Parathyroid hormone-dependent familial hypercalcemia with low measured PTH levels and a presumptive novel pathogenic mutation in CaSR

Abstract

Familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant condition characterized by lifelong asymptomatic hypercalcemia. FHH is typically caused by a heterozygous inactivating mutation of the calcium-sensing receptor (CaSR) and characterized by moderate hypercalcemia, inappropriately normal or elevated serum parathyroid hormone (PTH), and relative hypocalciuria (FeCa < 2%) with histologically normal parathyroid glands. FHH should be distinguished from primary hyperparathyroidism so that unnecessary parathyroid surgery is avoided. We report a case that presented with asymptomatic, familial hypercalcemia but low PTH and normal (non-low) urinary calcium excretion found to be secondary to a novel pathogenic inactivating mutation of the CaSR gene. We present an asymptomatic 54-year-old Malaysian woman with incidentally discovered hypercalcemia, intermittent hypophosphatemia, and FeCa > 2%. PTH levels were repeatedly below the mean of the reference range (on two separate assays) and sometimes even below the lower reference limit. Two siblings, one niece, and her son had hypercalcemia without nephrolithiasis. Cinacalcet, used as a PTH-suppression test, normalized serum total and ionized calcium after 7 days of cinacalcet 30 mg BID, confirming her hypercalcemia was PTH-mediated. Given her family history, genetic testing was pursued and discovered a novel pathogenic mutation of the CaSR gene confirming the diagnosis of FHH type 1. Our case represents an atypical presentation of FHH1 with low PTH and FeCa > 2%. This contributes to the expanding clinical and biochemical spectrum of CaSR inactivating mutations and presents an innovative approach to evaluating biochemically uncertain familial hypercalcemia with cinacalcet before pursuing expensive genetic analysis.

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Fig. 1

Abbreviations

FHH:

familial hypocalciuric hypercalcemia

CaSR:

calcium-sensing receptor

PTH:

parathyroid hormone

PHPT:

primary hyperparathyroidism

GNA11:

G protein subunit alpha11 gene

AP2S1:

adaptor-related protein complex 2 gene

BMI:

body mass index

FeCa :

fractional excretion of calcium

ExAC:

exome aggregation consortium

ECD:

extracellular domain

TMD:

transmembrane domains

ICD:

intracellular domain

FHH1:

familial hypocalciuric hypercalcemia type 1

VFT:

Venus flytrap

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Correspondence to A. Mahajan.

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University of Calgary ethical approval was given for publication of biochemical data for a local control population.

The article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants (patient and her son) included in the study.

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Mahajan, A., Buse, J. & Kline, G. Parathyroid hormone-dependent familial hypercalcemia with low measured PTH levels and a presumptive novel pathogenic mutation in CaSR. Osteoporos Int 31, 203–207 (2020). https://doi.org/10.1007/s00198-019-05170-9

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Keywords

  • Calcium-sensing receptor gene
  • Familial hypocalciuric hypercalcemia
  • Hypercalcemia
  • Parathyroid hormone