Familial hypocalciuric hypercalcemia (FHH) type 1, caused by a heterozygous inactivating mutation of the gene encoding the calcium-sensing receptor (CaSR), is characterized by mild to moderate hypercalcemia, hypocalciuria and inappropriately normal or elevated parathyroid hormone (PTH). FHH must be differentiated from primary hyperparathyroidism (PHPT) because parathyroidectomy is ineffective in the former. Herein, we report a 39-year-old male patient with a 13-year history of asymptomatic PTH-dependent hypercalcemia (mean calcium of 2.88 mmol/l; reference range 2.15-2.55 mmol/l) and calcium-to-creatinine clearance ratio (Ca/Cr) ranging from 0.007 to 0.0198, which is consistent with either FHH or PHPT. Although a family history of hypercalcemia was negative, and PET-CT with fluorocholine was suggestive of a parathyroid adenoma, genetic analysis of the CaSR gene identified a heterozygous inactivating mutation NM_000388.4:c.1670G>A p. (Gly557Glu) in exon 6 and a polymorphism NM_000388.4:c.1192G>A p. (Asp398Asn) in exon 4. The G557E mutation has been previously reported in a Japanese family in which all family members with the mutation had Ca/Cr below 0.01 consistent with FHH. The biochemical profile of FHH and PHPT may overlap. Our FHH patient with a G557E CaSR mutation illustrates that the differential diagnosis can be difficult in an index case with no family history, (false) positive parathyroid imaging and higher calciuria than expected for FHH. Calcium intake, vitamin D status and bone resorption might have contributed to the Ca/Cr variations over a 13-year clinical follow up. This case thus emphasizes the irreplaceable role of genetic testing of the CaSR gene when clinical evaluation is inconclusive.

Institute of Endocrinology Prague Czech Republic

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ABUGASSA S, NORDENSTRÖM J, JÄRHULT J. Bone mineral density in patients with familial hypocalciuric hypercalcaemia (FHH) Eur J Surg. 1992;158:397–402. PubMed

BARTH JH, FIDDY JB, PAYNE RB. Adjustment of serum total calcium for albumin concentration: effects of non-linearity and of regression differences between laboratories. Ann Clin Biochem. 1996;33:55–58. PubMed

BERTOCCHIO JP, TAFFLET M, KOUMAKIS E, MARUANI G, VARGAS-POUSSOU R, SILVE C, NISSEN PH, BARON S, PROT-BERTOYE C, COURBEBAISSE M, SOUBERBIELLE JC, REJNMARK L, CORMIER C, HOUILLIER P. Pro-FHH: a risk equation to facilitate the diagnosis of parathyroid-related hypercalcemia. J Clin Endocrinol Metab. 2018;103:2534–2542. doi: 10.1210/jc.2017-02773. PubMed DOI

BILEZIKIAN JP, BRANDI ML, EASTELL R, SILVERBERG SJ, UDELSMAN R, MARCOCCI C, POTTS JT., JR Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99:3561–3569. PubMed PMC

CIANFEROTTI L, GOMES AR, FABBRI S, TANINI A, BRANDI ML. The calcium-sensing receptor in bone metabolism: from bench to bedside and back. Osteoporos Int. 2015;26:2055–2071. doi: 10.1007/s00198-015-3203-1. PubMed DOI

CUDERMAN A, SENICA K, REP S, HOCEVAR M, KOCJAN T, SEVER MJ, ZALETEL K, LEZAIC L. 18F-fluorocholine PET/CT in primary hyperparathyroidism: superior diagnostic performance to conventional scintigraphic imaging for localization of hyperfunctioning parathyroid glands. J Nucl Med. 2020;61:577–583. doi: 10.2967/jnumed.119.229914. PubMed DOI

GENG Y, MOSYAK L, KURINOV I, ZUO H, STURCHLER E, CHENG TC, SUBRAMANYAM P, BROWN AP, BRENNAN SC, MUN HC, BUSH M, CHEN Y, NGUYEN TX, CAO B, CHANG DD, QUICK M, CONIGRAVE AD, COLECRAFT HM, McDONALD P, FAN QR. Structural mechanism of ligand activation in human calcium-sensing receptor. eLife. 2016;19:1–25. doi: 10.7554/eLife.13662.032. PubMed DOI PMC

GOLTZMAN D, HENDY GN. The calcium-sensing receptor in bone--mechanistic and therapeutic insights. Nat Rev Endocrinol. 2015;11:298–307. doi: 10.1038/nrendo.2015.30. PubMed DOI

HANNAN FM, BABINSKY VN, THAKKER RV. Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. J Mol Endocrinol. 2016;57:R127–R142. doi: 10.1530/JME-16-0124. PubMed DOI PMC

HENDY GN, D'SOUZA-LI L, YANG B, CANAFF L, COLE DEC. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2000;16:281–296. doi: 10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A. PubMed DOI

ISAKSEN T, NIELSEN CS, CHRISTENSEN SE, NISSEN PH, HEICKENDORFF L, MOSEKILDE L. Forearm bone mineral density in familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a comparative study. Calcif Tissue Int. 2011;89:285–294. doi: 10.1007/s00223-011-9517-x. PubMed DOI

JABOR A. Vnitřní prostředí. Jabor a kolektiv; Grada, Praha: 2008. Albumin corrected calcium. (In Czech) p. 74.

JAKOBSEN NF, ROLIGHED L, MOSER E, NISSEN PH, MOSEKILDE L, REJNMARK L. Increased trabecular volumetric bone mass density in familial hypocalciuric hypercalcemia (FHH) type 1: a cross-sectional study. Calcif Tissue Int. 2014;95:141–152. doi: 10.1007/s00223-014-9877-0. PubMed DOI

KOBAYASHI M, TANAKA H, TSUZUKI K, TSUYUKI M, IGAKI H, ICHINOSE Y, AYA K, NISHIOKA N, SEINO Y. Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism. J Clin Endocrinol Metab. 1997;82:2716–2719. doi: 10.1210/jcem.82.8.4135. PubMed DOI

KUZMINSKI SJ, SOSA JA, HOANG JK. Update in parathyroid imaging. Magn Reson Imaging Clin N Am. 2018;26:151–166. PubMed

LEE JY, SHOBACK DM. Familial hypocalciuric hypercalcemia and related disorders. Best Pract Res Clin Endocrinol Metab. 2018;32:609–619. doi: 10.1016/j.beem.2018.05.004. PubMed DOI PMC

MARX SJ. Multiplicity of hormone-secreting tumors: common themes about cause, expression, and management. J Clin Endocrinol Metab. 2013;98:3139–3148. doi: 10.1210/jc.2013-1511. PubMed DOI PMC

MOORE EC, BERBER E, JIN J, KRISHNAMURTHY V, SHIN J, SIPERSTEIN A. Calcium creatinine clearance ratio is not helpful in differentiating primary hyperparathyroidism from familial herpercalcemic hypocalciuria: a study of 1000 patients. Endocr Pract. 2018;24:1–7. doi: 10.1177/1078155218796724. PubMed DOI

NAKAYAMA T, MINATO M, NAKAGAWA M, SOMA M, TOBE H, AOI N, KOSUGE K, SATO M, OZAWA Y, KANMATSUSE K, KOKUBUN S. A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. Endocrine. 2001;15:277–282. doi: 10.1385/ENDO:15:3:277. PubMed DOI

PIDASHEVA S, D'SOUZA-LI L, CANAFF L, COLE DEC, HENDY GN. CASR db: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2004;24:107–111. doi: 10.1002/humu.20067. PubMed DOI

POLLAK MR, BROWN EM, CHOU YH, HEBERT SC, MARX SJ, STEINMANN B, LEVI T, SEIDMAN CE, SEIDMAN JG. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75:1297–1303. doi: 10.1016/0092-8674(93)90617-Y. PubMed DOI

SHINALL MC, JR, DAHIR KM, BROOME JT. Differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism. Endocr Pract. 2013;19:697–702. doi: 10.4158/EP12284.RA. PubMed DOI

SZABO E, HELLMAN P, LUNDGREN E, CARLING T, RASTAD J. Parathyroidectomy in familial hypercalcemia with clinical characteristics of primary hyperparathyroidism and familial hypocalciuric hypercalcemia. Surgery. 2002;131:257–263. doi: 10.1067/msy.2002.120674. PubMed DOI

THAKKER RV. Calcium-sensing receptor: role in health and disease. Indian J Endocrinol Metab. 2012;16:S213–S216. PubMed PMC

THAKKER RV, NEWEY PJ, WALLS GV, BILEZIKIAN J, DRALLE H, EBELING PR, MELMED S, SAKURAI A, TONELLI F, BRANDI ML, ENDOCRINE SOCIETY. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1) J Clin Endocrinol Metab. 2012;97:2990–3011. doi: 10.1210/jc.2012-1230. PubMed DOI

VERROKEN C, ZMIERCZAK HG, GOEMAERE S, KAUFMAN JM, LAPAUW B. Bone turnover in young adult men: cross-sectional determinants and associations with prospectively assessed bone loss. J Bone Miner Res. 2018;33:261–268. doi: 10.1002/jbmr.3303. PubMed DOI

VONDRA K, STÁRKA L, HAMPL R. Vitamin D and thyroid diseases. Physiol Res. 2015;64(Suppl 2):S95–S100. doi: 10.33549/physiolres.933083. PubMed DOI

ZAJÍČKOVÁ K, ZOGALA D, KUBINYI J. Parathyroid imaging by (18)F-fluorocholine PET/CT in patients with primary hyperparathyroidism and inconclusive conventional methods: clinico-pathological correlations. Physiol Res. 2018;28(Suppl 3):S551–S557. doi: 10.33549/physiolres.934029. PubMed DOI

ŽOFKOVÁ I. Hypercalcemia. Pathophysiological aspects. Physiol Res. 2016;65:1–10. doi: 10.33549/physiolres.933059. PubMed DOI