Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese

Abstract

ObjectiveMultiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) differs in many aspects from sporadic PHPT (SHPT). The aims of this study were to summarize the clinical features and genetic background of Chinese MHPT patients and compare the severity of the disease with those of SHPT.Design and MethodsA total of 40 MHPT (27 sporadic, 7 families) and 169 SHPT cases of Chinese descent were retrospectively analyzed. X-rays and ultrasound were used to assess the bone and urinary system. Dual energy x-ray absorptiometry (DXA) were performed to measure bone mineral density (BMD). Besides direct sequencing of the MEN1 and CDKN1B genes, multiplex ligation-dependent probe amplification (MLPA) was used to screen gross deletion for the MEN1 gene.ResultsCompared with SHPT patients, MHPT patients showed lower prevalence of typical X-ray changes related to PHPT (26.3% vs. 55.7%, P = 0.001) but higher prevalence of urolithiasis/renal calcification (40.2% vs. 60.0%, P = 0.024). MHPT patients showed higher phosphate level (0.84 vs. 0.73mmol/L, P<0.05) but lower ALP (103.0 vs. 174.0U/L, P<0.001) and PTH (4.0 vs. 9.8×upper limit, P<0.001) levels than SHPT patients. There were no significant differences in BMD Z-scores at the lumbar spine and femoral neck between the two groups. Mutations in the MEN1 gene were detected in 27 MHPT cases. Among the nine novel mutations were novel, one of them involved the deletion of exon 5 and 6.ConclusionsMHPT patients experienced more common kidney complications but less skeletal issues, and a milder biochemical manifestation compared with SHPT patients. MEN1 mutation detection rate was 79.4% and 9 of the identified mutations were novel.

Primary hyperparathyroidism in Chinese children and adolescents: A single‐centre experience at Peking Union Medical College Hospital

“…The relative lower mutation rate of the MEN1 gene in this study compared to previous studies may be due to ethnic differences or incomplete detection of MEN1 mutations. Previous reports have documented that MEN1 mutations may undetected in some patients with clinically diagnosed MEN1; the negative detection rate ranged from 5% to 20% in Western populations and was 21.6% at our centre …”

“…Genomic DNA was extracted from peripheral blood lymphocytes of 24 paediatric patients using the QIAamp blood DNA kit (Qiagen, Hilden, Germany). All coding exons and exon‐intron boundaries of the MEN1 , CDKN1B , CDC73 and CaSR genes and exons 8, 10‐11 and 13‐16 of the RET gene were amplified by polymerase chain reaction (PCR) with primers as previously described . Direct sequencing of PCR products was performed using a TaqBig Dye terminator sequencing kit and an ABI3730 automated sequencer (Applied Biosystems, Foster City, CA, USA).…”

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

“…Until recently, mutations in coding region and splicing sites of MEN1 have been usually investigated by SS complemented by MLPA for large deletions. However, SS presents limitations in the analysis of the MEN1 gene and besides it may not routinely cover the MEN1 non-coding regions (5,8,10,13,18,19,23,28,29,30,56). In addition, it is highly challenging to perform MEN1 testing in the extended number of cases fulling the current criteria for genetic analysis, using SS (5).…”

“…MEN1 testing has been usually performed using both Sanger sequencing (SS) and MLPA assays (5,8,9,13,23,28,29,30). Although genetic testing should be ideally performed in literally all cases fulfilling current criteria, SS technology has limitations to achieve this purpose.…”

“…Moreover, in MEN1 patients with no mutation in the coding region of the MEN1 gene, it has been postulated the existence of MEN1 mutations in introns far from intron/exon boundaries, untranslated or regulatory regions (5,8,10,13,18,19,23,28,29,30). However, SS may not usually cover such gene regions, preventing systematic studies on this topic (5,8,10,13,18,19,23,28,29,30). Therefore, novel, higherthroughput and greater capacity of data generation, robust and affordable strategies as NGS technologies are required (31,32,33,34).…”