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Background: Autosomal Dominant Hypocalcemia Type 1 is an underdiagnosed condition due to the vast majority of patients being asymptomatic and having mild hypocalcemia. Imatinib has been associated with hypophosphatemia and hypocalcemia. Clinical Case: 69-year-old man who had a long history of asymptomatic mild hypocalcemia, calcium level of 7.9 mg/dL (8.4 – 10.2 mg/dL) diagnosed with chronic myeloid leukemia and developed symptoms of hypocalcemia within 2 months of treatment with imatinib. After the initiation of imatinib, his calcium reduced to 6.8 mg/dL (8.4 – 10.2 mg/dL) with a corresponding ionized calcium of 0.98 mmol/L (1.12–1.32 mmol/L) within 2 months. He developed tetany. With the reduced calcium level his PTH was unexpectedly low-normal at 34 pg/mL (16–62 pg/mL). He also had a higher than expected urinary calcium of 342 mg/24 hours. The PTH and 24-hour urinary calcium levels raised concern for an underlying diagnosis of autosomal dominant hypocalcemia type 1. His phosphorous was normal at 3.3 mg/dL (2.6–4.9 mg/dL). He never had hypophosphatemia, which is common with imatinib. After two doses of IV calcium and initiation of oral calcium replacement, 1000 mg BID, his level continued to be reduced with symptoms. Given his symptoms, laboratory results, and continued hypocalcemia he underwent genetic testing. Results of his genetic testing showed a p.Thr151Met mutation in the CASR gene consistent with autosomal dominant hypocalcemia type 1. With this diagnosis, there is concern for nephrolithiasis with over treatment. His symptoms resolved with treatment with calcium 1000mg TID, calcitriol 0.25 mg BID and vitamin D3 2000 IU daily. He has not developed nephrolithiasis and his urinary calcium increased to 424mg/24 hours. A thiazide diuretic is being considered to decrease urinary calcium excretion. He continues on imatinib with an excellent response to therapy. It is likely that the trigger for symptomatic severe hypocalcemia was initiation of imatinib superimposed on the hypocalcemia type 1. Possible mechanisms for this are decreased intestinal absorption, increased urinary loss, or decreased dissolution from bone. 1 These mechanisms are also associated with hypophosphatemia, which our patient did not have. Another possible cause could be an immune mediated destruction of the parathyroid gland, a rare finding seen with other tyrosine kinase inhibitors.2 Conclusion: This is the first reported case of imatinib triggering severe symptomatic hypocalcemia leading to the diagnosis of underlying autosomal dominant hypocalcemia type 1. References: 1. Vandyke, Kate, et al. “Dysregulation of Bone Remodeling by Imatinib Mesylate.” Blood, vol. 115, no. 4, 2010, pp. 766–774., doi:10.1182/blood-2009-08-237404. 2. Petrić, Marija, et al. “A Rare Case of Hypocalcemia Induced by Nilotinib.” Endocrine Oncology and Metabolism, 3 Mar. 2017, pp. 32–53., doi:10.21040/eom/2017.3.5.1.

The history of parathyroid hormone (PTH) replacement therapy for hypoparathyroidism begins in 1929. In 2015, the Food and Drug Administration approved recombinant human PTH(1-84) [rhPTH(1-84)] as a treatment for hypoparathyroidism. Long-term studies of rhPTH(1-84), up to 6 years, have demonstrated continued efficacy of this replacement agent. Approaches to optimize PTH treatment in hypoparathyroidism include subcutaneous pump delivery systems, long-lived carrier molecules, and long-acting PTH analogues that show promise to prolong efficacy. Calcilytic compounds have been explored as a treatment for autosomal dominant hypocalcemia. Calcilytics are negative modulators of the calcium-sensing receptor and may present a therapeutic opportunity to increase endogenous PTH synthesis and secretion.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, with inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D supplementation, which can lead to or exacerbate hypercalciuria. As a result, patients may develop nephrolithiasis and/or nephrocalcinosis, which can progress to renal insufficiency. Calcilytics (antagonists of the CaSR) have demonstrated in in vitro and in vivo models of ADH1, as well as in a small clinical trial (Roberts et al, JBMR 2019), the ability to shift the dose-response relationship between extracellular calcium and the cellular response of cells bearing the mutant CaSR towards normal. This shift has the potential to increase endogenous PTH secretion which in turn may promote skeletal release of calcium into the bloodstream, production of endogenous calcitriol, renal excretion of phosphate, and renal reabsorption of calcium. Additionally, direct effects of calcilytics on renal CaSRs may further reduce renal calcium and magnesium excretion in ADH1. Taken together, this class of drugs has the capacity to restore normal mineral homeostasis, without calcium and activated vitamin D supplements and without attendant risks of iatrogenic hypercalciuria. This Phase 2b, open-label, dose-ranging study will evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of the calcilytic encaleret (CLTX-305) in up to 16 participants with ADH1 (NCT04581629). The study will consist of 3 periods. In periods 1 and 2, participants will undergo a 1-week inpatient evaluation to study the safety and tolerability of daily and twice-daily doses of encaleret. Period 3 will follow participants for up to 24 weeks of continuous outpatient dosing, with periodic inpatient and outpatient assessments. The primary endpoint of period 3 is the change from baseline in albumin-corrected blood calcium concentration. Secondary endpoints of the study include the change in urine calcium (fractional and 24-hour excretion), 1,25-dihydroxy-Vitamin D, phosphate, magnesium, and other blood/urine biomarkers. Enrollment for this study at the National Institutes of Health (NIH) began in September 2020 with topline results expected in 2021. This study is supported by Calcilytix Therapeutics, Inc. and the NIH Intramural Research Program.

Hypoparathyroidism is a rare endocrine disorder most commonly caused by anterior neck surgery. The next most common cause is thought to be autoimmune disorders. After this, less common causes include iron or copper overload, tumor infiltration of the parathyroid glands, or radiation treatment. Rare patients have inherited or genetic forms of hypoparathyroidism, either presenting as isolated hypoparathyroidism or with syndromic features.

Hypoparathyroidism, a disorder characterized by hypocalcemia ensuing from inadequate parathyroid hormone secretion, is a rather rare disorder caused by multiple etiologies. When not caused by inadvertent damage or removal of the parathyroids during neck surgery, it is usually genetically determined. Epidemiological figures of this disease are still scarce and mainly limited to countries where non-anonymous databases are available and to surgical case series. Both the surgical and non-surgical forms pose diagnostic challenges. For surgical hypoparathyroidism, transient forms have to be ruled out even in the long term, in order to avoid unnecessary chronic replacement therapy with calcium and calcitriol. Regarding non-surgical hypoparathyroidism, once referred to as idiopathic, a systematic clinically and genetically-driven approach to define the precise diagnosis have to be pursued. In the case of syndromic hypoparathyroidism, patients have to be screened for associated abnormalities. Autoimmune, non-genetic hypoparathyroidism is still a diagnosis of exclusion, since no specific autoantibodies are specific for this condition.

Objective: To discuss the case of a woman and her father with autosomal dominant hypocalcemia (ADH), a rare disorder caused by an activating mutation of the calcium-sensing receptor (CaSR).Methods: Previous ADH case reports were obtained by Medline search and from an updated CaSR database.Results: A 37-year-old female presented with intermittent leg cramps and hypocalcemia. Her father had been previously diagnosed with asymptomatic hypocalcemia at age 54. Genetic analysis in both individuals revealed identical missense mutations in nucleotide c.2489G>A that resulted in a glycine to aspartic acid change at codon 830 (G830D) in the CaSR.Conclusion: The same mutation of the CaSR gene was identified in a woman and her father. This warrants the need for genetic testing in adults with mild hypocalcemia and a family history of hypocalcemia.Abbreviations: ADH = autosomal dominant hypocalcemia CaSR = calcium-sensing receptor iPTH = intact parathyroid hormone OMIM = Online Mendelian Inheritance in Man TMD = transmembrane domain

The calcium sensing receptor (CaSR) plays an important role in calcium homeostasis. Activating mutations of CaSR cause autosomal dominant hypocalcemia by affecting parathyroid hormone secretion in parathyroid gland and calcium resorption in kidney. They can also cause a type 5 Bartter syndrome by inhibiting the apical potassium channel in the thick ascending limb of the loop of Henle in the kidney. This study presents a patient who had autosomal dominant hypocalcemia with Bartter syndrome due to an activating mutation Y829C in the transmembrane domain of the CaSR. Symptoms of hypocalcemia occurred 12 days after birth and medication was started immediately. Medullary nephrocalcinosis and basal ganglia calcification were found at 7 years old and at 17 years old. Three hypercalcemic episodes occurred, one at 14 years old and two at 17 years old. The Bartter syndrome was not severe while the serum calcium concentration was controlled, but during hypercalcemic periods, the symptoms of Bartter syndrome were aggravated.

Subcutaneous Parathyroid Hormone in ADH1 In this letter, the investigators report that continuous subcutaneous infusion of parathyroid hormone (1-34) in six patients who were between the ages of 5 ...