Endocrine Abstracts

Introduction: Autosomal dominant hypocalcemia (ADH) type 1 is a rare form of hypoparathyroidism, caused by heterozygous, inherited or de novo, activating mutations in the CASR. CASR is also expressed in the kidney and activating mutations lead to decreased calcium renal absorption. Activating mutations in the CasR, inhibits salt transport, leading to Bartteŕs syndrome (BS) type V which can co-exist with ADH1. Chronic myeloid leukemia (Cml) is characterized by the clonal hyperproliferation of immature blood cells. Recently, CaSR has been raised as a targetable factor in Aml progression, however, data on its role in Cml are scarce.

Clinical presentation: 33-year-old man was referred to the outpatient for poorly controlled hypoparathyroidism along with hypomagnesemia, and mild hypokalemia and dehydration. His hypoparathyroidism was diagnosed on the second day of birth. The patient presented nephrolithiasis and basal ganglia calcification. In 2020, he was also diagnosed with Cml. He was treated with calcium carbonate, alfacalcidol, cholocalciferol, hydroclorothiazide. He also received dasatinib for the Cml. At the outpatient, rhPTH was initiated along with magnesium supplements leading to reduction of the alfacalcidol and calcium supplements and to a better control of hypocalcemia and hypercalciuria. NGS was performed and demonstrated a genetic change (c.2486A>G) in exon 7 of the CaSR. The patient had a heterozygous substitution of adenine (TAT) for guanine (TGT) at codon 829.

Discussion: This is the third case of the specific mutation. In one case, mild Bartter V syndrome was also co-exist. The clinical presentations and onset timing of BS phenotype differ according to the type of mutation. Moreover, BS phenotype can differ between patients who have the same CaSR mutation, deteriorating the loss of water and predisposing to hypokalemia to varying extent. Of interest, this is the second case presenting with ADH1 and Cml. In the first reported case, severe hypocalcemia was triggered by imatinib leading to the diagnosis of underlying ADH1. CaSR has been found to modulate intracellular levels of Ca2+ and consequently calcium-dependent protein kinases which coordinate several signaling pathways (i.e. P-ERK and b-catenin) which are crucial to Cml malignant transformation in the same manner as BCR-ABL does. Conclusively,1)in Cml patients treated with TKIs and presented with severe hypocalcemia, the possible existence of ADH1 may need to be investigated, 2) a potential role CASR activating mutations in the pathogenesis and progress of Cml merits investigation.

References: 1. Jones- Ryan M, et al. J Endocr Soc. 2020 May 8; 4(Suppl 1): SAT-347.

2. Choi KH, et al. Korean J Pediatr [Internet]. 2015;58(4):148.