Familial hypocalciuric hypercalcemia

Calcium Metabolismmedium

A 37-year-old previously healthy man is referred for hypercalcemia; serum calcium has ranged from 10.7 to 11.3 mg/dL over the past year. He feels well, takes no medications, and is adopted, so family history is unknown. Examination is unremarkable. Creatinine is 0.7 mg/dL, calcium 11.2 mg/dL, intact PTH 64 pg/mL (10–65), 25-hydroxyvitamin D 35 ng/mL, and urine calcium-to-creatinine ratio 0.005 (<0.14). Kidney ultrasound is normal. What is the most likely cause of his hypercalcemia?

  1. A.Heterozygous inactivating mutation of the CASR geneCorrect
  2. B.Germline inactivating mutation of the MEN1 gene
  3. C.Parathyroid adenoma
  4. D.Homozygous inactivating mutation of the CASR gene

Explanation

The most likely cause is a heterozygous inactivating variant in the CASR gene, causing familial hypocalciuric hypercalcemia type 1. This young, asymptomatic man has stable mild hypercalcemia (10.7 to 11.3 mg/dL) for a year, a high-normal PTH of 64 pg/mL, replete vitamin D, normal kidney ultrasound, and strikingly low urinary calcium excretion. His calcium-to-creatinine clearance ratio, calculated as urine Ca × serum Cr divided by serum Ca × urine Cr, is approximately equal to the urine Ca/Cr ratio adjusted for serum calcium; with a urine calcium-to-creatinine ratio of 0.005, the clearance ratio is far below 0.01, the threshold that strongly favors familial hypocalciuric hypercalcemia over primary hyperparathyroidism. The calcium-sensing receptor in the parathyroid gland and the thick ascending limb normally suppresses PTH and calcium reabsorption when calcium rises. Loss of function of one CASR allele shifts the set point upward, so higher calcium is required to suppress PTH, and the kidney avidly reabsorbs calcium. The condition is autosomal dominant with high penetrance, benign, and does not respond to parathyroidectomy, so distinguishing it from primary hyperparathyroidism prevents unnecessary surgery. Genetic testing of CASR (and GNA11 and AP2S1 for types 2 and 3) confirms the diagnosis, and relatives should be screened. A germline MEN1 mutation causes multiple endocrine neoplasia type 1, in which primary hyperparathyroidism from multigland hyperplasia is the most common and earliest feature. It produces hypercalciuria, not a clearance ratio below 0.01, and often kidney stones. Homozygous or compound heterozygous inactivating CASR mutations cause neonatal severe hyperparathyroidism, presenting in infancy with marked hypercalcemia, very high PTH, bone demineralization, and failure to thrive, which requires urgent parathyroidectomy. It is incompatible with an asymptomatic adult. A parathyroid adenoma is the most common cause of PTH-dependent hypercalcemia, but primary hyperparathyroidism typically raises urinary calcium, with a calcium-to-creatinine clearance ratio above 0.02, and a ratio this low makes it very unlikely.

Why each option

A.
Correct. Lifelong-pattern mild hypercalcemia with high-normal PTH and urinary calcium-to-creatinine ratio of 0.005 indicates familial hypocalciuric hypercalcemia from heterozygous CASR loss of function.
B.
MEN1 causes primary hyperparathyroidism from multigland hyperplasia with hypercalciuria and stones, not a calcium-to-creatinine clearance ratio below 0.01.
C.
Parathyroid adenoma raises urinary calcium with clearance ratios usually above 0.02; profound hypocalciuria argues strongly against primary hyperparathyroidism.
D.
Homozygous CASR inactivation causes neonatal severe hyperparathyroidism with life-threatening hypercalcemia in infancy, not stable mild hypercalcemia in a healthy adult.

Reference: Bilezikian JP, J Bone Miner Res 2022 (Fifth International Workshop on primary hyperparathyroidism); Marx SJ, J Bone Miner Res 2018 (familial hypocalciuric hypercalcemia)

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