An Uncommon Cause of Hypomagnesemia With Hypercalciuria and Nephrocalcinosis in a Young Woman

Background: Mutations of the calcium-sensing receptor (CaSR) gene resolve in a change of calcium homeostasis with autosomal dominant and/or sporadic hypocalcemia with hypercalciuria (ADH) (gain-of-function) and familial hypocalciuric hypercalcemia (loss-of-function-mutation). Additionally, genetic mutations in renal tubular transporters are also associated with hypomagnesemia, hypercalciuria and nephrocalcinosis. Such,,magnesium-losing-diseases“ are disorders like familiar hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) which shows a mutation in the Claudin 16 gene (CLD16) and the primary hypomagnesemia with secondary hypocalcaemia caused by a genetic defect in the Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6) gene. Clinical Case: A 35- year old woman with a first episode of pyelonephritis presented herself in our emergency unit in January 2020. Kidney ultrasound showed an advanced stage of nephrocalcinosis and normocalcemia, hypomagnesemia, suppressed PTH and hypercalciuria were observed in laboratory analyses. Several family members from her father`s side and her brother have all been diagnosed with nephrocalcinosis developed in young age. A gene sequencing of CASR and CLD16 gene provided no sequence or copy changes. Thiazide diuretic was initiated for correction of hypercalciuria, but the patient developed hypotonic blood pressure and stopped the drug. In November 2020 she unexpectedly died. Conclusions: In our patient ADH due an activating mutation of the CaSR gene was supposed, but no abnormality in gene sequence was detected. Since CaSR are not only expressed in PTH-secreting cells in the parathyroid but also along the nephron, particularly in the thick ascending limp of loop of Henle, activating mutations of CaSR gene will lead to a decreased reabsorption of divalent cations (like calcium and magnesium). Thus, this phenotype results in low or normal PTH, low or normal serum calcium levels, hypomagnesemia, high- normal urinary calcium and magnesium excretion (due to increased activation of the CaSR gene in kidneys) and nephrocalcinosis with recurrent nephrolithiasis. Thiazide diuretics are effective in these patients and vitamin D supplementation should be considered with caution. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently investigated. However, familiar hypomagnesemia with hypercalciuria and nephrocalcinosis as well as primary hypomagnesemia with secondary hypocalcaemia should also be discussed as differential diagnoses in this case. The teaching point of our case is the need of magnesium testing and additional cardiological observation regarding possibly fatal arrhythmias in these subjects. Also genetic and metabolic phenotyping of all family members in such cases is important.