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Abstract A 3-day-old male presented to a peripheral remote hospital in New South Wales, Australia, with tachypnea. He was found to have hypercalcemia, with ionized calcium >2.5 mmol/L (>10 mg/dL) (0.97-1.5 mmol/L or 1.14-1.3 mg/dL) and serum calcium of 3.85 mmol/L (15.43 mg/dL) (2.2-2.8 mmol/L or 8.5-10.5 mg/dL). Peak serum calcium was 5.4 mmol/L (21.64 mg/dL). He was transferred to a tertiary pediatric intensive care unit. Medical management (including hyperhydration, diuretics, corticosteroids, bisphosphonates, cinacalcet, and calcitonin) failed to maintain normocalcemia; therefore, total parathyroidectomy was performed on day 16 of life. Hungry bones syndrome developed postoperatively, requiring high doses of calcium, calcitriol, and phosphate supplementation. Genetic testing identified compound heterozygosity for 2 likely pathogenic variants in the calcium-sensing receptor gene. He is now 3 years old and is growing and developing without any concerns. This case highlights the importance of aggressive initial management in addressing severe hypercalcemia through perioperative management principles as well as the prolonged nature of hungry bones syndrome.

Abstract Background Common causes of parathyroid hormon (PTH)-independent hypercalcemia in adulthood are malignancy, granulomatous diseases, and endocrinopathies. Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, can also be a rare cause of supressed intact PTH levels, usually associated with, nephrolithiasis and nephrocalcinosis. This disease, defined as idiopathic infantile hypercalcemia, classically presents with hypercalcemia in infants. However, some individuals have also been reported with late-onset clinical manifestation or late diagnosis in adulthood. Clinical Case A 59-year-old male patient with a known diagnosis of type 2 diabetes mellitus for 30 years. He had a history of recurrent kidney stones since 2006. His blood and urine tests revealed elevated creatinine level, hypercalcemia with normal phosphorus levels, normal 25-hydroxycholecalciferol levels, suppressed intact PTH level and normal 24-hour urinary calcium level (Table 1). Urinary ultrasonography was consisted with medullary nephrocalcinosis and chronic kidney disease. PTH-independent causes of hypercalcemia were investigated. Malignancies, granulomatous diseases and endocrinopathies were ruled out. The 1,25-dihydroxycholecalciferol level was within the normal range. Parathormone related peptide level was determined as 1.60 pmol/L (normal value <4.2). Genetic workup revealed a homozygous loss-of-function mutation p.E143del in the CYP24A1 gene. Thereupon, genetic screening started on the siblings of the patient which not been finalized yet. However, none of them were found to have hypercalcemia in the laboratory evaluation. Treatment was started with low-dose fluconazole, which inhibits enzymes (including 25-hydroxylases and 1-α-hydroxylase) synthesizing vitamin D. After a month of treatment at a dose of 50 mg/day, no change was observed in the patient's calcium values. Follow-up with calcium-restricted diet and adequate oral hydration therapy was planned. Conclusion Idiopathic infantile hypercalcemia may manifest later or diagnosed later in adulthood. Genetic examination should be considered in adult patients in whom other causes of PTH-independent hypercalcemia have been excluded. Table 1. Patient's laboratory parameters

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone–related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.

Primary hyperparathyroidism is characterized by hypercalcemia and hypophosphatemia caused by excessive parathyroid hormone secretion. Gitelman syndrome, a rare autosomal recessive salt-losing tubulopathy, presents with hypokalemia, hypomagnesemia, hypocalciuria, and secondary hyperaldosteronism. The coexistence of these conditions leads to an atypical clinical picture and may result in a refractory hypercalcemic crisis that responds poorly to standard therapies. We describe a case of refractory hypercalcemia accompanied by hypophosphatemia, elevated parathyroid hormone levels, hypokalemia, hypomagnesemia, and, notably, hypocalciuria that was inconsistent with the degree of hypercalcemia. The patient experienced recurrent hypercalcemic crises that required treatment with zoledronic acid and denosumab after conventional interventions failed. The diagnosis was ultimately confirmed through postoperative pathology and genetic testing. This case emphasizes that hypocalciuria in the setting of persistent hypercalcemia—especially when severe hypomagnesemia is present—should raise suspicion for underlying Gitelman syndrome. Early identification of this coexistence is essential, as optimal management requires surgical treatment of primary hyperparathyroidism followed by targeted correction of electrolyte abnormalities associated with Gitelman syndrome, ultimately improving clinical outcomes.

There are many causes of hypercalcaemia including hyperparathyroidism, drugs, granulomatous disorders and malignancy. Parathyroid hormone (PTH) related hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) and more rarely by familial hypocalciuric hypercalcaemia (FHH). Algorithms for diagnosis of PTH related hypercalcaemia require assessment of a 24-h urinary calcium and creatinine excretion to calculate calcium/creatinine clearance ratio and radiological investigations including ultrasound scan and 99mTc-sestamibi-SPECT/CT. To illustrate investigations and management of parathyroid-related hypercalcaemia, we present a selection of distinct cases of PHPT due to eutopic and ectopic parathyroid adenomas, as well as a case with a syndromic form of PHPT (multiple endocrine neoplasia type 1), and a case with FHH type 1 due to a CASR inactivating mutation. Additional cases with normocalcaemic hyperparathyroidism and secondary hyperparathyroidism are included for completeness of differential diagnosis. The common eutopic parathyroid adenomas are easily treated with parathyroidectomy while the less common ectopic parathyroid adenomas require more complex investigations and operative procedures such as video-assisted thoracoscopic surgery. On the other hand, the much less common FHH does not require treatment. Assessment of kin with FHH is important to identify members with this inherited condition in order to prevent unnecessary interventions.

Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

Abstract Background Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. Objective To develop guidelines for the treatment of adults with HCM. Methods A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. Results The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. Conclusions The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.