Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

Long-Term Outcomes of Parathyroidectomy in Hyperparathyroidism-Jaw Tumor Syndrome: Analysis of Five Families with CDC73 Mutations.

BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare disease caused by CDC73 germline mutations, with familial primary hyperparathyroidism (pHPT), ossifying jaw tumors, genito-urinary neoplasms. The present study was aimed at determining the long-term postoperative outcome of parathyroidectomy in HPT-JT. METHODS: A retrospective analysis of a single-center series of 20 patients from five unrelated HPT-JT families undergoing parathyroid surgery was performed. RESULTS: Pathology confirmed a single-gland involvement in 95% of cases at onset. Parathyroid carcinoma occurred in three patients undergoing en-bloc parathyroidectomy and thyroid lobectomy: parathyroid benign lesions in 17 patients undergoing subtotal parathyroidectomy for evident multiglandular involvement (n = 1) or selective parathyroidectomy for single-gland involvement (n = 16), during bilateral (n = 13) or targeted unilateral neck exploration (n = 7). At a median overall follow-up of 16 years (range 2.5-42), patients with parathyroid carcinoma had a persistent/recurrent disease in 66.6%; patients with benign lesions had recurrent pHPT in 23.5% after a prolonged disease-free period; recurrent benign pHPT occurred slightly more often in cases of discordant preoperative localization (60% vs 9%; p = 0.06). CONCLUSION: pHPT in HPT-JT is generally characterized by a benign and single-gland involvement, with a relatively increased risk of malignancy (15%). Parathyroid carcinoma needs extensive surgery because of high risk of permanent/recurrent disease (66.6%). In benign involvement, targeted unilateral exploration with selective parathyroidectomy may be effective in cases of concordant single-gland localization at preoperative localization imaging techniques. Bilateral neck exploration with subtotal parathyroidectomy might be preferred in cases of negative or discordant preoperative localization, because of the increased risk of multiglandular involvement and long-term recurrences (23.5%).

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.

Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma.

Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC.

Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory Tissue.

Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR. 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in CDC73. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects GCM2 activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression.

Genetics of parathyroid tumours.

Primary hyperparathyroidism (PHPT), due to parathyroid tumours, may occur as part of a complex syndrome or as an isolated (nonsyndromic) disorder, and both forms can occur as familial (i.e. hereditary) or nonfamilial (i.e. sporadic) disease. Syndromic PHPT includes multiple endocrine neoplasia (MEN) types 1 to 4 (MEN1 to MEN4) and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Syndromic and hereditary PHPT are often associated with multiple parathyroid tumours, in contrast to sporadic PHPT, in which single parathyroid adenomas are more common. In addition, parathyroid carcinomas may occur in ~15% of patients with the HPT-JT syndrome. MEN1 is caused by abnormalities of the MEN1 gene which encodes a tumour suppressor; MEN2 and MEN3 are due to mutations of the rearranged during transfection (RET) proto-oncogene, which encodes a tyrosine kinase receptor; MEN4 is due to mutations of a cyclin-dependent kinase inhibitor (CDNK1B); and HPT-JT is due to mutations of cell division cycle 73 (CDC73), which encodes parafibromin. Nonsyndromic PHPT, which may be hereditary and referred to as familial isolated hyperparathyroidism, may also be due to MEN1, CDC73 or calcium-sensing receptor (CASR) mutations. In addition, ~10% of patients presenting below the age of 45 years with nonsyndromic, sporadic PHPT may have MEN1, CDC73 or CASR mutations, and overall more than 10% of patients with PHPT will have a mutation in one of 11 genes. Genetic testing is available and of value in the clinical setting, as it helps in making the correct diagnosis and planning the management of these complex disorders associated with parathyroid tumours.

MAJOR MOLECULAR GENETIC DRIVERS IN SPORADIC PRIMARY HYPERPARATHYROIDISM.

Primary hyperparathyroidism is primarily due to a solitary parathyroid adenoma but multi-gland disease, parathyroid carcinoma, and ectopic parathyroid hormone production can occur. Although primary hyperparathyroidism mostly presents sporadically, strong familial predispositions also exist. Much is known about heritable genetic mutations responsible for these syndromes, including multiple endocrine neoplasia types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial hypocalciuric hypercalcemia. Acquired mutations in common sporadic hyperparathyroidism have also been discovered. Here we focus on the most common and well-established genetic drivers: 1) involvement of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumor types including breast cancer and B-lymphoid malignancy; and 2) somatic mutation of the MEN1 gene, first identified as the source of pathogenic germline mutations in patients with familial endocrinopathies, is found in a substantial fraction of non-familial parathyroid adenomas.

Hereditary hyperparathyroidism--a consensus report of the European Society of Endocrine Surgeons (ESES).

BACKGROUND: Hereditary hyperparathyroidism has been reported to occur in 5-10 % of cases of primary hyperparathyroidism in the context of multiple endocrine neoplasia (MEN) types 1, 2A and 4; hyperparathyroidism-jaw tumour (HPT-JT); familial isolated hyperparathyroidism (FIHPT); familial hypocalciuric hypercalcaemia (FHH); neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant moderate hyperparathyroidism (ADMH). This paper aims to review the controversies in the main genetic, clinical and pathological features and surgical management of hereditary hyperparathyroidism. METHODS: A peer review literature analysis on hereditary hyperparathyroidism was carried out and analyzed in an evidence-based perspective. Results were discussed at the 2015 Workshop of the European Society of Endocrine Surgeons devoted to hyperparathyroidism due to multiple gland disease. RESULTS: Literature reports scarcity of prospective randomized studies; thus, a low level of evidence may be achieved. CONCLUSIONS: Hereditary hyperparathyroidism typically presents at an earlier age than the sporadic variants. Gene penetrance and expressivity varies. Parathyroid multiple gland involvement is common, but in some variants, it may occur metachronously often with long disease-free intervals, simulating a single-gland involvement. Bilateral neck exploration with subtotal parathyroidectomy or total parathyroidectomy + autotransplantation should be performed, especially in MEN 1, in order to decrease the persistent and recurrent hyperparathyroidism rates; in some variants (MEN 2A, HPT-JT), limited parathyroidectomy can achieve long-term normocalcemia. In FHH, surgery is contraindicated; in NSHPT, urgent total parathyroidectomy is required. In FIHPT, MEN 4 and ADMH, a tailored case-specific approach is recommended.

Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese.

OBJECTIVE: Hyperparathyroidism-jaw tumour syndrome (HPT-JT) and familial isolated primary hyperparathyroidism (FIHP) are two subtypes of familial primary hyperparathyroidism, which are rarely reported in Chinese population. Here, we reported three FIHP families and one HPT-JT family with long-term follow-up and genetic analysis. DESIGN AND METHODS: A total of 22 patients, from four FIHP/HPT-JT families of Chinese descent, were recruited and genomic DNA was extracted from their peripheral blood lymphocytes. Direct sequencing for MEN1, CDC73, CASR gene was conducted. Reverse transcription PCR (RT-PCR) and quantitative real-time PCR (qRT-PCR) were used to study the effect of splice site mutations and gross deletion mutations. Immunohistochemistry was performed to analyse parafibromin expression in parathyroid tumours. Genotype-phenotype correlations were assessed through clinical characteristics and long-term follow-up data. RESULTS: Genetic analysis revealed four CDC73 germline mutations that were responsible for the four kindreds, including two novel point mutation (c.157 G>T and IVS3+1 G>A), one recurrent point mutation (c.664 C>T) and one deletion mutation (c.307+?_513-?del exons 4, 5, 6). RT-PCR confirmed that IVS3+1 G>A generated an aberrant transcript with exon3 deletion. Immunohistochemical analysis demonstrated reduced nuclear parafibromin expression in tumours supporting the pathogenic effects of these mutations. CONCLUSIONS: This study supplies information on mutations and phenotypes of HPT-JT/FIHP syndrome in Chinese. Screening for gross deletion and point mutations of the CDC73 gene is necessary in susceptible subjects.

Missense mutation in the MEN1 gene discovered through whole exome sequencing co-segregates with familial hyperparathyroidism.

Familial isolated hyperparathyroidism (FIHP) can be encountered in the context of multiple endocrine neoplasia type 1 (MEN1), hyperparathyroidism and jaw tumour syndrome (HPT-JT) and in familial hypocalciuric hypercalcaemia (FHH). In these syndromes, germline mutations in the relevant genes (MEN1, HPRT2 and CaSR, respectively) are detected. In some FIHP cases, the causative gene is still elusive. The objective of this study is to define the genetic basis of FIHP in a Georgian Jewish family with FIHP using whole exome capture and sequencing. DNA extracted from two sibs and one offspring from a single family all affected with multiglandular hyperparathyroidism was subjected to whole exome capturing and sequencing using the Roche NimbleGen V2 chip and the Illumina HiSeq2000 sequencing platform. Genetic variants were detected and annotated using a combination of the Genome Analysis Tool Kit and in-house scripts. Subsequent confirmation of the mutations and co-segregation analyses were carried out by Sanger sequencing in additional affected and unaffected family members. Whole exome capture and sequencing revealed the collection of variations common to the three-sequenced patients, including a very rare previously described missense mutation (c.T1021C: p.W341R) in the MEN1 gene. The p.W341R mutation in the MEN1 gene showed complete co-segregation in the family. Whole exome capture and sequencing led to the discovery of a missense mutation in the MEN1 gene and ruling out of the additional candidates in a single experiment. The limited expressivity of this mutation may imply a specific genotype-phenotype correlation for this mutation.

Rare duplication of the CDC73 gene and atypical hyperparathyroidism-jaw tumor syndrome: A case report and review of the literature.

BACKGROUND: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients. CASE REPORT: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait. CONCLUSION: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.

Detection of the first gross CDC73 germline deletion in an HPT-JT syndrome family.

Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned ∼ 547 kb, and included four additional genes: TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients.

Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism.

In this narrative review, we present data gathered over four decades (1980-2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1-MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Association Between Parafibromin Expression and Presence of Brown Tumors and Jaw Tumors in Patients with Primary Hyperparathyroidism: Series of Cases with Review of the Literature.

BACKGROUND Brown and jaw tumors are rare entities of poorly understood etiology that are regarded as end-stage of bone remodeling in patients with long-lasting and chronic hyperparathyroidism. Jaw tumors are mainly diagnosed in jaw tumors syndrome (HPT-JT syndrome) and are caused by mutation in the CDC73 gene, encoding parafibromin, a tumor suppressing protein. The aim of this work is to present 4 cases of patients in whom the genetic mutation of the CDC73 gene and clinical presentation coexist in an unusual setting that has not yet been described. CASE REPORT We present cases of 4 patients with primary hyperparathyroidism. Three were diagnosed with brown tumors (located in long bones, ribs, iliac, shoulders) and 1 with brown and jaw tumors. Expression of parafibromin in affected parathyroid tissues were analyzed. In patients without positive parafibromin staining, we searched for CDC73 mutation using next-generation sequencing. Parafibromin staining was positive in 1 patient with brown tumors and was negative in 2 individuals with brown tumors and 1 with brown and jaw tumors. CDC73 mutation was detected in two-thirds of patients (60%) with negative staining for parafibromin and brown tumors. MEN1 mutation was found in the patient with brown tumor and positive staining for parafibromin. CONCLUSIONS Patients with hyperparathyroidism and coexistence of brown tumors or jaw tumors might have decreased expression of parafibromin in parathyroid adenoma tissue, which might be caused by CDC73 mutation and suggest a genetic predisposition. Further research on much larger study groups is needed.

Molecular pathogenesis of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, mostly caused by a monoclonal parathyroid adenoma. The hereditary syndromes include multiple endocrine neoplasia types 1 (MEN 1) and 2A (MEN 2A), hereditary hyperparathyroidism-jaw tumor (HPTJT), familial isolated hyperparathyroidism (FIHP), familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Mutations of MEN1 and CDKN1B genes are responsible for MEN 1 in 70-80% and about 2% of cases, respectively. MEN1 and CDKN1B genes have also a role in the pathogenesis of sporadic parathyroid adenomas. HRPT2/CDC73 gene mutations are responsible for HPT-JT and sporadic parathyroid carcinoma. MEN1 and HRPT2/CDC73 genes mutations have also been found in a subset of FIHP families. FHH and NSHPT represent the mildest and severest variants of PHPT, caused by heterozygous and homozygous mutations in the calcium sensing receptor (CASR) gene, respectively.

Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia.

Primary hyperparathyroidism (pHPT) is associated with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), 2A (MEN2A), MEN-like syndromes (CDKN1B), and CDC73-related disorder (hyperparathyroidism - jaw tumor syndrome (HPJT)). Familial hypocalciuric hypercalcemia (FHH) caused by CASR variants is an important differential diagnosis for pHPT. In order to evaluate the contribution of hereditary causes to pHPT in patients encountered in a specialized clinic, we conducted a retrospective study on patients with pHPT that underwent germline genetic testing. We evaluated 46 patients referred to a Cancer Genetics Clinic. Reasons for referral were young age (age < 40) for 29 patients (63%), multi-gland disease for 23 patients (50%), and a positive family history of pHPT for 11 patients (24%). All 46 patients underwent genetic evaluation. A total of 11 rare variants were found (CASR (4), CDC73 (2), MEN1 (2) CDKN1B (1), and RET (2)). One MEN1 variant was classified as pathogenic, and all others were variants of uncertain significance (VUS). All patients with CASR variants had clinical features of FHH and were counselled against parathyroidectomy. Both patients with CDC73 variants were counselled about recurrence of pHPT and parathyroid cancer. Neither of the RET variants were MEN2-associated. The CDKN1B variant was regarded as a true VUS and no action was taken. In this study, genetic testing impacted clinical care in 7 (15%) patients. We suggest that all patients < 40 years of age, with multi-gland disease, single gland disease refractory to treatment, and a positive family history for pHPT or associated tumors should be considered for genetic evaluation.

Hereditary Parathyroid Disease: Sometimes Pathologists Do Not Know What They Are Missing.

Parathyroid gland excision specimens are common and sometimes underestimated cases that many surgical pathologists encounter regularly. In the vast majority of cases, these will be spot diagnoses of sporadic primary parathyroid adenomas or, perhaps, hyperplasias commonly in the setting of renal failure. However, a small but significant number of parathyroid gland excisions may be due to heritable disease. In most cases, hereditary disease is suspected by the referring clinicians. Nevertheless, a subset of these are undetected which is significant, particularly in the setting of the multiple endocrine neoplasia (MEN), and the hyperparathyroidism jaw tumour (HPT-JT) syndromes. There have been recent advances in recognition of the morphological and immunohistochemical characteristics of these tumours and hyperplasias. While hereditary kindreds are over-represented at specialist referral centres, with awareness of the characteristic clinical and morphological features, the general surgical pathologist is frequently able to suggest the possibility of hereditary parathyroid disease. We therefore provide a succinct guide for pathologists to increase the recognition of hereditary parathyroid disease.

Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred.

BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal disease caused by inactivating germ-line mutations of HRPT2 gene, with subsequent loss of Parafibromin expression. It is characterized by familial HPT, ossifying jaw tumors, and other associated neoplasms. METHODS: Clinical, histopathological, and genetic features of three large Italian unrelated HPT-JT kindred were assessed. RESULTS: Three different germ-line HRPT2 inactivating mutations were identified. Seventeen affected members and six healthy mutation carriers were found. HPT was diagnosed in virtually all affected patients, at a median age of 36.3 years (range 11-71). In all cases, a single parathyroid involvement was found at surgery, although a metachronous multiglandular involvement causing recurrence after selective parathyroidectomy occurred in 17.6% of cases, after a mean disease-free interval of 13.7 years (range 5-27). Parathyroid carcinoma, atypical parathyroid adenoma, and jaw tumor occurred in one case; uterine involvement in 61.5% of women; other associated neoplasms were thyroid carcinoma (two cases) and renal and colon carcinoma (one case). Immunohistochemistry confirmed the loss of Parafibromin as the distinctive feature of the disease both in parathyroid and uterine tumors. CONCLUSIONS: HPT-JT has a frequent single-gland parathyroid involvement and a relatively increased risk of parathyroid carcinoma. The penetrance of the disease is high but incomplete. Regardless of the denomination of the syndrome, jaw tumors occur rarely, while uterine involvement is frequently present. Selective parathyroidectomy may be an effective strategy, but a prolonged follow-up is required because of the risk of recurrences and malignancies. A systematic investigation is also required because of associated malignancies.

Parathyroid hormone-dependent hypercalcemia.

The past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

Familial and Hereditary Forms of Primary Hyperparathyroidism.

Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.