Familial hypocalciuric hypercalcemia in an index male: grey zones of the differential diagnosis from primary hyperparathyroidism in a 13-year clinical follow up
Language English Country Czech Republic Media print
Document type Case Reports, Journal Article
PubMed
33094630
PubMed Central
PMC8603734
DOI
10.33549/physiolres.934522
PII: 934522
Knihovny.cz E-resources
- MeSH
- Diagnosis, Differential MeSH
- Adult MeSH
- Hypercalcemia blood congenital diagnosis diagnostic imaging MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Positron Emission Tomography Computed Tomography methods MeSH
- Hyperparathyroidism, Primary blood diagnosis diagnostic imaging MeSH
- Prognosis MeSH
- Receptors, Calcium-Sensing blood MeSH
- Calcium blood MeSH
- Vitamin D blood MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Names of Substances
- Receptors, Calcium-Sensing MeSH
- Calcium MeSH
- Vitamin D MeSH
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.
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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