Treatment of Hypercalcemic Hyperparathyroidism After Kidney Transplantation Is Associated With Improved Allograft Survival.

BACKGROUND: Hyperparathyroidism (HPT) and malignancy are the most common causes of hypercalcemia. Among kidney transplant (KT) recipients, hypercalcemia is mostly caused by tertiary HPT. Persistent tertiary HPT after KT is associated with allograft failure. Previous studies on managing tHPT were subjected to survivor treatment selection bias; as such, the impact of tertiary HPT treatment on allograft function remained unclear. We aim to assess the association between hypercalcemic tertiary HPT treatment and kidney allograft survival. MATERIALS AND METHODS: We identified 280 KT recipients (2015-2019) with elevated post-KT adjusted serum calcium and parathyroid hormone (PTH). KT recipients were characterized by treatment: cinacalcet, parathyroidectomy, or no treatment. Time-varying Cox regression with delayed entry at the time of first elevated post-KT calcium was conducted, and death-censored and all-cause allograft failure were compared by treatment groups. RESULTS: Of the 280 recipients with tHPT, 49 underwent PTx, and 98 received cinacalcet. The median time from KT to first elevated calcium was 1 month (IQR: 0-4). The median time from first elevated calcium to receiving cinacalcet and parathyroidectomy was 0(IQR: 0-3) and 13(IQR: 8-23) months, respectively. KT recipients with no treatment had shorter dialysis vintage (P = .017) and lower PTH at KT (P = .002), later onset of hypercalcemia post-KT (P < .001). Treatment with PTx (adjusted hazard ratio (aHR) = 0.18, 95%CI 0.04-0.76, P = .02) or cinacalcet (aHR = 0.14, 95%CI 0.004-0.47, P = .002) was associated with lower risk of death-censored allograft failure. Moreover, receipt of PTx (aHR = 0.28, 95%CI 0.12-0.66, P < .001) or cinacalcet (aHR = 0.38, 95%CI 0.22-0.66, P < .001) was associated with lower risk of all-cause allograft failure. CONCLUSIONS: This study demonstrates that treatment of hypercalcemic tertiary HPT post-KT is associated with improved allograft survival. Although these findings are not specific to hypercalcemia of malignancy, they do demonstrate the negative impact of hypercalcemic tertiary HPT on kidney function. Hypercalcemic HPT should be screened and aggressively treated post-KT.

Efficacy of denosumab in the treatment of hypercalcemic renal dysfunction in sarcoidosis: a case report.

A 70-year-old female patient was admitted for close examination and treatment of hypercalcemia (corrected serum calcium levels: 3.04 mmol/L) and renal dysfunction (serum creatinine levels: 254.59 µmol/L). The patient had a history of sarcoidosis, diagnosed based on epithelioid cell granulomas in subcutaneous nodule biopsies, uveitis, and bilateral hilar lymphadenopathy, which had spontaneously remitted 10 years before admission. Because the patient was diagnosed with hypercalcemia associated with recurrent sarcoidosis, prednisone (20 mg/day) was initiated, and its dose was tapered following the decrease in serum calcium and creatinine levels. However, the levels of these parameters increased again when the prednisone dose was reduced to ≤ 4 mg/day. We were concerned about glucocorticoid-induced osteoporosis in the patient but hesitated to use first-line bisphosphonates because of renal dysfunction. Therefore, denosumab was initiated to reduce the risk of hypercalcemia, renal dysfunction, and glucocorticoid-induced osteoporosis. Serum creatinine and corrected serum calcium levels subsequently decreased. The prednisone dose could be reduced following repeated denosumab administration.Thus, denosumab can be a multifaceted, beneficial option for sarcoidosis-induced hypercalcemia, as it alleviates renal dysfunction indirectly by normalizing serum calcium levels, facilitates reduction of the glucocorticoid dose, and ameliorates glucocorticoid-induced osteoporosis.

Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma.

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

Testing for Primary Hyperparathyroidism in 17,491 Patients With Hypercalcemia.

BACKGROUND: Primary hyperparathyroidism (PHPT) is underdiagnosed and associated with many adverse health effects. Historically, many hypercalcemic patients have not received parathyroid hormone (PTH) testing; however, underlying reasons are uncertain. Our goals are to determine the PTH testing rate among hypercalcemic individuals at a large academic health system and to assess for characteristics associated with testing versus not testing for PHPT to inform future strategies for closing testing gaps. METHODS: This retrospective study included adult patients with ≥1 elevated serum calcium result between 2018 and 2022. Based on the presence or absence of a serum PTH result, individuals were classified as "screened" versus "unscreened" for PHPT. Demographic and clinical characteristics of these groups were compared. RESULTS: The sample comprised 17,491 patients: 6567 male (37.5%), 10,924 female (62.5%), mean age 59 y. PTH testing was performed in 6096 (34.9%). Characteristics independently associated with the greatest odds of screening were 5+ elevated calcium results (odds ratio [OR] 5.02, P < 0.0001), chronic kidney disease (OR 3.63, P < 0.0001), maximum calcium >12.0 mg/dL (OR 2.48, P < 0.0001), and osteoporosis (OR 2.42, P < 0.0001). Characteristics associated with lowest odds of screening were age <35 y (OR 0.60, P < 0.0001), death during the study period (OR 0.68, P < 0.0001), age ≥85 y (OR 0.70, P = 0.0007), and depression (OR 0.84; P = 0.0081). CONCLUSIONS: Only 35% of hypercalcemic patients received PTH testing. Although the presence of PHPT-associated morbidity was generally associated with increased rates of screening, hypercalcemic patients with depression were 16% less likely to be tested.

Modern Trends for Primary Hyperparathyroidism: Intervening on Less Biochemically Severe Disease.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is defined by autonomous parathyroid hormone secretion, which has broad physiologic effects. Parathyroidectomy is the only cure and is recommended for patients demonstrating symptomatic disease and/or end organ damage. However, there may be a benefit to intervening before the development of complications. We sought to characterize institutional trends in the biochemical and symptomatic presentation of PHPT and the associated cure and complication rates. METHODS: We performed a retrospective cohort study of 1087 patients undergoing parathyroidectomy for PHPT, evaluating patients at 2-year intervals between 2002 and 2019. We identified signs and symptoms of PHPT based on the 2016 American Association of Endocrine Surgery Guidelines. Trends were evaluated with Kruskal Wallis, Chi-square tests, and Fisher's exact tests. RESULTS: Patients with PHPT are presenting with lower parathyroid hormone (P = 0.0001) and calcium (P = 0.001) in the current era. Parathyroidectomy is more commonly performed for borderline guideline concordant patients with osteopenia (40.2%) and modest calciuria (median 246 mg/dL/24 h). 93.7% are cured, with no difference over time or between groups by guideline concordance. CONCLUSIONS: Parathyroidectomy is increasingly performed for patients who demonstrate modest bone and renal dysfunction. Patients experience excellent cure rates and rarely experience postoperative hypocalcemia, suggesting a role for broader surgical indications.

Hypercalcemia as a rare manifestation of immune reconstitution inflammatory syndrome (IRIS) in a person living with Human Immunodeficiency Virus (HIV) with disseminated nontuberculous mycobacteriosis.

INTRODUCTION: Granulomatosis due to immune reconstitution inflammatory syndrome (IRIS) and disseminated Mycobacterium avium-intracellulare (M. avium) infection may trigger hypercalcemia. Here, we report a rare case of hypercalcemia and acute kidney damage related to IRIS in a person living with Human Immunodeficiency Virus (HIV). CASE PRESENTATION: A 39-year-old male person living with HIV presented with muscle weakness and unwanted weight loss of 8 kg within the last 2 weeks. Laboratory findings included serum hypercalcemia of 3.27 mmol/mL associated with elevated calcitriol and acute kidney damage. Since the first diagnosis of HIV and concomitant disseminated M. avium infection, the patient received antiretroviral therapy (ART), rifabutin, clarithromycin, and ethambutol. 18Fluoro-D-glucose positron emission computed tomography (18FDG-PET/CT) showed progressive multilocular lymphadenopathy. Biopsy specimen from the duodenum as well as retroperitoneal and mediastinal lymph nodes revealed granulomatous inflammation consistent with IRIS. Treatment with forced diuresis, bisphosphonates, and calcitonin normalized serum calcium and kidney function recovered. CONCLUSION: Hypercalcemia due to IRIS is a rare differential diagnosis in persons living with HIV and may lead to acute kidney damage, despite sufficient ART and antimycobacterial treatment.

Denosumab in a pediatric kidney transplant recipient with late, resistant hypercalcemia secondary to Pneumocystis jirovecii pneumonia.

Kidney transplant recipients (KTR) are at an increased risk of developing Pneumocystis jirovecii pneumonia (PCP), especially during the first year after transplantation. This is the first reported pediatric KTR, with chronic kidney disease (CKD) secondary to kidney dysplasia and vesicoureteral reflux, who developed refractory and symptomatic hypercalcemia 5 years after transplantation. The hypercalcemia was resistant to treatment with intravenous hyperhydration, furosemide, and a low-calcium diet. A respiratory tract infection due to PCP treated with trimethoprim-sulfamethoxazole did not improve calcium levels. Due to the hypercalcemic symptom burden for the patient, a single dose of subcutaneous denosumab was used to achieve sustained clinical and biochemical improvement, without any severe adverse events. This case highlights the potential use of denosumab as a treatment option in pediatric KTR with refractory hypercalcemia related to PCP. Further study of denosumab in young people with CKD or kidney transplants is needed before routine use can be recommended.

Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2.

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis.

Pamidronate-induced irreversible symptomatic hypocalcemia in a dog with hypercalcemia after glucocorticoid withdrawal: a case report.

BACKGROUND: Pamidronate is used for the treatment of hypercalcemia. However, a rare but potential adverse event of pamidronate treatment is hypocalcemia. This report describes an unusual case of severe, irreversible hypocalcemia after a single injection of pamidronate for the treatment of hypercalcemia due to glucocorticoid withdrawal in a dog. CASE PRESENTATION: An 11-year-old castrated male Maltese dog presented with anorexia, vomiting, and diarrhea (day 0). The patient had calcinosis cutis throughout the body, calcification of intraabdominal organs, mild azotemia, and severe hypercalcemia. The severe calcification was attributed to long-term glucocorticoid administration, which was discontinued 1 month before presentation. Fluid therapy, diuretics, calcitonin, and a single intravenous injection of pamidronate were used for the treatment of hypercalcemia. On day 14, normocalcemia was achieved, but renal failure occurred. On day 20, severe and irreversible hypocalcemia occurred, and on day 42, the patient was euthanized at the owner's request because of worsened hypocalcemia and renal failure. CONCLUSIONS: Although hypocalcemia is an extremely rare adverse event of bisphosphonate treatment, bisphosphonates like pamidronate can result in potentially life-threatening conditions according to the patient's underlying conditions. Therefore, the patient's condition should be closely monitored and any underlying conditions should be carefully evaluated before initiating the treatment for hypercalcemia using pamidronate.

The calcium-clot connection: investigating the association between primary hyperparathyroidism and acute venous thromboembolism.

Primary hyperthyroidism (PHPT) is a relatively uncommon disease and leads to increased calcium levels. Ionized calcium, known as clotting Factor IV, may lead to overt coagulation cascade activation, increasing the risk of venous thromboembolism (VTE). National Inpatient Sample Database was used to sample individuals with primary hyperparathyroidism, and baseline demographics and comorbidities were collected using ICD-10 codes. Patients with missing data and age less than 18 were excluded. Moreover, patients with other types of hyperparathyroidism and risk factors for VTE, such as malignancy, thrombophilia, chronic kidney and liver disease, fractures, trauma, oral contraceptive/steroid use, and organ transplant, were excluded. Greedy propensity matching using R was performed to match patients with and without primary hyperparathyroidism on age, race, gender, and 10 other comorbidities, including chronic deep venous thromboembolism. Univariate analysis pre- and post-match were performed. Binary logistic regression was performed after matching to assess whether primary hyperparathyroidism was an independent risk factor for acute VTE. A p-value of < 0.05 was considered statistically significant. Out of 460,529 patients included in the study, 1114 (6.5%) had PHPT. Baseline comorbidities were more common in the PHPT group. On univariate analysis, patients with PHPT were more likely to have acute VTE (2.5% vs. 1.4%; p < 0.001). After 1:1 matching, PHPT patients were twice as likely to have Acute VTE. (OR: 2.1 [1.08-4.1]; p < 0.025). These findings suggest an association between PHPT and VTE, which should be further investigated to prevent the increasing incidence of VTE and its recurrence.

Primary Hyperparathyroidism due to Parathyroid Adenoma in Children and Adolescents.

OBJECTIVE: In contrast to adults, primary hyperparathyroidism (PHPT) in children and adolescents is a rare endocrine disorder. METHODS: A retrospective review of PHPT cases between 2005 and 2022 from a single tertiary university medical center, including clinical signs and symptoms, laboratory findings, radiological evaluation, treatment, and postoperative complications. RESULTS: Ten children (mean age at diagnosis 16.3 ± 1.3 years) were diagnosed with PHPT. All patients were in late pubertal stages without sex predominance and 8 were symptomatic. Mean calcium level was 13.6 ± 2.5 mg/dL, and mean parathyroid hormone levels were 204.8 ± 163.1 pg/mL. Parathyroid adenoma was confirmed by the postsurgical pathology results. CONCLUSIONS: PHPT in children and adolescents is often symptomatic and more severe than adults. The main cause is single parathyroid adenoma. Associated hypercalcemic syndromes were not found. Patients were cured after surgical removal of the adenoma without significant postoperative complications and no recurrence during 10.4 ± 5.9 years follow-up.

Acute pancreatitis and refractory hypercalcemia in the third trimester caused by parathyroid carcinoma.

BACKGROUND: Hypercalcemia can be a rare contributor to acute pancreatitis (AP) in pregnancy. This is primarily due to primary hyperparathyroidism (PHPT), resulting from parathyroid carcinoma. We exhibited a case report to analyze the diagnosis and treatment during the onset of hypercalcemia-induced AP. CASE PRESENTATION: A 32-year-old primigravida presented with acute pancreatitis near full-term gestation. Following a cesarean delivery, there was a reduction in serum amylase and peripancreatic exudate, but her serum calcium concentrations persistently elevated over 4.0 mmol/L. Interventions to lower the hypercalcemia were only temporarily effective, until a high serum parathyroid hormone (PTH) concentration of 1404 pg/mL was detected. Ultrasound revealed a 31 mm × 24 mm hypoechoic oval nodule in the left lower lobe of the thyroid gland. She underwent a parathyroidectomy, resulting in a dramatic decrease in serum PTH level, from preoperative levels of 2051 pg/mL to 299 pg/mL just 20 minutes after removal. Similarly, her serum calcium declined from 3.82 mmol/L to 1.73 mmol/L within 24 hours postoperatively. The final histopathology suggested parathyroid carcinoma. CONCLUSION: When refractory hypercalcemia is present, serum PTH levels should be measured to determine PHPT. Parathyroidectomy is the optimal strategy for alleviating hypercalcemia and clarifying the underlying pathology.

Infantile hypercalcemia type 1 (HCINF1): a rare disease resulting in nephrolithiasis and nephrocalcinosis caused by mutations in the vitamin D catabolic enzyme, CYP24A1.

Infantile hypercalcemia type 1 (HCINF1), formerly known as Lightwood syndrome, is a subtype of hypercalcemia caused by loss-of-function biallelic mutations in the vitamin D catabolic enzyme, CYP24A1, which 24-hydroxylates the hormone 1,25-(OH)2D3. This short review focuses on the main features of the HCINF1 disease; emerging knowledge of the structure and function of the cytochrome P450, CYP24A1 and the location of inactivating mutations; the development of a rapid LC-MS/MS-based laboratory test for defective 24-hydroxylation; and future implications for bioanalytical assay and treatment of all types of vitamin D-related hypercalcemic conditions.

When to suspect infantile hypercalcemia-1?

PURPOSE: The screening test to suspect infantile hypercalcemia-1 (HCINF1) is the measure of 25(OH)D3/24,25(OH)2D3 ratio at mass spectroscopy (MS). When the ratio is > 80, the gold standard for the diagnosis is genetic analysis. Given its limited availability, MS may not represent a screening test and most cases of HCINF1 remain undiagnosed. Aim of the study is to identify cut-offs of serum calcium and PTH useful to suspect patients with HCINF1. METHODS: We compared the levels of total serum calcium and PTH of 6 patients with HCINF1 harboring biallelic CYP24A1 pathogenic variants with 3 different control groups: (1) 12 subjects wild type for CYP24A1; (2) 12 subjects matched for age and sex; (3) 12 subjects matched for vitamin D levels. We validated the cut-offs, testing the number of adult patients affected by HCINF1 reported in the literature that could be identified using these cut-offs. RESULTS: A serum calcium level > 9.6 mg/dL showed the highest sensitivity (100%) and specificity (91%) in the comparison between homozygous and wild-type subjects. A serum PTH index < 0.315 showed the highest sensitivity (100%) and specificity (83.3%). A serum calcium level > 9.6 mg/dL was able to identify all adult HCINF1 patients whereas a PTH ratio < 0.315 identified 89.8% of the cases. Superimposable results were obtained using the other control groups. CONCLUSION: Patients with serum calcium levels higher than 9.6 mg/dL and a PTH index lower than 0.315 are likely to be affected by HCINF1. Their diagnosis may be confirmed using MS and genetic analysis.

A case of hypercalcemia from Pneumocystis jirovecii in an immunosuppressed non-HIV patient.

BACKGROUND: The prevalence of non-HIV related Pneumocystis jirovecii pneumonia (PJP) is increasing with use of immunosuppressive therapies. There are case reports of solid organ transplant recipients on immunosuppressive therapy presenting with mild hypercalcemia, leading to a diagnosis of PJP. Recent studies have shown efficacy of PJP prophylaxis for patients treated with rituximab with a favourable adverse effect profile. CASE PRESENTATION: A 78-year-old male with a history of PR3-ANCA vasculitis, chronic kidney disease and heart failure with reduced ejection fraction presented to our tertiary care hospital with a two-week history of confusion and non-productive cough. Background immunosuppression with rituximab was completed every six months. The patient was found to have hypercalcemia and new infiltrates and ground glass opacities on cross-sectional imaging. Bronchoscopy was performed that was positive for Pneumocystis jirovecii. He was treated with 21 days of trimethoprim-sulfamethoxazole and prednisone with resolution of symptoms and hypercalcemia. CONCLUSIONS: Herein, we present a novel case of PJP in a non-transplant recipient preceded by hypercalcemia. Our case demonstrates the importance for a high suspicion for PJP in chronically immunosuppressed patients on rituximab presenting with PTH-independent hypercalcemia.

Cytology of a parietal swelling in a 52-year-old man.

Primary FNA diagnosis of brown tumour is challenging because overlapping of cytomorphologic features with other giant cell lesions. Clinical information, imaging and laboratory tests benefits the correct diagnosis.

Is a Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism a Risk Factor for Nephrolithiasis in Sarcoidosis?

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79-33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.

Clinical and epidemiologic characteristics of hospitalized oncological patients with hypercalcemia: a longitudinal, multicenter study.

BACKGROUND: There are few studies that have analyzed the characteristics of hypercalcemia in hospitalized oncological patients. Our objectives were to describe the clinical characteristics of hospitalized patients with paraneoplastic hypercalcemia and to identify prognostic variables for mortality. METHODS: This was an observational, longitudinal, retrospective, and bicentric study. It included adult patients admitted to two hospitals in Málaga, Spain (2014-2018). The minimum follow-up period was 2 years or until death. RESULTS: A total of 154 patients were included; the majority (71.4%) were admitted to the internal medicine department. The median follow-up was 3.5 weeks (interquartile range [IQR] 1.1-11.5). The mean (standard deviation) age was 67.6 (12.3) years, with a predominance of males (58.4%). The median (IQR) serum calcium at admission was 13.2 (11.8-14.6) mg/dl. The most common neoplasms were pulmonary (27.3%), hematologic (23.4%), urological (13%), and breast (12.3%). Furthermore, 56.5% of cases had a known history of neoplasia at the time of diagnosis. The parathyroid hormone (PTH) level was determined in 24%; of these, 10.8% had elevated levels. In all, 95.5% of patients died during follow-up. The median survival was 3.4 weeks (95% confidence interval 2.6-4.3). Factors associated with higher mortality were age, serum calcium at admission, previous history of neoplasia, etiology other than multiple myeloma, and noncorrection of hypercalcemia. CONCLUSIONS: In hospitalized patients, paraneoplastic hypercalcemia was associated with high short-term mortality. Several factors associated with a worse prognosis were identified in these patients.

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

Surgical Management and Denosumab for Aneurysmal Bone Cysts of the Spine in an Australian Tertiary Paediatric Centre.

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.