PSAT210 A Case of Asymptomatic Severe Hypocalcemia: Consideration of Genetic Causes
Authors: Rosenberg Rebecca , Saxon David 
Published: November 2022

Calcium sensing receptor (CaSR) activating mutations are a rare etiology of calcium dyscrasias in the general population. Of these, hypocalciuric hypocalcemia and autosomal dominant hypocalcemia (ADH) type 1 are the most common subtypes, with a prevalence of 74.1 and 3.9 per 100,000, respectively. Although rare, these mutations should be considered in patients with a family history of hypocalcemia, particularly if asymptomatic, as the treatment goals and replacement strategies differ from typical primary hypoparathyroidism, with which they are often mistaken. We present a case of a 41-year-old male with a history of treated vitamin D deficiency and anxiety who presented to endocrinology clinic for severe asymptomatic hypocalcemia (serum calcium 6.0-7.0). Family history pertinent for a mother, sister, and brother also with hypocalcemia, and brother with single childhood hypocalcemic seizure at age 4. Patient reported being on and off calcium, calcitriol, and ergocalciferol for years and has never had any symptoms regardless of his regimen or serum calcium. Specifically, he had no personal history of paresthesia, muscle cramping, or kidney stones. No family history of osteoporosis, fracture, kidney stone, or renal disease. Laboratory evaluation over the last 30 years most pertinent for serum calcium 6.0-9.5 on varying supplement/medication regimens, low-normal PTH, initially elevated and now normal serum phosphorous, low-normal serum magnesium, and 24h urinary calcium quite variable but as high as &gt;300mg/d (when serum calcium within normal limits). Genetic testing revealed a heterozygous DNA sequence change detected on exon 7 of the CaSR gene, which has been previously found to be a pathogenic cause of ADH. Activating mutations of the CaSR (typically ADH type 1) clinically present as hypocalcemia, low or low-normal PTH, hyperphosphatemia, hypomagnesemia, and increased urinary calcium. When starting the evaluation for these mutations, it is important to note that there are two types of ADH. Type 1 mutations occur as an activating mutation at the CaSR causing hypersensitivity to calcium, while type 2 activating mutations occur at a different locale (G alpha 11 subunit). Despite mutations at different sites, each type leads to a similar gain-of-function mutation and a very similar clinical presentation. The clinical significance of differentiating these diagnoses from primary hypoparathyroidism (PHP) lies in the goals of treatment and in the adverse effects of over-supplementation of calcium in ADH. In PHP, patients generally have symptomatic hypocalcemia, and calcium can and should be supplemented to prevent adverse events of chronic hypocalcemia. Contrastingly, in CaSR mutation conditions, mild and even significant hypocalcemia is well tolerated. If patients’ serum calcium is normalized, they often experience significant hypercalciuria and renal manifestations therein, such has nephrocalcinosis and nephrolithiasis. Therefore, treatment of patients with CaSR activating mutations should be aimed at relieving hypocalcemia symptoms, if any are present.

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