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Context: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. Objective: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. Design and Patients: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction–amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. Results: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). Conclusions: Observed in vitro–activating GCM2 variant alleles are significantly over-represented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is sporadic in the majority of cases. Hereditary forms of PHPT are rarer, however, they are of particular interest because they allow a deeper understanding of pathogenesis of parathyroid neoplasia. Hereditary forms of PHPT include multiple endocrine neoplasia type 1 (MEN-1), type 2A (MEN-2A), type 4 (MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), variants of familial hypocalciuric hypercalcemia (FHH) and familial isolated hyperparathyroidism (FIHP). Mutations in the following genes cause the development of MEN-1, MEN-2A, MEN4, HPT-JT: MEN1, RET, CDKN1B, CDC73, respectively. Variants of FHH are caused by mutations in CASR, AP2S1, GNA11. Gene(s) responsible for the development of the majority of FIHP cases remain unknown. Identification of hereditary forms of PHPT is important for patients and their first-degree relatives, as it allows defining the necessity of screening to reveal other components of the syndrome, in some cases determines the surgical approach to PHPT, and the risk of development of the disease in offsprings. This article provides information on hereditary syndromes associated with PHPT and special features of PHPT in each syndrome.

Background: Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. Objective: To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. Design: We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. Methods: The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed. Results: NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. Conclusions: Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at

Primary hyperparathyroidism is a heterogeneous clinical entity. In the clinical setting, the diagnosis and management of familial isolated hyperparathyroidism (FIHP) and other familial hyperparathyroidism (FHPT) forms continue to rely on clinical, laboratory, and histological findings, with careful examination of the family. In this article, we report a case series of FIHP in a four-generation Greek family, with no identifiable gene mutations. Clinical approach and long-term follow-up are discussed and a narrative review of the genetic basis of this entity has been performed. [ABSTRACT FROM AUTHOR]

Aim of the study: Primary hyperparathyroidism usually affects elderly patients. Juvenile primary hyperparathyroidism is rare, and raises diagnostic and pronostic problems. The aim of this retrospective study on 24 patients is to establish clinical, histological, and therapeutic features of juvenile primary hyperparathyroi¨dism.Patients and methods: From 1986 to 2001, 673 patients were treated for primary hyperparathyroi¨dism in our department. Twenty four patients were younger than 30 years old (3,5%). There were 14 women and 10 men. Mean age was 23 year (14–30). Clinical manifestations, pathologics findings and postoperative results were studied.Results: Sixteen patients presented a sporadic form of primary hyperparathyroidism with a single adenoma. Clinical manifestations were renal symptoms in 11 cases and acute hypercalcemia syndrome in 2 cases. Seven patients had a NEM I syndrome: parathyroid lesions were 6 hyperplasia and one adenoma. A 27 years old woman presented a recurrent familial isolated hyperparathyroidism. She was operated on 10 years before and at reoperation parathyroid carcinoma was found. Nineteen patients were cured after a post operative follow up ranging from 3 to 168 months. One patient had an asymptomatic hypercalcemia recurrence. Two patients presented permanent hypoparathyroidism treated whith calcitriol and calcium.Conclusion: Sporadic forms represent majority of cases of juvenile hyperparathyroidism. Renal manifestations are usual. Nevertheless, multiple endocrine neoplasia type 1 has to be evocated. [Copyright &y& Elsevier]

Primary Hyperparathyroidism (PHPT) has been reported to occur in members of same family either alone or in syndromic association. We report a family of patients with multi glandular disease wherein we have successfully used intra operative PTH (IOPTH) to assess the completeness of resection. Three members of one family were affected (One male and two females). Two of them had symptomatic disease whereas one was asymptomatic. Since the genetic studies are not available we used a combination of radiological, clinical and laboratory findings to rule out the other components of MEN syndromes. Extent of surgery in familial isolated hyperparathyroidism (FIHP) is controversial. Hence for confirmation of adequate parathyroid tissue resection we used IOPTH. Role of IOPTH has been well established in sporadic PHPT but controversial in multi glandular syndromes. IOPTH was successfully used to confirm the excision and establish cure. [ABSTRACT FROM AUTHOR]

Background: Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial., Objective: To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age., Design: We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome., Methods: The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT ( MEN1 , CASR , CDC73 , CDKN1A , CDKN1B , CDKN1C , CDKN2A , CDKN2C , CDKN2D ). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed., Results: NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8., Conclusions: Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations., (© 2017 The authors.)

Context: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID)., Objective: We investigated the ethnicity of individuals with germline variants in the GCM2 CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database., Design: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the GCM2 CCID region. Luciferase reporter assays were performed to determine the functional impact of GCM2 variants., Setting and Patients: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients., Results: The GCM2 p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with GCM2 -activating variants often had multigland involvement or postoperative recurrent or persistent disease., Conclusions: Specific GCM2 -activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT.