Familial Primary Hyperparathyroidism Research Articles

Novel germline variant of CDC73 identified during screening for familial primary hyperparathyroidism

Novel germline variant of CDC73 identified during screening for familial primary hyperparathyroidism

Identification of a new mutation in the MEN1 gene responsible for familial primary hyperparathyroidism in a Tunisian family

Identification of a new mutation in the MEN1 gene responsible for familial primary hyperparathyroidism in a Tunisian family

Familial states of primary hyperparathyroidism: an update.

Familial primary hyperparathyroidism (PHPT) includes syndromic and non-syndromic disorders. The former are characterized by the occurrence of PHPT in association with extra-parathyroid manifestations and includes multiple endocrine neoplasia (MEN) types 1, 2, and 4 syndromes, and hyperparathyroidism-jaw tumor (HPT-JT). The latter consists of familial hypocalciuric hypercalcemia (FHH) types 1, 2 and 3, neonatal severe primary hyperparathyroidism (NSHPT), and familial isolated primary hyperparathyroidism (FIHP). The familial forms of PHPT show different levels of PHPT penetrance, developing earlier and with multiglandular involvement compared to sporadic counterpart. All these diseases exhibit Mendelian inheritance patterns, and for most of them, the genes responsible have been identified. DNA testing for predisposing mutations is helpful in index cases or in individuals with a high suspicion of the disease. Early recognition of hereditary disorders of PHPT is of great importance for the best clinical and surgical approach. Genetic testing is useful in routine clinical practice because it will also involve appropriate screening for extra-parathyroidal manifestations related to the syndrome as well as the identification of asymptomatic carriers of the mutation. The aim of the review is to discuss the current knowledge on the clinical and genetic profile of these disorders along with the importance of genetic testing in clinical practice.

Abstract LB153: Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2

Abstract Tumors of one or multiple parathyroid glands and elevated serum calcium and parathyroid hormone (PTH) are the common characteristics of primary hyperparathyroidism (PHPT). Genes associated with familial PHPT (hereditary parathyroid tumors) include - MEN1, CDKN1B, CDC73, RET, MAX and GCM2. The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development. Heterozygous germline missense variants located within the C-terminal conserved inhibitory domain (CCID) of GCM2 have been reported in a subset of patients with familial PHPT. In functional assays, these missense variants enhance the transcriptional activity of GCM2, suggesting that GCM2 could act as a proto-oncogene in parathyroid neoplasia. A recurrent germline activating missense variant of GCM2, p.Y394S in patients with familial PHPT has been reported in various publications. To study the direct contribution of this missense variant in parathyroid neoplasia, we used the CRISPR/Cas9 system to generate a heterozygous germline knock-in of p.Y392S in the mouse Gcm2 gene (which corresponds to the human variant p.Y394S in GCM2). In GCM2-binding site mediated luciferase reporter assays, the mouse Gcm2 variant p.Y392S also exhibited the transcription enhancing effect that was observed for the human GCM2 p.Y394S variant. However, mice with this variant (Gcm2 +/Y392S) did not show obvious parathyroid tumors. Because the mouse Gcm2 variant p.Y392S exhibited enhanced transcriptional activity, we performed spatial transcriptomics of parathyroid glands from wildtype (WT) and Gcm2 +/Y392S mice to examine differentially expressed transcripts in parathyroid cells with the p.Y392S variant of Gcm2. Using the 10X Genomics Visium platform, spatially resolved RNA-seq analysis was performed on parathyroid gland cells of WT and Gcm2 +/Y392S mice specifically marked by the expression of Pth and Gcm2. Spatial transcriptomics and Pathway analysis was performed to evaluate transcripts with more than 2-fold increased expression in parathyroid cells from the p.Y392S variant of Gcm2 compared to WT. Further investigation of these genes and pathways in mouse and human parathyroid cells can provide insights into the functional consequences of GCM2 activating variants and the pathophysiology of parathyroid tumorigenesis. Citation Format: Priyanka Bolel, Jeremie O. Pina, Fabio R. Faucz, Lee S. Weinstein, Sunita K. Agarwal. Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB153.

A Knock-In Mouse Model of the Gcm2 Variant p.Y392S Develops Normal Parathyroid Glands.

The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development, and variants in this gene have been associated with 2 parathyroid diseases: isolated hypoparathyroidism in patients with homozygous germline inactivating variants and primary hyperparathyroidism in patients with heterozygous germline activating variants. A recurrent germline activating missense variant of GCM2, p.Y394S, has been reported in patients with familial primary hyperparathyroidism. To determine whether the GCM2 p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model. CRISPR/Cas9 gene editing technology was used to generate a mouse model with the germline heterozygous Gcm2 variant p.Y392S that corresponds to the human GCM2 p.Y394S variant. Wild-type (Gcm2+/+) and germline heterozygous (Gcm2+/Y392S) mice were evaluated for serum biochemistry and parathyroid gland morphology. Gcm2 +/Y392S mice did not show any change compared to Gcm2+/+ mice in serum calcium and parathyroid hormone levels, parathyroid gland histology, cell proliferation, or parathyroid gland size. The mouse model of the p.Y392S variant of Gcm2 shows that this variant is tolerated in mice, as it does not increase parathyroid gland cell proliferation and circulating calcium or PTH levels. Further investigation of Gcm2+/Y392S mice to study the effect of this variant of Gcm2 on early events in parathyroid gland development will be of interest.

THU236 Mild Asymptomatic Hypercalcemia Secondary To A Novel Calcium-sensing Receptor Mutation

Abstract Disclosure: J. Tarkoff: None. Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of mild hypercalcemia that is usually secondary to heterozygous mutations of the calcium-sensing receptor (CaSR) with autosomal dominant inheritance. The distinction between this entity and primary hyperparathyroidism can be difficult. Clinical Case: A 15-year-old female presented to the endocrinology clinic for an incidentally found elevated total calcium of 10.9 mg/dl (8.9-10.4) and elevated ionized calcium 5.5 mg/dl (4.8-5.3 mg/dl). Her labs at that time also showed a PTH of 29 pg/mL (12-71) and phosphorus 3.5 mg/dl (2.5-4.5 mg/dl). She denied any symptoms of hypercalcemia and there is no reported family history of mineral disorders or fractures. She does not take any medications. Her physical exam was unremarkable. Our evaluation showed calcium 10.5 mg/dl, phosphorus 4 mg/dl, magnesium 2.2 mg/dl (1.5-2.5 mg/dl) 25-hydroxyvitamin D 32 ng/ml (30-100 ng/ml), fractional excretion of calcium (FeCa) based upon spot urine sample = 0.0104, TSH 1.29 mIU/L (0.5-4.3 mIU/L), alkaline phosphatase 79 U/L (45-150 U/L), and normal renal function. Given her spot FeCa being <0.02, sequencing of the CASR gene was offered to the family because of potential overlap of her FeCa with primary hyperparathyroidism for which the treatment would be surgical (1). Commercial genetic testing was notable for a previously unreported heterozygous nonsense mutation, c.3001C>T (p.Gln1001X). It is expected to disrupt the final 78 amino acids of the protein in its intracellular domain and may play a role in preventing downstream signaling. At follow-up without treatment, her calcium has ranged between 10-10.9 mg/dl and she remains asymptomatic. Clinical lesson/conclusion: Hypocalciuria in the setting of hypercalcemia should raise the suspicion of FHH even without family history. Genetic testing of the CaSR is a crucial step in facilitating the diagnosis of FHH, especially given the importance of distinguishing it from primary hyperparathyroidism. Reference: (1) Christensen, S.E., Nissen, P.H., Vestergaard, P., Heickendorff, L., Brixen, K. and Mosekilde, L. (2008), Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a follow-up study on methods. Clinical Endocrinology, 69: 713-720. Presentation: Thursday, June 15, 2023

Variant Tyr 394Ser in the GCM2 Gene Is Rare in a Cohort of Ashkenazi Jews With Primary Hyperparathyroidism.

Various genes have been associated with familial and sporadic primary hyperparathyroidism (PHPT), including activating mutations of the glial cells missing transcription factor 2 (GCM2) gene. The aim of this study was to assess the prevalence of the GCM2 p.Tyr394Ser variant in the Jerusalem Ashkenazi Jewish (AJ) population with PHPT, and to conclude whether routine genetic testing is justified. The blood of 40 self-reported AJ patients with PHPT and 200 AJ controls was tested for the GCM2 p.Tyr394Ser variant. Demographic and medical information was extracted from the patients' charts and evaluated accordingly. Two (5%) PHPT patients and 3 (1.5%) controls were heterozygotes for the tested variant. Our patients were mostly (87.5%) sporadic cases. One of the heterozygote patients had familial PHPT; the other had 2 parathyroid adenomas, and the levels of his blood and urinary calcium were extremely high. Our results suggest that in AJ patients with sporadic, single-gland PHPT, the likelihood of the tested variant is low and genetic testing should be limited to those with familial PHPT or multiglandular disease.

Differences in the Presentation and Outcome between Premenopausal and Postmenopausal Primary Hyperparathyroidism Indian Women: A Single-Center Experience.

Primary hyperparathyroidism (PHPT) is an endocrine disorder wherein enlargement of one or more of the parathyroid glands causes autonomous overproduction of the parathyroid hormone (PTH), which leads to high serum calcium levels. The objective of this study was to compare the clinical, laboratory, and operative variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. A retrospective analysis of the data of female patients who underwent surgery for PHPT at a single center, from January 2011 to December 2020, was done. Patients with familial PHPT and secondary hyperparathyroidism were not included. Of the 130 women with PHPT, 44.6% were pre-M and 55.4% were post-M. A significantly higher number of pre-M females were symptomatic compared to post-M females (pre-M vs. post-M, 84.5% vs. 68.1%, P = 0.031). Renal calculi were more common in pre-M women (34.5% vs. 18.1%, P = 0.032), while the rest of the clinical features were comparable between the two groups. The proportion of women with osteoporosis (6.7% vs. 19.4%, P = 0.071), hypertension (13.8% vs. 34.7%, P = 0.012), and diabetes mellitus (3.5% vs. 16.7%, P = 0.033) was lesser in the pre-M group. Elevated serum alkaline phosphatase levels were significantly more prevalent in the pre-M group (37.9% vs. 20.8%, P = 0.032). The mean serum calcium (12.35 ± 1.28 vs. 11.96 ± 1.22 mg/dL, P = 0.079), median serum PTH (334 vs. 239 pg/mL, P = 0.051), and median weight of the operated adenomas (1.75 vs. 1.45 g, P = 0.075) were also higher in pre-M females. The proportion of ectopic adenomas and multiple adenomas, presurgery adenoma localization rates, and disease cure rates did not differ according to the menopausal status. The occurrence of postoperative hungry bone syndrome was higher in the pre-M women (15.5% vs. 1.4%, P = 0.008). The majority of women with PHPT are post-M, but symptomatic presentation is more common in pre-M females. The severity of the disease appears to be more in pre-M women; however, imaging and operative variables generally did not significantly differ between the two groups.

Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

PurposeCDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT).MethodsDuring genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples.ResultsDNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3.ConclusionGermline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

A novel mutation on MEN1 as a cause of familial primary hyperparathyroidism

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Germline Mutations Related to Primary Hyperparathyroidism Identified by Next-Generation Sequencing.

Primary hyperparathyroidism (PHPT) is characterized by overproduction of parathyroid hormone and subsequent hypercalcemia. Approximately 10% of PHPT cases are hereditary, and several genes, such as MEN1, RET, CASR, and CDC73, are responsible for the familial forms of PHPT. However, other genetic mutations involved in the etiology of PHPT are largely unknown. In this study, we identified genetic variants that might be responsible for PHPT, including familial PHPT, benign sporadic PHPT, and sporadic parathyroid cancer, using next-generation sequencing (NGS). A total of 107 patients with PHPT who underwent NGS from 2017 to 2021 at Severance Hospital were enrolled. We reviewed the pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Of the 107 patients (mean age: 47.6 ± 16.1 years, women 73.8%), 12 patients were diagnosed with familial PHPT, 13 with parathyroid cancer, and 82 with benign sporadic PHPT. Using NGS, we identified three pathogenic variants in two genes (CDC73 and MEN1), 10 likely pathogenic variants in six genes (CASR, CDC73, LRP5, MEN1, SDHA, and VHL), and 39 non-synonymous VUS variants that could be related to parathyroid disease. Interestingly, we identified one GCM2 variant (c.1162A>G [p.Lys388Glu]) and five APC variants that were previously reported in familial isolated hyperparathyroidism, benign sporadic PHPT, and parathyroid cancer. We also analyzed the characteristics of subjects with positive genetic test results (pathogenic or likely pathogenic variants), and 76.9% of them had at least one of the following features: 1) age < 40 years, 2) family history of PHPT, 3) multiglandular PHPT, or 4) recurrent PHPT. In this study, we analyzed the NGS data of patients with PHPT and observed variants that could possibly be related to PHPT pathogenesis. NGS screening for selected patients with PHPT might help in the diagnosis and management of the disease.

Excluding familial hypocalciuric hypercalcaemia before surgery for primary hyperparathyroidism - a practical evaluation of urinary calcium using a retrospective cohort design.

Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) are both associated with raised serum calcium and parathyroid hormone (PTH) levels; the former should be excluded in patients undergoing surgery for the latter. Twenty-four-hour urinary calcium collections (24UCA) can be performed to quantify total calcium excreted; however, results of this method do not take into account factors such as kidney function. Current guidelines suggest measuring urine calcium to creatinine clearance ratio (CCCR) as the initial step. The aim of this study was to evaluate the use of CCCR and 24UCA in a cohort design, to reliably exclude FHH patients before surgery for PHPT. A retrospective cohort study of all patients having urine calcium investigations in a single centre, over a 2-year period was performed. Relevant biochemical data and recorded diagnoses were collected. In total, 296 urine calcium measurements were included from 199 patients. Ten (5%) had genetically confirmed or suspected FHH, 171 (85.9%) had surgically proven or suspected PHPT and the remainder had other diagnoses. At a CCCR cut-off of ≤0.020, positive and negative predictive values (PPV and NPV) were 2.33% and 100%, respectively. At a cut-off of ≤0.015, NPV was maintained at 100% and PPV increased to 3.28%. Low 24UCA measurements (<2.5mmol/L/24h) generated a NPV for FHH of 95.2%. A CCCR measurement below 0.020 should raise the possibility of FHH and genetic screening should be considered. 24UCA had a lower predictive power to exclude FHH (NPV), and measurements should be interpreted in the context of renal function.

Comparison of Parathyroid Autofluorescence Signals in Different Types of Hyperparathyroidism.

There are scant data in the literature regarding whether parathyroid autofluorescence (AF) signal patterns vary based on the etiology of hyperparathyroidism. The aim of this study was to compare AF signals of parathyroid glands across different etiologies of hyperparathyroidism. As a prospective institutional review board-approved study between 2016 and 2019, AF intensities and heterogeneity indexes (HIs) of parathyroid glands in patients who underwent parathyroidectomy using AF were calculated and compared using Chi-square, Kruskal Wallis, Mann Whitney U, and logistic regression tests. Of the total of 183 patients, 127 patients had sporadic classic primary hyperparathyroidism, 30 patients had sporadic normohormonal primary hyperparathyroidism, 10 patients had sporadic normocalcemic primary hyperparathyroidism, 12 patients had tertiary hyperparathyroidism, and 4 patients had familial primary hyperparathyroidism related to multiple endocrine neoplasia (MEN) 2A. There were no statistical differences in AF signals of abnormal parathyroid glands in classic, normohormonal or normocalcemic sporadic hyperparathyroidism. Parathyroid glands in patients with tertiary hyperparathyroidism were similar in intensity, but more homogenous compared to those in sporadic primary hyperparathyroidism. The pattern of AF exhibited by abnormal parathyroid glands was similar across different spectrums of primary hyperparathyroidism, in accordance with observations in the literature. However, parathyroid glands in tertiary hyperparathyroidism were more homogeneous, despite exhibiting a similar intensity of AF compared to those in sporadic primary hyperparathyroidism. These differences should be kept in mind when using the AF pattern as an adjunct to visual assessment in parathyroid exploration.

Oral health aspects in sporadic and familial primary hyperparathyroidism.

BackgroundPrimary hyperparathyroidism (pHPT) is the third most common endocrinopathy, affecting 1-3% of postmenopausal women, with a total incidence of 21.6 cases per 100,000 people in the adult population. This study aimed to analyze the oral health and related aspects of individuals with pHPT. Material and MethodsA cross-sectional observational study was carried out on 51 patients diagnosed with pHPT associated with multiple endocrine neoplasia type 1 (MEN-1) (G1) or sporadic pHPT (G2). The oral aspects investigated were periodontal parameters, salivary flow, presence of dental caries, number of restored or missing teeth, and presence of tori. The biochemical parameters were collected in periods close to the dental evaluation. ResultsIn G1, 29 individuals (19 females) aged 40.24±13.06 years were included; in G2, 22 individuals (21 females) aged 64.09±10.01 years were included. Grade 2 mobility (p=0.031), mean probing depth (p<0.001), loss of clinical insertion level (p<0.001), gingival bleeding (p=0.009), and presence of palatine tori (p=0.007) were higher in G1. A higher mean of tooth loss (17.90±13.42; p=0.031), teeth with active and/or inactive caries (p<0.001), and visual change in enamel/enamel breakdown (p<0.001) were also observed in G1. Most patients were 50 years old or younger, with a higher prevalence of older individuals in G2 (p<0.001). G1 showed low socioeconomic status and G2 medium-high status (p<0.001). ConclusionsDespite the greater number of younger individuals, higher tooth loss and periodontal changes were observed in G1 patients. Differences in the degree of severity of pHPTor socioeconomic status alone could not explain these findings. Key words:Oral health, Primary hyperparathyroidism, Multiple endocrine neoplasia type 1, osteopenia, osteoporosis.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

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. Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. 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. 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). Observed in vitro-activating GCM2 variant alleles are significantly overrepresented 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.

A contemporary clinical approach to genetic testing for heritable hyperparathyroidism syndromes.

The improved access and affordability of next generation sequencing has facilitated the clinical use of gene panel testing to test concurrently patients for multiple heritable hyperparathyroidism syndromes. However, there is little guidance as to which patients should be selected for gene panel testing and which genes should be included in such panels. In this review, we provide a practical approach to considering, interpreting and managing genetic testing for familial primary hyperparathyroidism (PHPT) syndromes and familial hypocalciuric hypercalcaemia (FHH) in patients with PTH-dependent hypercalcaemia. We discuss known genes implicated in PHPT and FHH, testing criteria and yields, pre-test counselling, laboratory considerations, and post-test management. In addition to reviewing the literature, we conducted audits of local genetic testing data to examine the real-world yield of genetic testing in patients with PTH-dependent hypercalcaemia. Our local audits revealed a positive genetic testing rate of 15-26% in patients with suspected hyperparathyroidism syndromes. Based on the particular testing criteria met, affected patients should be tested for variants in the genes currently implicated in PHPT (MEN1, CDC73, RET, CDKN1B, GCM2, CASR) and/or FHH (CASR, GNA11, AP2S1). Patients should be provided with pre- and post-test counselling, including consideration of potential implications for family members.

A novel long-range deletion spanning CDC73 and upper-stream genes discovered in a kindred of familial primary hyperparathyroidism.

To confirm the exact break-point of a novel long-range deletion discovered in one female parathyroid carcinoma (PC) patient who has a strong family history suggesting familial hyperparathyroidism, and to investigate the expression of parafibromin in the patient's affected lesion. Clinical information of one female patient as well as five of her relatives was collected. Their genomic DNA extracted from peripheral blood went through Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). After completing whole genome sequencing (WGS), clone sequencing was also performed, whose result was aligned with standard human genome database after Sanger sequencing. The medical history of recurrent hypercalcemia after parathyroidectomy and histopathological investigation confirmed that the female patient was diagnosed with PC. WGS displayed a novel 130 kb long-range deletion spanning UCHL5 to CDC73 that was later confirmed by clone sequencing. MLPA showed similar results in four of her five relatives, suggesting these people to be carriers of the same long-range deletion, and three among them had a history of primary hyperparathyroidism (PHPT) ahead of the proband's first visit. We discovered a novel 130 kb long-range deletion spanning CDC73 in a family of 5 persons, and the existence of the deletion was related to PHPT and PC. Our discovery validated the role of CDC73 mutation in the occurrence of PHPT and PC, which provided new information to the genetic studies of PC.

Primary hyperparathyroidism: Disease of diverse genetic, symptomatic, and biochemical phenotypes.

Genetic, symptomatic, and biochemical heterogeneity of patients with primary hyperparathyroidism (PHPT) has become apparent in recent years. An in-depth, evidence-based review of the phenotypes of PHPT was conducted. This review was intended to provide the resulting information to surgeons who operate on patients with hyperparathyroidism. This review revealed that the once relatively clear distinction between familial and sporadic PHPT has become more challenging by the finding of various germline mutations in patients with seemingly sporadic PHPT. On the one hand, the genetic and clinical characteristics of some syndromes in which PHPT is an important component are now better understood. On the other hand, knowledge is emerging about novel syndromes, such as the rare multiple endocrine neoplasia type IV (MEN4), in which PHPT occurs frequently. It also revealed that, currently, the classical array of symptoms of PHPT is seen rarely upon initial presentation for evaluation. More common are nonspecific, nonclassical symptoms and signs of PHPT. In areas of the world where serum calcium levels are checked routinely, most patients today are "asymptomatic" and they are diagnosed after an incidental finding of hypercalcemia; however, some of them have subclinical involvement of bones and kidneys, which is demonstrated on radiographs, ultrasound, and modern imaging techniques. Last, the review points out that there are three distinct biochemical phenotypes of PHPT. The classical phenotype in which calcium and parathyroid hormone levels are both elevated, and other disease presentations in which the serum levels of calcium or intact parathyroid hormone are normal. Today several, distinct phenotypes of the disease can be identified, and they have implications in the diagnostic evaluation and treatment of patients, as well as possible screening of relatives.

Atypical Presentation of Familial Hypocalciuric Hypercalcemia: Case Report

Background: Differentiation between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHPT) can be challenging in certain cases in the absence of DNA analysis of the calcium sensing receptor gene. The distinction between those two clinical entities with overlapping biochemical features therefore relies on the calcium to creatinine clearance ratio (CCCR), which is expected to be low in FHH (<0.01 in 80% of cases and between 0.01 and 0.02 in approximately 20% of patients)1. Patients with PHPT usually have a CCCR of>= 0.02. A lower CCCR between 0.01 and 0.02 can be seen in approximately 20% of patients1,2and is more commonly seen in the presence of vitamin D insufficiency, impaired renal function, low calcium intake or being of African descent. It is advised to stop drugs which can contribute to hypercalcemia and lower the CCCR such as thiazide diuretics prior to evaluating the CCCR. Clinical Case: A 56-year-old lady was referred for evaluation of persistent hypercalcemia post parathyroidectomy and fatigue. She had mildly elevated ionized serum calcium (iCa) and a mid-normal PTH with a CCCR of 0.024. She had a normal BMD with no prior fragility fractures and passed a kidney stone prior to her presentation. Physical exam was unremarkable. She had previously travelled to Tampa and had a subtotal parathyroidectomy 3 glands (RU, LU, RL) for a possible diagnosis of PHPT, tissue biopsy showed hyperplastic parathyroids. Her MEN1 gene analysis was negative for MEN1 mutation and MRI of the abdomen was unremarkable. Her mother had a diagnosis of PHPT and osteoporosis. The iCa remained mildly elevated at 1.43 mmol/L (1.15–1.3) with a 24 hr urinary CCCR at 0.024 and a mid-normal PTH of 4.4 pmol/L (1.6–6.9). Her eGFR was 104 mls/min, 25 vitamin D 82 nmol/L (75–250), 1,25 dihydroxy vitamin D 122 pmol/L (60–206), PO4 0.90 mmol/L (0.8–1.45) and alkaline phosphatase 46 U/L (35–120) were all normal. She continued to have mild symptoms of hypercalcemia and her bone scan was negative for underlying skeletal pathology.DNA studies for mutations in the CaSR gene were completed. This confirmed the presence of a heterozygous loss of function mutation in the CASR gene at c493-2A>G which appears to be pathogenic. Conclusion: The CCCR is useful in differentiating PHPT from FHH however in certain cases of FHH the CCCR may be higher then expected and we have now confirmed the presence of FHH with a molecular diagnosis in a patient with a CCCR as high as 0.02.

An update on parathyroid carcinoma

Parathyroid carcinoma is a rare malignant disease that presents as a sporadic or familial primary hyperparathyroidism (PHP). The latter is associated with some genetic syndromes. It occurs with equal frequency in both sexes, unlike PHP caused by parathyroid adenoma that is more common in women. It should be suspected in cases of severe hypercalcemia, with high parathyroid hormone levels and a palpable cervical mass. Given the difficulty in distinguishing between parathyroid carcinoma and adenoma prior to the surgery, the diagnosis is often made after parathyroidectomy. The only curative treatment is complete surgical resection with oncologic block resection of the primary tumor to ensure free margins. Adjuvant therapies with chemotherapy or radiation therapy do not modify overall or disease-free survival. Recurrences are common and re-operation of resectable recurrent disease is recommended. The palliative treatment of symptomatic hypercalcemia is crucial in persistent or recurrent disease after surgery since morbidity and mortality are more associated with hypercalcemia than with tumor burden.