A 51-year-old woman with a history of primary hyperparathyroidism (PHPT) with prior parathyroidectomy, osteoporosis, and learning disability was referred for hypercalcemia discovered after a fall. Family history was negative for PHPT, pituitary, enteropancreatic neuroendocrine, or jaw tumors. Dysmorphic facies, multiple cutaneous melanocytic nevi, café au lait macules, long fingers, and scoliosis were observed. Laboratory evaluation showed an elevated parathyroid hormone (PTH) level, hypercalcemia, and hypophosphatemia, all consistent with PHPT. Preoperative imaging revealed a right inferior candidate parathyroid lesion. The patient underwent right inferior parathyroidectomy with normalization of PTH, calcium, and phosphorus. Genetic testing showed a likely pathogenic de novo heterozygous germline missense variant p.R764W in the ZFX gene that encodes a zinc-finger transcription factor previously shown to harbor somatic missense variants in a subset of sporadic parathyroid tumors. Germline variants in ZFX have been reported in patients with an X-linked intellectual disability syndrome with an increased risk for congenital anomalies and PHPT. Further research may determine if genetic testing for ZFX could be of potential benefit for patients with PHPT and developmental anomalies, even in the absence of a family history of parathyroid disease.

BACKGROUND: Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or distant metastasis, leading to uncertainty regarding its malignant potential.
OBJECTIVE: To characterize the molecular landscape and deregulated pathways in APT.
METHODS: Whole exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000.
RESULTS: A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT.
CONCLUSIONS: APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.

Introduction Primary hyperparathyroidism (PHPT) has undergone a considerable change from being symptomatic to asymptomatic. This is the first large study from North India to study the clinical and biochemical features and surgical outcomes in the present era. Study design This is a cross-sectional study that was conducted in the Department of Endocrinology (SKIMS) from February 2021 to December 2022, in which 103 patients diagnosed with PHPT were included. Evaluation included measurement of total calcium, phosphorus, alkaline phosphate, intact parathyroid hormone, 25-hydroxy vitamin, 24-hour urinary calcium, radiological survey of hands and skull, Dual Energy X-ray absorptiometry, and ultrasonography (USG) of the abdomen. USG neck and technetium-99m sestamibi scans were used for preoperative localization; however, in cases of discordance between these investigations or suspicions of multi-glandular disease, four-dimensional computerized tomography of the neck was used. Patients were subjected to surgery according to the guidelines and monitored post-surgery for complications like hypocalcemia and hungry bone syndrome and to document the cure. Results The mean age of patients was 42.8±14.73 years, with a female-to-male ratio of 4.4:1. The mean eGFR of patients was 99.1±30.87 ml/min, with 55 (53.4%) of them having renal disease. Osteoporosis and fractures were present in 41 (39.8%) and 5 (4.8%) patients, respectively. Cholelithiasis and pancreatitis were present in 25 (24.3%) and 5 (4.9%) patients, respectively. Hypertension (HTN) and diabetes mellitus (DM) were the commonest comorbidities, which were present in 34 (33.1%) and 15 (14.5%) patients, respectively. Mean preoperative levels of calcium, phosphorus (PO4), alkaline phosphate (ALP), intact parathyroid hormone (iPTH), 25(OH)vitamin D, and 24-hour urinary calcium were 12.1 mg/dl, 2.35 mg/dl, 210.2 U/L, 332.9 pg/ml, 25.7 ng/ml, and 452.1 mg/day, respectively. The most common type was right inferior parathyroid adenoma, present in 45 cases (43.7%), followed by left inferior parathyroid adenoma in 31 cases (30.1%). A total of 75 patients (72.8%) underwent minimally invasive parathyroidectomy, with 68 patients (90.7%) achieving a biochemical cure. The mean adenoma weight was 3.19±2.25 g. There was no statistically significant correlation (r) between preoperative biochemical parameters and adenoma weight. Conclusion Despite improvements in imaging and the easy availability of immunoassays for early diagnosis, renal disease continued to be the most common presentation, followed by skeletal involvement in our population. In developing countries like India, any patient presenting with nephrolithiasis or nephrocalcinosis, low bone mass, or fragility fractures should be evaluated for PHPT.

OBJECTIVE: Primary Hyperparathyroidism (PHPT) is a common disease, frequently diagnosed in post-menopausal women, among whom Osteoporosis (OP) is a common finding. To date, no study has specifically evaluated the asymptomatic PHPT (aPHPT) patients without OP, in particular post-menopausal women who are exposed to an increased risk of developing OP.
METHODS: This study involved a retrospective cross-sectional evaluation.
METHODS: From our database of 500 consecutive patients diagnosed with PHPT, 178 postmenopausal aPHPT were retrieved.
RESULTS: The clinical, biochemical, and imaging data of the 85 patients without OP were not different from those of the 93 with OP, except for bone alkaline phosphatase (significantly higher in the latter group). Among these 85 patients without OP, the 45 patients meeting surgical criteria for parathyroidectomy had significantly higher values of serum PTH (240 vs. 99 ng/L, p =0.03) and calcium (total, 11.2 ± 0.7 vs. 10.6 ± 0.4 mg/dL, p <0.001; ionized, 1.45 ± 0.12 vs. 1.36 ± 0.8 mmol/L, p =0.044) and lower values of serum phosphate (2.57 ± 0.7 vs. 2.94 ± 0.5 mg/dL, p =0.009) and eGFR (68.5 ± 23.8 vs 80.8 ± 14.4 mL/min/1.73 m2, p =0.006) than the 40 aPHPT patients not meeting surgical criteria, without any difference in densitometric data and calculated fracture risk.
CONCLUSIONS: In our series, post-menopausal aPHPT patients without OP accounted for almost a sixth of the whole PHPT series. About half of these patients did not meet surgical criteria, but their T scores and 10-year fracture risk calculated by FRAX were not significantly different from post-menopausal aPHPT without OP meeting surgical criteria.

OBJECTIVE: Primary hyperparathyroidism (PHPT) in paediatric and adolescent age group presents with some unique challenges for clinicians. While the disease in the adult counterparts presents with symptoms which are described quite extensively in literature, children/adolescents have manifestations which are quite different and severe compared to the former. The present case series aimed to highlight the peculiarities of presentation of PHPT in children and adolescents.
METHODS: In this case series, we present experience of 5 cases of PHPT in children and adolescents from our centre. We compared our data with the data already available in literature. We have also described salient presenting features of PHPT in individuals less than 19 years old previously reported in literature and pointed out the specificities of this disease at this age group.
CONCLUSIONS: PHPT in children and adolescents should be considered as a separate entity compared to that in adults, given its unique features, such as rachitic features, and severity of different presenting phenotypes. Persistence of rachitic features despite vitamin D correction, pancreatitis, bilateral nephrolithiasis and otherwise unexplained psychiatric abnormalities of insidious onset require greater clinical vigilance and serum/urine calcium testing to rule out this uncommon yet possible entity.

BACKGROUND: Vitamin D (Vit D) deficiency is common in patients with hyperparathyroidism, but the importance of replacement before surgery is controversial. It can be predicted that hypocalcemia risk will be higher in patients with high bone turnover.
OBJECTIVE: In this study, the effect of preoperative ALP/Vit D ratio on postoperative hypocalcemia was investigated.
METHODS: Among the primary hyperparathyroidism cases who were operated between 2015 and 2022, 158 patients with complete data were included in the study. Preoperative laboratory results, radiological images, and pathology reports of the patients were evaluated retrospectively. The cross-sectional value of the ALP/Vit D value predicting hypocalcemia was calculated. The effect of these parameters on postoperative hypocalcemia was investigated.
RESULTS: The mean age of our patients was 54 (21-81 years). When factors affecting postoperative hypocalcemia were evaluated by univariable analysis, Vit D deficiency and insufficiency (p < 0.001), ALP (p < 0.001), ALP/Vit D ratio (p < 0.001), and T score (p = 0.026) found to be factors affecting postoperative hypocalcemia. In multivariate analysis, the ALP/Vit D ratio was found to be an independent variable in predicting hypocalcemia. It was found that hypocalcemia was 45 times more common in patients with ALP/Vit D > 6.34 (p < 0.001). ALP/Vit D ratio predicts patients who will develop postoperative hypocalcemia with 87.2% sensitivity and 87.1% specificity.
CONCLUSIONS: Vit D deficiency increases the risk of postoperative hypocalcemia, but it is not sufficient alone to predict it. The risk increases more in patients with high bone turnover. The preoperative ALP/Vit D ratio is the strongest predictor of postoperative hypocalcemia risk.

Primary hyperparathyroidism (PHPT) is an endocrinological disease that affects systemic inflammation. This study is aimed to investigate the preoperative and postoperative effect of PHPT on systemic inflammation. A total of 203 patients who were successfully operated for PHPT and 98 healthy controls were included in the study. The blood tests of the patients in the last month preoperatively and in the postoperative 6th month were compared. In addition, preoperative and postoperative tests were compared with the healthy control group. When the preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic inflammation index (SII) values of the patients who were operated for parathyroid adenoma were compared with the control group (p values were < 0.05, 0.01, 0.19, < 0.05), the NLR, PLR, and SII values were significantly lower in the patient group with parathyroid adenoma than in the control group. When the preoperative and postoperative 6th month NLR, PLR, LMR, and SII values of the patients were compared (p values: 0.026, 0.56, 0.023, 0.016, respectively), there was a significant increase in NLR and SII values after excision, while a significant decrease was observed in the LMR value. When the postoperative 6th month NLR, PLR, LMR, SII values were compared with the healthy control group (p values: 0.22, 0.29, 0.19, 0.29, respectively), no significant difference was observed between all values. We found that the immune system was suppressed in PHPT and this returned to normal levels after a successful surgery.

OBJECTIVE: Baseline renal dysfunction predicts mortality in primary hyperparathyroidism (PHPT). However, it remains controversial whether renal insufficiency in PHPT is due to disease severity alone or other risk factors. This study aimed to explore the association of clinico-biochemical variables with renal dysfunction [estimated glomerular filtration rate (eGFR) < 60 ml/min/m2] in PHPT.
METHODS: A total of 112 patients of PHPT were selected and divided into following subgroups: renal dysfunction (n = 28) and normal renal function (n = 84). Demographic characteristics, traditional risk factors, phenotypes of PHPT based on target organ involvement, and biochemical parameters were compared between these subgroups.
RESULTS: Patient subgroups of PHPT with and without renal dysfunction had similar age, frequency of diabetes, and hypertension. Renal dysfunction was more prevalent in males (p < 0.05). Compared to normal renal function subgroup, individuals with renal dysfunction had higher serum levels of calcium, phosphate, alkaline phosphatase, intact parathormone (all p < 0.05), while having lower hemoglobin levels (p < 0.05) and higher nephrolithiasis rates (p < 0.05). Multiple regression analysis revealed that nephrolithiasis, serum calcium-phosphorous product (CaxP), parathormone levels were positively associated with baseline renal dysfunction (all p < 0.01). A baseline PTH > 456 pg/mL and CaxP > 30.0 mg2/dl2 could discriminate renal dysfunction from normal renal function with sensitivity and specificity of 75% and 74.5% and 92.6% and 74.4%, respectively.
CONCLUSIONS: Renal dysfunction was associated with presence of nephrolithiasis, elevated serum CaxP and PTH levels in our cohort with predominantly symptomatic PHPT, indicating an association with the underlying disease itself. Serum CaxP may additionally be appraised during risk assessment in PHPT.

Primary hyperparathyroidism (PHPT), a relatively common disorder characterized by hypercalcemia with raised or inappropriately normal serum parathyroid hormone (PTH) concentrations, may occur as part of a hereditary syndromic disorder or as a non-syndromic disease. The associated syndromic disorders include multiple endocrine neoplasia types 1-5 (MEN1-5) and hyperparathyroidism with jaw tumor (HPT-JT) syndromes, and the non-syndromic forms include familial hypocalciuric hypercalcemia types 1-3 (FHH1-3), familial isolated hyperparathyroidism (FIHP), and neonatal severe hyperparathyroidism (NS-HPT). Such hereditary forms may occur in > 10% of patients with PHPT, and their recognition is important for implementation of gene-specific screening protocols and investigations for other associated tumors. Syndromic PHPT tends to be multifocal and multiglandular with most patients requiring parathyroidectomy with the aim of limiting end-organ damage associated with hypercalcemia, particularly osteoporosis, nephrolithiasis, and renal failure. Some patients with non-syndromic PHPT may have mutations of the MEN1 gene or the calcium-sensing receptor (CASR), whose loss of function mutations usually cause FHH1, a disorder associated with mild hypercalcemia and may follow a benign clinical course. Measurement of the urinary calcium-to-creatinine ratio clearance (UCCR) may help to distinguish patients with FHH from those with PHPT, as the majority of FHH patients have low urinary calcium excretion (UCCR < 0.01). Once genetic testing confirms a hereditary cause of PHPT, further genetic testing can be offered to the patients\' relatives and subsequent screening can be carried out in these affected family members, which prevents inappropriate testing in normal individuals.

UNASSIGNED: 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.
UNASSIGNED: To determine whether the GCM2 p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.