HPT-JT) family were all caused by CDC73mutations, including two novel mutations and one gross deletion mutation detected by qRT-PCR. Clinical analysis of these ten CDC73related fPHPT patients revealed that the median age at diagnosis of PHPT was21y, male/female ratio was1:1,7cases was uniglandar involvement (70%), parathyroid carcinoma (PC) presented in1cases (10%), and recurrent/persistent rate was50%(5cases). IHC analysis demonstrated complete or partial loss of nuclear Parafibromin expression in CDC73related parathyroid tumors.2. Genetic analysis revealed27mutations of MEN1gene in MEN1patients (79.4%). Nine of them were novel. One gross deletion mutations was detected by MLPA. Clinical analysis of forty MEN1related PHPT (MHPT) patiens was performed. The mean age at diagnosis of PHPT was45.0±14.0y. The male/female ratio was1:2.1.The mean serum calcium, plasma ionic calcium and serum phosphate levels were was2.87±0.24mmom/L,1.40±0.18mmom/L and0.83±0.14mmom/L, respectively. The median level of PTH levels was237.0pg/mL (Q25:150.0, Q75:428.0pg/mL). The main clinical manifestations of PHPT included urolithiasis (60.0%) and skeletal disorders (57.5%).58.3%of the cases were multiglandular involved. Parathyroid hyperplasia (PH) presented in54.1%cases. The recurrent/persistent rate was41.2%. No definite genotype-phenotype correlations were found in this study. IHC analysis demonstrated complete or partial loss of nuclear Menin expression in MEN1related parathyroid tumors.Conclusion1. This is the largest study about fPHPT/synPHPT in Chinese and the first report of Chinese HPT-JT syndrome and FIHPT families caused by CDC73mutations. fPHPT/synPHPT is characterized by early onset age and high recurrent/persistent rate.2. In addition, CDC73related fPHPT is mainly uniglandular involved with high risk of PC, minimally invasive parathyroidectomy is appropriate option for CDC73related fPHPT unless PC is suspected. Multiglandular involvement and PH are more common in MHPT, among which subtotal parathyroidectomy or total parathyroidectomy is recommended.3. Four CDC73mutations (two are novel) and27MEN1mutations (nine are novel) were detected by genetic analysis. The mutation rate in this study is the highest among the congeneric studies till now. Detection of gross deletions of CDC73and MEN1gene reinforces the concept of screening for gross deletion when traditional sequencing can not find positive results in targeted patients.