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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
familial hypocalciuric hypercalcemia
G protein subunit alpha11 gene
adaptor-related protein complex 2 gene
body mass index
- FeCa :
fractional excretion of calcium
exome aggregation consortium
familial hypocalciuric hypercalcemia type 1
Carling T, Szabo E, Bai M, Ridefelt P, Westin G, Gustavsson P et al (2000) Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 85(5):2042–2047
Thakker RV (2004) Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium 35(3):275–282
Christensen SE, Nissen PH, Vestergaard P, Mosekilde L (2011) Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 18(6):359–370
Mastromatteo E, Lamacchia O, Campo MR, Conserva A, Baorda F, Cinque L et al (2014) A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria. BMC Endocr Disord 14:81
CASRdb Calcium Sensing Receptor Locus Mutation Database [Internet]. Available from: http://www.casrdb.mcgill.ca/?Topic=CasrSeqs2&v=new
Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L et al (2017) Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. Endocrine. 55(3):741–747
Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV (2014) Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 99(10):3570–3579
Hannan FM, Thakker RV (2013) Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract Res Clin Endocrinol Metab. 27(3):359–371
Tyler MR (2013) Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Pract Res Clin Endocrinol Metab 27(3):345–358
Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE (2000) Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 16(4):281–296
Brown EM (2000) Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium. Endocrinol Metab Clin N Am 29(3):503–522
Nissen PH, Christensen SE, Heickendorff L, Brixen K, Mosekilde L (2007) Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population. J Clin Endocrinol Metab 92(11):4373–4379
CASR calcium sensing receptor [ Homo sapiens (human) ] Gene: NCBI; 2019 [updated July 30, 2019. Available from: https://www.ncbi.nlm.nih.gov/gene/846#top
Hu J, Reyes-Cruz G, Goldsmith PK, Spiegel AM (2001) The Venus's-flytrap and cysteine-rich domains of the human Ca2+ receptor are not linked by disulfide bonds. J Biol Chem 276(10):6901–6904
Hu J, Hauache O, Spiegel AM (2000) Human Ca2+ receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J Biol Chem 275(21):16382–16389
Lee S, Mannstadt M, Guo J, Kim SM, Yi HS, Khatri A et al (2015) A homozygous [Cys25]PTH(1-84) mutation that impairs PTH/PTHrP receptor activation defines a novel form of hypoparathyroidism. J Bone Miner Res 30(10):1803–1813
Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B et al (2012) Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet 21(12):2768–2778
Ward BK, Magno AL, Blitvich BJ, Rea AJ, Stuckey BG, Walsh JP et al (2006) Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia. Clin Endocrinol 64(5):580–587
Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW, Lasker RD (1981) The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 60(6):397–412
Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T (1995) Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. J Clin Endocrinol Metab 80(9):2594–2598
Taylor EN, Curhan GC (2009) Demographic, dietary, and urinary factors and 24-h urinary calcium excretion. Clinical journal of the American Society of Nephrology : CJASN 4(12):1980–1987
Pak CY, Sakhaee K, Moe OW, Poindexter J, Adams-Huet B, Pearle MS et al (2011) Defining hypercalciuria in nephrolithiasis. Kidney Int 80(7):777–782
Sakhaee K, Baker S, Zerwekh J, Poindexter J, Garcia-Hernandez PA, Pak CY (1994) Limited risk of kidney stone formation during long-term calcium citrate supplementation in nonstone forming subjects. J Urol 152(2 Pt 1):324–327
Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L (2008) Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol 69(5):713–720
Jones AN, Shafer MM, Keuler NS, Crone EM, Hansen KE (2012) Fasting and postprandial spot urine calcium-to-creatinine ratios do not detect hypercalciuria. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 23(2):553–562
Cailleux A, Vuillermet P, Basuyau JP, Ménard JF, Lefebvre H, Kuhn JM, et al. A step towards cinacalcet testing for the diagnosis of primary hyperparathyroidism: comparison with the standardized intravenous calcium loading. A pilot study. Clin Endocrinol 2015;82(5):663-669
Ethics approval and consent to participate
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.
Informed consent was obtained from all individual participants (patient and her son) included in the study.
Conflicts of interest
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
About this article
Cite this article
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
- Calcium-sensing receptor gene
- Familial hypocalciuric hypercalcemia
- Parathyroid hormone