RARE DISEASE
Familial primary hyperparathyroidism
Familial primary hyperparathyroidism
Familial primary hyperparathyroidism
Drug discovery
1
drug
With orphan designation
Overview
Familial Primary Hyperparathyroidism (FHPT) is a rare inherited endocrine disorder characterized by hypercalcemia due to excessive parathyroid hormone (PTH) secretion. It accounts for 2-5% of primary hyperparathyroidism cases and is linked to germline mutations in genes like CASR, MEN1, and CDC73. FHPT often manifests earlier than sporadic cases, with potential progression to syndromes like MEN1 or hyperparathyroidism-jaw tumor syndrome. Diagnosis hinges on genetic testing, family history, and biochemical confirmation of hypercalcemia with elevated PTH [1][2][16].
Burden
Increased morbidity from osteoporosis, fractures, nephrolithiasis, and chronic kidney disease [9][19].
Elevated cardiovascular risk and mortality if untreated; neonatal severe hyperparathyroidism can be fatal without intervention [1][9].
Underdiagnosis due to variable penetrance and overlapping features with sporadic cases, necessitating lifelong surveillance [16][19].
Therapies
Surgical: Parathyroidectomy (curative for most cases), particularly in symptomatic patients or those meeting NIH criteria (e.g., calcium >1 mg/dL above normal, osteoporosis, kidney stones) [3][5][18].
Medical: Calcimimetics (e.g., cinacalcet) for nonsurgical candidates; bisphosphonates for bone protection [3][13].
Monitoring: Regular calcium/PTH tracking and genetic screening for early detection in family members [5][16].
Categories: rare endocrine diseases, rare genetic diseases, rare neoplastic diseases
Research Papers
464 drug discovery papers about Familial primary hyperparathyroidism, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
464 drug discovery papers about Familial primary hyperparathyroidism, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-01 | Clinical and Genetic Profile of Chinese Familial Hypocalciuric Hypercalcemia Type 1 (FHH1): A Retrospective Study.
PURPOSE: To characterize the clinical and genetic features of Chinese FHH type 1 (FHH1) patients and evaluate biochemical discriminators between FHH1 and sporadic primary hyperparathyroidism (s-PHPT). METHODS: This retrospective study included 11 genetically confirmed FHH1 and 55 s-PHPT patients. Their clinical, biochemical, and imaging data were compared. Genetic testing was conducted via targeted next-generation or whole-exome sequencing. The key discriminators were assessed by receiver operating characteristic (ROC) analysis. RESULTS: Among the 11 FHH1 patients, 63.6% were females and 63.6% had a family history. Incidentally detected hypercalcemia was the most common cause (72.7%). Compared with s-PHPT, FHH1 were younger at diagnosis [38.1 ± 17.4 years vs. 53.6 ± 14.0, P = 0.002], had lower parathyroid hormone level [41.80 (28.89, 124.00) pg/mL vs. 233.90 (136.6, 521.6) pg/mL, P < 0.001], higher serum phosphate (1.06 ± 0.28 mmol/L vs. 0.77 ± 0.17 mmol/L, P = 0.008), and lower 24-hour urinary calcium excretion (24hUCa) (P < 0.001). Bone turnover markers (BTMs) were lower (P ≤ 0.001), low bone mass was less frequent (P = 0.005), and parathyroid imaging results were frequently negative in FHH1. Eight CASR variants were identified, including 4 novel variants (c.197G > C, c.488 C >T, c.1042del, c.2386 A >G). ROC analysis indicated that 24hUCa < 3.71 mmol/24 h optimally distinguished FHH1 from s-PHPT. CONCLUSION: The relatively large single-center Chinese FHH1 cohort presented younger with similar serum calcium, milder PTH elevation, relatively normal BTMs, and less target-organ involvement than s-PHPT. A new cut-off value of 24hUCa may serve as a practical pre-genetic screening tool.
2026-01-13 | O-25 THE MASQUERADE OF BONES: A CASE REPORT OF BROWN TUMOURS CONFOUNDING DIAGNOSES
Abstract Introduction Brown tumour (osteitis fibrosa cystica) is a rare, benign bone lesion resulting from excess osteoclastic activity in hyperparathyroidism. Although typically found in the pelvis, femur, and ribs, it can affect any bone and radiologically mimic skeletal metastases or multiple myeloma. Clinical Case A 39-year-old woman with no significant history presented to the emergency department with right lower abdominal pain, vomiting, and fever. She was septic, and CT revealed right-sided pyelonephritis with hydronephrosis from an obstructing mid-ureteric stone. Incidental findings included a 21 mm left adrenal nodule, a 15 mm endometrial mass, and multiple lytic bone lesions in the vertebrae, pelvis, and scapulae. She underwent emergency percutaneous nephrostomy and improved with treatment for urosepsis due to hypercalcaemic nephrolithiasis. Her presentation biochemistry as table 1, showed severe hypercalcaemia (corrected calcium 15.4 mg/dL) and markedly elevated parathyroid hormone (PTH 2099.1 pg/mL). She received intravenous zolendronate and calcitonin, with biochemical improvement, and was started on a loading Vitamin D3 course. Parathyroid SPECT-CT showed a 3.5 cm partially cystic mass at the inferior pole of the left thyroid lobe, with tracer uptake confirming localisation. Ultrasound supported these findings. Due to significantly elevated PTH and imaging features, parathyroid carcinoma was also considered as a differential. After exclusion of pheochromocytoma (normal plasma metanephrines), she underwent urgent left inferior parathyroidectomy and hemithyroidectomy. Histology revealed completely excised cystic parathyroid lesion without malignancy features. One week post-operation, she developed paraesthesia with hypocalcaemia (8.0 mg/dL), managed with increase daily oral calcium intake to 2 grams. PTH initially remained elevated (207 pg/mL), attributed to hungry bone syndrome and vitamin D deficiency. At follow-up, she had persistently elevated PTH (296.1 pg/mL) with normocalcaemia. Bone profile revealed severe hypophosphataemia (<0.62 mg/dL), requiring intravenous phosphate, due to prior ferric carboxymaltose treatment given pre-op for uterine fibroid. The fibroid was excised and confirmed benign. The adrenal incidentaloma (2.1 cm, HU <6) remained stable on interval imaging and was biochemically non-functional. Genetic analysis for familial hypercalcaemia was negative. Follow-up CT imaging showed complete resolution of the lytic bone lesions. Patient is waiting for bone density scan appointment. In recent follow up, bone profile had normalized. Conclusion This case illustrates a rare presentation of primary hyperparathyroidism with severe hypercalcaemia and brown tumours, radiologically mimicking metastatic disease. The clinical course was further complicated by incidental findings of a non-functional adrenal adenoma and a benign uterine fibroid. Effective management required timely interventions and coordinated multidisciplinary care.Figure 1:Presentation CT imagingCT abdomen and pelvis, in coronal view, shows lytic lesions in the lumbar vertebrae (indicated by yellow arrows) and a right-sided hydroureter. Table 1:Presentation biochemical parameters
2025-10-01 | MON-776 When Electrolytes Tell the Story: Hypomagnesemia and Its Paradoxical Interaction with Parathyroid Disorders: A case report
Abstract Disclosure: R. Reguram: None. S. Neti: None. D.K. Yerasuri: None. Background: While hypomagnesemia can cause hypocalcemia, it also serves as an indicator for severity of primary hyperparathyroidism (PHPT) by contributing to hypercalcemia. This rare case presents a mixed picture of PHPT and familial hypocalciuric hypercalcemia (FHH) and the relationship between magnesium metabolism and parathyroid disorders. Presentation: A 76-year-old female with type 2 diabetes, hypertension, and chronic diarrhea presented with persistent hypomagnesemia despite oral and IV supplementation. Laboratory results showed consistently low magnesium (1.3-1.7 mg/dL), high-normal calcium (10.1-10.9 mg/dL), significantly elevated PTH (119.1-202.4 pg/mL), low 24-hour urine calcium (55-74 mg), and a high 24-hour urinary magnesium (186.9 mg) that indicated renal magnesium wasting. A Sestamibi scan identified a parathyroid adenoma. She also had a history of skeletal complications including an atraumatic radial fracture and severe osteoporosis on DEXA (radial T-score: -3.3). Despite these features pointing towards PHPT, presence of hypocalciuria and a low calcium-creatinine clearance ratio (<0.01) suggested coexisting FHH. Discussion: This case shows the complex interaction between magnesium, calcium and parathyroid (PTH) regulation. Hypomagnesemia can impair calcium-sensing receptor (CaSR) function and PTH secretion, potentially modifying PHPT presentation or mimicking FHH. Renal magnesium wasting likely exacerbated the patient's symptoms and complicated diagnosis. While FHH typically presents in younger individuals with mild hypercalcemia, this patient’s advanced age, significant osteoporosis and parathyroid adenoma supported PHPT. Hypomagnesemia is associated with more severe PHPT manifestations and increased risk of postoperative hypocalcemia. Hence comprehensive evaluation of magnesium status becomes critical, especially in patients with persistent hyperparathyroidism and atypical biochemical profiles. Conclusion: This case focuses on the importance of recognizing hypomagnesemia as both a modulator and a confounder in the diagnosis and management of parathyroid disorders. Persistent magnesium imbalance may complicate the presentation of PHPT or mimic FHH, leading to diagnostic uncertainty. Early and aggressive correction of hypomagnesemia is crucial not only for improving symptoms but also for ensuring accurate diagnosis and optimizing management. Further research is needed to clarify magnesium’s role in parathyroid pathophysiology and its impact on clinical outcomes. Presentation: Monday, July 14, 2025
2025-04-03 | Bone in Parathyroid Diseases Revisited: Evidence From Epidemiological, Surgical and New Drug Outcomes.
PTH-related disorders have a major impact on bone metabolism and skeletal properties because of the pivotal role of PTH in calcium and phosphate homeostasis and bone remodeling. Hyperparathyroidism is characterized by continuous exposure to excessive endogenous PTH, causing increased bone turnover in favor of bone resorption. Depending on the background of PTH overproduction, hyperparathyroidism is divided into primary, secondary, and tertiary hyperparathyroidism. The clinical presentation varies from deterioration of bone microarchitecture and decreased bone mineral density to profound bone involvement, such as osteitis fibrosa cystica and fragility fractures. Although successful parathyroidectomy represents the definitive treatment and may promote regression of most of the skeletal defects, the medical approach of calcimimetics and antiresorptive agents is a promising alternative in cases where parathyroidectomy is not feasible or unsuccessful. Hypoparathyroidism is the pathophysiological counterpart of hyperparathyroidism and also leads to disorders of bone metabolism and structure. Chronic PTH deprivation is associated with low bone remodeling and increased bone mineral density. The defective microarchitecture might affect bone strength and raise the risk for adverse skeletal events. Recombinant human PTH acts as a replacement therapy and is safe and efficient in restoring calcium/phosphate homeostasis and bone turnover. However, it is approved only for refractory cases, as conventional management with calcium and active vitamin D remains the first-line treatment. This article reviews the skeletal involvement in the most frequent parathyroid disorders, hyperparathyroidism and hypoparathyroidism, and rare familial disorders of PTH metabolism, as assessed by clinical, laboratory, and imaging parameters, and the effect of the available treatment strategies.
2024-11-01 | Rising Trend in the Frequency of Secondary and Tertiary Hyperparathyroidism: Observations from the Indian PHPT Registry
Primary hyperparathyroidism (PHPT) is the third common endocrine disorder characterised by hypercalcaemia with inappropriately elevated parathyroid hormone (PTH) levels. PHPT is primarily a sporadic disease (85–90%); however, hereditary/familial cases with known genetic causes account for 10–15% of the cases. Sporadic PHPT is mainly caused by parathyroid adenoma (PA) (80–85%), followed by parathyroid hyperplasia (15–20%) and rarely by parathyroid carcinoma (PC) (<1%). Secondary hyperparathyroidism (SHPT) usually results from vitamin D deficiency, chronic kidney disease (CKD), and malabsorption states. However, tertiary hyperparathyroidism (THPT) is the end result of long-standing secondary hyperparathyroidism associated with CKD on renal replacement therapy (RRT). Patients with severe SHPT or THPT due to CKD often require surgical intervention in the form of subtotal parathyroidectomy. The Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, maintains an online database named The Indian PHPT Registry (www.indianphptregistry.com) of patients undergoing parathyroid surgery for PHPT, SHPT, and THPT.[1,2] It is noteworthy that the majority of the cases enrolled in the Indian registry are PHPT; however, of late, there has been a noticeable rise in the frequency of SHPT and THPT cases. We retrieved the data from the registry of all patients who had undergone parathyroid surgery at our institute from 1 January 2013 to 1 January 2023. A total of 404 adults had been enlisted in this decade with 171 patients having undergone surgery between 2013 and 2017, while the rest 233 are operated between 2018 and 2023. The frequency of PHPT, SHPT, and THPT was 96.5%, 0.7%, and 1.7%, respectively, in the first half of the decade (2013–2017). However, over the next 5 years (2018–2023), there was an appreciable rise in the frequency of SHPT and THPT cases to 4.3% and 10.3%, respectively. This apparent rise in the frequency of SHPT and THPT could be the result of increased awareness among physicians, nephrologists, and endocrinologists about these entities along with an increased lifespan of patients with CKD, courtesy more efficient forms of RRTs. Accordingly, more CKD patients are being diagnosed with SHPT and THPT. Besides, as renal transplantation has become more widespread and affordable, more CKD patients are undergoing renal transplantation. Correction of severe SHPT and THPT is of paramount importance prior to renal transplantation, which could also explain the apparent rise in the frequency encountered over the past half a decade.[3] Author contribution SG is the primary author. RP edited the manuscript. SKB is the corresponding author. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
gene therapies
2024-11-04 | Molecular genetics in familial primary hyperparathyroidism: A study from Northern India
Purpose Familial primary hyperparathyroidism (FPHPT) accounts for about 10% of cases, owing to germline mutations in specific genes. The genetic profile of FPHPT has not been studied in our population. This is most likely the first study in our region to examine the genetic profile to search for any other PHPT-related tumours in these patients. Methods This prospective cross-sectional study was conducted in the Department of Endocrinology SKIMS from February 2021 to February 2023, in which 103 patients diagnosed with PHPT were taken. A customised gene panel (CDC 73, MEN 1/2A/4 mutation) using next-generation sequencing (NGS)was performed in 39 patients with strong suspicious of FPHT based on age < 35 years, multiglandular disease, cystic parathyroid adenoma (PA), parathyroid carcinoma (PC), suspicious of MEN 1/2A/4 syndrome. We tried to compare the clinical characteristics of individuals with those of positive and negative genetic tests. Results Germline variants were observed in 11/39 (28.2%). 7(17.9%) patients tested positive for MEN 1 mutation while 4(10.2%) patients tested positive for CDC 73 mutation; however, no one tested positive for MEN 2A/4 mutation. 4 patients with MENI syndrome had c.1366-2A > G p? while as 1 had c.247_250del CTGT(p.Ile85SerfsTer33), 1 had c.1763C > T (p.S588L), 1 had c.415 C > T(p.H139Y). Out of 7 who tested positive for MEN 1 mutation, 2 patients had microprolactinomas, 2 had multi-glandular disease, 1 had recurrent disease, 1 had persistent disease, 1 had gastric neuroendocrine tumour. In contrast, out of 4 who tested positive for CDC 73 mutation, 2 had familial PHPT, 1 had multiple uterine fibroids, and 1 had bilateral renal cysts. In the case of patients with CDC 73 mutations, 1 patient had codon 222 CGA (Arg) > TGA, 1 had c.415C > T at codon 139 (R139X), 1 had c.687_688dellAG (p.Arg229Serfs37), other had c76delA (p.Ile26SerfsX11). These were all reported mutations. Age, greater serum calcium, higher ALP and more skeletal involvement were statistically significant characteristics of those who tested positive for the mutation. Conclusion The observed prevalence of genetic variants in our population was remarkably higher than in other populations. Recognition of predisposing germline mutations can have significant implications in patient management, such as preventing PC in HPT-JT and optimizing the approach to parathyroidectomy in MEN 1. So, we strongly recommend genetic screening in PHPT patients with high-risk features.
2020-04-07 | Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.
We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.
2020-03-16 | Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?
Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease. The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT). From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance. We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.
2010-06-02 | Development of a Technique for Introduction of an Expressed Complementary Deoxyribonucleic Acid into Parathyroid Cells by Direct Injection
PTH is a major mediator of bone and mineral metabolism. However, physiological and pathological investigations of parathyroid cells (PTCs) have been limited because of the lack of available cell lines and because the organ is too small for detailed studies. Here, we describe a novel method for adenovirus-mediated cDNA transfer into PTCs, and we show the accuracy of the method in a rat model of uremia-induced secondary hyperparathyroidism. Rats underwent a 5/6-nephrectomy and were fed with a high-phosphate diet for 8 wk. The parathyroid glands were surgically exposed and adenoviruses containing LacZ or Ca-sensing receptor (CaSR) were directly injected into the glands under a zoom-stereo microscope. The parathyroid glands were analyzed for infection of adenovirus and immunohistochemically for expression of CaSR. The functional activity of exogenous CaSR in PTCs after this treatment was investigated based on changes of the calcium and PTH curve. A virus concentration of more than 109 plaque-forming units/ml was required for adequate infection of PTCs within 7 d after treatment. Marked increase of CaSR-positive PTCs by 2.39 ± 0.72 times relative to control treatment, and significant colocalization of CaSR overexpression and virus labeling, were observed in glands after gene introduction. The calcium and PTH curve was shifted to the left from the basal position (set point, 1.10 ± 0.09 to 0.76 ± 0.12 mm; P < 0.0001), indicating successful introduction of a functionally active cDNA into the PTCs. This technique may facilitate an elucidation of biological effects through targeting and identification of specific features of PTCs, which may provide the basis for new clinical approaches.
small molecules
2026-04-01 | Clinical and Genetic Profile of Chinese Familial Hypocalciuric Hypercalcemia Type 1 (FHH1): A Retrospective Study.
PURPOSE: To characterize the clinical and genetic features of Chinese FHH type 1 (FHH1) patients and evaluate biochemical discriminators between FHH1 and sporadic primary hyperparathyroidism (s-PHPT). METHODS: This retrospective study included 11 genetically confirmed FHH1 and 55 s-PHPT patients. Their clinical, biochemical, and imaging data were compared. Genetic testing was conducted via targeted next-generation or whole-exome sequencing. The key discriminators were assessed by receiver operating characteristic (ROC) analysis. RESULTS: Among the 11 FHH1 patients, 63.6% were females and 63.6% had a family history. Incidentally detected hypercalcemia was the most common cause (72.7%). Compared with s-PHPT, FHH1 were younger at diagnosis [38.1 ± 17.4 years vs. 53.6 ± 14.0, P = 0.002], had lower parathyroid hormone level [41.80 (28.89, 124.00) pg/mL vs. 233.90 (136.6, 521.6) pg/mL, P < 0.001], higher serum phosphate (1.06 ± 0.28 mmol/L vs. 0.77 ± 0.17 mmol/L, P = 0.008), and lower 24-hour urinary calcium excretion (24hUCa) (P < 0.001). Bone turnover markers (BTMs) were lower (P ≤ 0.001), low bone mass was less frequent (P = 0.005), and parathyroid imaging results were frequently negative in FHH1. Eight CASR variants were identified, including 4 novel variants (c.197G > C, c.488 C >T, c.1042del, c.2386 A >G). ROC analysis indicated that 24hUCa < 3.71 mmol/24 h optimally distinguished FHH1 from s-PHPT. CONCLUSION: The relatively large single-center Chinese FHH1 cohort presented younger with similar serum calcium, milder PTH elevation, relatively normal BTMs, and less target-organ involvement than s-PHPT. A new cut-off value of 24hUCa may serve as a practical pre-genetic screening tool.
2026-01-13 | O-25 THE MASQUERADE OF BONES: A CASE REPORT OF BROWN TUMOURS CONFOUNDING DIAGNOSES
Abstract Introduction Brown tumour (osteitis fibrosa cystica) is a rare, benign bone lesion resulting from excess osteoclastic activity in hyperparathyroidism. Although typically found in the pelvis, femur, and ribs, it can affect any bone and radiologically mimic skeletal metastases or multiple myeloma. Clinical Case A 39-year-old woman with no significant history presented to the emergency department with right lower abdominal pain, vomiting, and fever. She was septic, and CT revealed right-sided pyelonephritis with hydronephrosis from an obstructing mid-ureteric stone. Incidental findings included a 21 mm left adrenal nodule, a 15 mm endometrial mass, and multiple lytic bone lesions in the vertebrae, pelvis, and scapulae. She underwent emergency percutaneous nephrostomy and improved with treatment for urosepsis due to hypercalcaemic nephrolithiasis. Her presentation biochemistry as table 1, showed severe hypercalcaemia (corrected calcium 15.4 mg/dL) and markedly elevated parathyroid hormone (PTH 2099.1 pg/mL). She received intravenous zolendronate and calcitonin, with biochemical improvement, and was started on a loading Vitamin D3 course. Parathyroid SPECT-CT showed a 3.5 cm partially cystic mass at the inferior pole of the left thyroid lobe, with tracer uptake confirming localisation. Ultrasound supported these findings. Due to significantly elevated PTH and imaging features, parathyroid carcinoma was also considered as a differential. After exclusion of pheochromocytoma (normal plasma metanephrines), she underwent urgent left inferior parathyroidectomy and hemithyroidectomy. Histology revealed completely excised cystic parathyroid lesion without malignancy features. One week post-operation, she developed paraesthesia with hypocalcaemia (8.0 mg/dL), managed with increase daily oral calcium intake to 2 grams. PTH initially remained elevated (207 pg/mL), attributed to hungry bone syndrome and vitamin D deficiency. At follow-up, she had persistently elevated PTH (296.1 pg/mL) with normocalcaemia. Bone profile revealed severe hypophosphataemia (<0.62 mg/dL), requiring intravenous phosphate, due to prior ferric carboxymaltose treatment given pre-op for uterine fibroid. The fibroid was excised and confirmed benign. The adrenal incidentaloma (2.1 cm, HU <6) remained stable on interval imaging and was biochemically non-functional. Genetic analysis for familial hypercalcaemia was negative. Follow-up CT imaging showed complete resolution of the lytic bone lesions. Patient is waiting for bone density scan appointment. In recent follow up, bone profile had normalized. Conclusion This case illustrates a rare presentation of primary hyperparathyroidism with severe hypercalcaemia and brown tumours, radiologically mimicking metastatic disease. The clinical course was further complicated by incidental findings of a non-functional adrenal adenoma and a benign uterine fibroid. Effective management required timely interventions and coordinated multidisciplinary care.Figure 1:Presentation CT imagingCT abdomen and pelvis, in coronal view, shows lytic lesions in the lumbar vertebrae (indicated by yellow arrows) and a right-sided hydroureter. Table 1:Presentation biochemical parameters
2025-10-01 | MON-776 When Electrolytes Tell the Story: Hypomagnesemia and Its Paradoxical Interaction with Parathyroid Disorders: A case report
Abstract Disclosure: R. Reguram: None. S. Neti: None. D.K. Yerasuri: None. Background: While hypomagnesemia can cause hypocalcemia, it also serves as an indicator for severity of primary hyperparathyroidism (PHPT) by contributing to hypercalcemia. This rare case presents a mixed picture of PHPT and familial hypocalciuric hypercalcemia (FHH) and the relationship between magnesium metabolism and parathyroid disorders. Presentation: A 76-year-old female with type 2 diabetes, hypertension, and chronic diarrhea presented with persistent hypomagnesemia despite oral and IV supplementation. Laboratory results showed consistently low magnesium (1.3-1.7 mg/dL), high-normal calcium (10.1-10.9 mg/dL), significantly elevated PTH (119.1-202.4 pg/mL), low 24-hour urine calcium (55-74 mg), and a high 24-hour urinary magnesium (186.9 mg) that indicated renal magnesium wasting. A Sestamibi scan identified a parathyroid adenoma. She also had a history of skeletal complications including an atraumatic radial fracture and severe osteoporosis on DEXA (radial T-score: -3.3). Despite these features pointing towards PHPT, presence of hypocalciuria and a low calcium-creatinine clearance ratio (<0.01) suggested coexisting FHH. Discussion: This case shows the complex interaction between magnesium, calcium and parathyroid (PTH) regulation. Hypomagnesemia can impair calcium-sensing receptor (CaSR) function and PTH secretion, potentially modifying PHPT presentation or mimicking FHH. Renal magnesium wasting likely exacerbated the patient's symptoms and complicated diagnosis. While FHH typically presents in younger individuals with mild hypercalcemia, this patient’s advanced age, significant osteoporosis and parathyroid adenoma supported PHPT. Hypomagnesemia is associated with more severe PHPT manifestations and increased risk of postoperative hypocalcemia. Hence comprehensive evaluation of magnesium status becomes critical, especially in patients with persistent hyperparathyroidism and atypical biochemical profiles. Conclusion: This case focuses on the importance of recognizing hypomagnesemia as both a modulator and a confounder in the diagnosis and management of parathyroid disorders. Persistent magnesium imbalance may complicate the presentation of PHPT or mimic FHH, leading to diagnostic uncertainty. Early and aggressive correction of hypomagnesemia is crucial not only for improving symptoms but also for ensuring accurate diagnosis and optimizing management. Further research is needed to clarify magnesium’s role in parathyroid pathophysiology and its impact on clinical outcomes. Presentation: Monday, July 14, 2025
2025-04-03 | Bone in Parathyroid Diseases Revisited: Evidence From Epidemiological, Surgical and New Drug Outcomes.
PTH-related disorders have a major impact on bone metabolism and skeletal properties because of the pivotal role of PTH in calcium and phosphate homeostasis and bone remodeling. Hyperparathyroidism is characterized by continuous exposure to excessive endogenous PTH, causing increased bone turnover in favor of bone resorption. Depending on the background of PTH overproduction, hyperparathyroidism is divided into primary, secondary, and tertiary hyperparathyroidism. The clinical presentation varies from deterioration of bone microarchitecture and decreased bone mineral density to profound bone involvement, such as osteitis fibrosa cystica and fragility fractures. Although successful parathyroidectomy represents the definitive treatment and may promote regression of most of the skeletal defects, the medical approach of calcimimetics and antiresorptive agents is a promising alternative in cases where parathyroidectomy is not feasible or unsuccessful. Hypoparathyroidism is the pathophysiological counterpart of hyperparathyroidism and also leads to disorders of bone metabolism and structure. Chronic PTH deprivation is associated with low bone remodeling and increased bone mineral density. The defective microarchitecture might affect bone strength and raise the risk for adverse skeletal events. Recombinant human PTH acts as a replacement therapy and is safe and efficient in restoring calcium/phosphate homeostasis and bone turnover. However, it is approved only for refractory cases, as conventional management with calcium and active vitamin D remains the first-line treatment. This article reviews the skeletal involvement in the most frequent parathyroid disorders, hyperparathyroidism and hypoparathyroidism, and rare familial disorders of PTH metabolism, as assessed by clinical, laboratory, and imaging parameters, and the effect of the available treatment strategies.
2024-11-01 | Rising Trend in the Frequency of Secondary and Tertiary Hyperparathyroidism: Observations from the Indian PHPT Registry
Primary hyperparathyroidism (PHPT) is the third common endocrine disorder characterised by hypercalcaemia with inappropriately elevated parathyroid hormone (PTH) levels. PHPT is primarily a sporadic disease (85–90%); however, hereditary/familial cases with known genetic causes account for 10–15% of the cases. Sporadic PHPT is mainly caused by parathyroid adenoma (PA) (80–85%), followed by parathyroid hyperplasia (15–20%) and rarely by parathyroid carcinoma (PC) (<1%). Secondary hyperparathyroidism (SHPT) usually results from vitamin D deficiency, chronic kidney disease (CKD), and malabsorption states. However, tertiary hyperparathyroidism (THPT) is the end result of long-standing secondary hyperparathyroidism associated with CKD on renal replacement therapy (RRT). Patients with severe SHPT or THPT due to CKD often require surgical intervention in the form of subtotal parathyroidectomy. The Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, maintains an online database named The Indian PHPT Registry (www.indianphptregistry.com) of patients undergoing parathyroid surgery for PHPT, SHPT, and THPT.[1,2] It is noteworthy that the majority of the cases enrolled in the Indian registry are PHPT; however, of late, there has been a noticeable rise in the frequency of SHPT and THPT cases. We retrieved the data from the registry of all patients who had undergone parathyroid surgery at our institute from 1 January 2013 to 1 January 2023. A total of 404 adults had been enlisted in this decade with 171 patients having undergone surgery between 2013 and 2017, while the rest 233 are operated between 2018 and 2023. The frequency of PHPT, SHPT, and THPT was 96.5%, 0.7%, and 1.7%, respectively, in the first half of the decade (2013–2017). However, over the next 5 years (2018–2023), there was an appreciable rise in the frequency of SHPT and THPT cases to 4.3% and 10.3%, respectively. This apparent rise in the frequency of SHPT and THPT could be the result of increased awareness among physicians, nephrologists, and endocrinologists about these entities along with an increased lifespan of patients with CKD, courtesy more efficient forms of RRTs. Accordingly, more CKD patients are being diagnosed with SHPT and THPT. Besides, as renal transplantation has become more widespread and affordable, more CKD patients are undergoing renal transplantation. Correction of severe SHPT and THPT is of paramount importance prior to renal transplantation, which could also explain the apparent rise in the frequency encountered over the past half a decade.[3] Author contribution SG is the primary author. RP edited the manuscript. SKB is the corresponding author. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
gene therapies
2024-11-04 | Molecular genetics in familial primary hyperparathyroidism: A study from Northern India
Purpose Familial primary hyperparathyroidism (FPHPT) accounts for about 10% of cases, owing to germline mutations in specific genes. The genetic profile of FPHPT has not been studied in our population. This is most likely the first study in our region to examine the genetic profile to search for any other PHPT-related tumours in these patients. Methods This prospective cross-sectional study was conducted in the Department of Endocrinology SKIMS from February 2021 to February 2023, in which 103 patients diagnosed with PHPT were taken. A customised gene panel (CDC 73, MEN 1/2A/4 mutation) using next-generation sequencing (NGS)was performed in 39 patients with strong suspicious of FPHT based on age < 35 years, multiglandular disease, cystic parathyroid adenoma (PA), parathyroid carcinoma (PC), suspicious of MEN 1/2A/4 syndrome. We tried to compare the clinical characteristics of individuals with those of positive and negative genetic tests. Results Germline variants were observed in 11/39 (28.2%). 7(17.9%) patients tested positive for MEN 1 mutation while 4(10.2%) patients tested positive for CDC 73 mutation; however, no one tested positive for MEN 2A/4 mutation. 4 patients with MENI syndrome had c.1366-2A > G p? while as 1 had c.247_250del CTGT(p.Ile85SerfsTer33), 1 had c.1763C > T (p.S588L), 1 had c.415 C > T(p.H139Y). Out of 7 who tested positive for MEN 1 mutation, 2 patients had microprolactinomas, 2 had multi-glandular disease, 1 had recurrent disease, 1 had persistent disease, 1 had gastric neuroendocrine tumour. In contrast, out of 4 who tested positive for CDC 73 mutation, 2 had familial PHPT, 1 had multiple uterine fibroids, and 1 had bilateral renal cysts. In the case of patients with CDC 73 mutations, 1 patient had codon 222 CGA (Arg) > TGA, 1 had c.415C > T at codon 139 (R139X), 1 had c.687_688dellAG (p.Arg229Serfs37), other had c76delA (p.Ile26SerfsX11). These were all reported mutations. Age, greater serum calcium, higher ALP and more skeletal involvement were statistically significant characteristics of those who tested positive for the mutation. Conclusion The observed prevalence of genetic variants in our population was remarkably higher than in other populations. Recognition of predisposing germline mutations can have significant implications in patient management, such as preventing PC in HPT-JT and optimizing the approach to parathyroidectomy in MEN 1. So, we strongly recommend genetic screening in PHPT patients with high-risk features.
2020-04-07 | Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.
We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.
2020-03-16 | Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?
Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease. The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT). From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance. We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.
2010-06-02 | Development of a Technique for Introduction of an Expressed Complementary Deoxyribonucleic Acid into Parathyroid Cells by Direct Injection
PTH is a major mediator of bone and mineral metabolism. However, physiological and pathological investigations of parathyroid cells (PTCs) have been limited because of the lack of available cell lines and because the organ is too small for detailed studies. Here, we describe a novel method for adenovirus-mediated cDNA transfer into PTCs, and we show the accuracy of the method in a rat model of uremia-induced secondary hyperparathyroidism. Rats underwent a 5/6-nephrectomy and were fed with a high-phosphate diet for 8 wk. The parathyroid glands were surgically exposed and adenoviruses containing LacZ or Ca-sensing receptor (CaSR) were directly injected into the glands under a zoom-stereo microscope. The parathyroid glands were analyzed for infection of adenovirus and immunohistochemically for expression of CaSR. The functional activity of exogenous CaSR in PTCs after this treatment was investigated based on changes of the calcium and PTH curve. A virus concentration of more than 109 plaque-forming units/ml was required for adequate infection of PTCs within 7 d after treatment. Marked increase of CaSR-positive PTCs by 2.39 ± 0.72 times relative to control treatment, and significant colocalization of CaSR overexpression and virus labeling, were observed in glands after gene introduction. The calcium and PTH curve was shifted to the left from the basal position (set point, 1.10 ± 0.09 to 0.76 ± 0.12 mm; P < 0.0001), indicating successful introduction of a functionally active cDNA into the PTCs. This technique may facilitate an elucidation of biological effects through targeting and identification of specific features of PTCs, which may provide the basis for new clinical approaches.
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Drug Discovery Landscape
1 orphan drug designation for Familial primary hyperparathyroidism, including 1 approved therapy.
1 orphan drug designation for Familial primary hyperparathyroidism, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
cinacalcet [Sensipar] | small molecules | FDA | Approved | Amgen, Inc. |
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