Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy

Overview

Journal J Clin Med

Specialty General Medicine

Date 2022 May 14

PMID 35566721

Authors

Jakob Hoppner

Kathrin Sinningen

Adalbert Raimann

Barbara Obermayer-Pietsch

Corinna Grasemann

Affiliations

Soon will be listed here.

Abstract

Familial hypocalciuric hypercalcemia (FHH) is a mostly benign condition of elevated calcium and PTH levels based on a hyposensitive calcium sensing receptor () in FHH 1 or its downstream regulatory pathway in FHH2 and FHH3. In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy. However, inheritance of FHH may result in neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), conditions with high morbidity, and in the latter even high mortality. This review focuses on the genetic and pathophysiological framework that leads to the severe neonatal form, gives recommendations for counselling and summarizes treatment options.

Citing Articles

Case Report: Familial hypocalciuric hypercalcemia type 1 with a novel mutation combined with Gitelman syndrome and a review of the literature.

He T, Li X, Li G, Wang W, Fu H, Gao Z Front Endocrinol (Lausanne). 2025; 16:1503128.

PMID: 40070587 PMC: 11893564. DOI: 10.3389/fendo.2025.1503128.

Retrospectively diagnosed familial hypocalciuric hypercalcaemia following total parathyroidectomy in an asymptomatic patient.

Severaj R EJIFCC. 2025; 35(4):329-332.

PMID: 39810898 PMC: 11726324.

Novel Mutation in the Calcium-Sensing Receptor Gene Associated With Familial Hypocalciuric Hypercalcemia.

Al Kayed H, Islam S, Akanmode O, Ezike L, Mirza L Cureus. 2024; 16(8):e66498.

PMID: 39246902 PMC: 11380763. DOI: 10.7759/cureus.66498.

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism.

Carsote M, Stanciu M, Popa F, Gheorghe A, Ciuche A, Nistor C Biomedicines. 2023; 11(10).

PMID: 37893182 PMC: 10603939. DOI: 10.3390/biomedicines11102810.

Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.

Cuny T, Romanet P, Goldsworthy M, Guerin C, Wilkin M, Roche P J Clin Endocrinol Metab. 2023; 109(2):549-556.

PMID: 37602721 PMC: 7615553. DOI: 10.1210/clinem/dgad494.

References

Riccardi D, Hall A, Chattopadhyay N, Xu J, Brown E, Hebert S . Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol. 1998; 274(3):F611-22. DOI: 10.1152/ajprenal.1998.274.3.F611. View

Waller S, Kurzawinski T, Spitz L, Thakker R, Cranston T, Pearce S . Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr. 2004; 163(10):589-94. DOI: 10.1007/s00431-004-1491-0. View

Sethi B, Nagesh V, Kelwade J, Parekh H, Dukle V . Utility of Cinacalcet in Familial Hypocalciuric Hypercalcemia. Indian J Endocrinol Metab. 2017; 21(2):362-363. PMC: 5367245. DOI: 10.4103/2230-8210.202034. View

Sands J, Naruse M, Baum M, Jo I, Hebert S, Brown E . Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest. 1997; 99(6):1399-405. PMC: 507956. DOI: 10.1172/JCI119299. View

Christensen S, Nissen P, Vestergaard P, Heickendorff L, Rejnmark L, Brixen K . Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism. Clin Endocrinol (Oxf). 2009; 71(6):798-807. DOI: 10.1111/j.1365-2265.2009.03557.x. View

Toke J, Czirjak G, Enyedi P, Toth M . Rare diseases caused by abnormal calcium sensing and signalling. Endocrine. 2021; 71(3):611-617. PMC: 8016752. DOI: 10.1007/s12020-021-02620-5. View

Brown E, MacLeod R . Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 2001; 81(1):239-297. DOI: 10.1152/physrev.2001.81.1.239. View

Rodd C, Goodyer P . Hypercalcemia of the newborn: etiology, evaluation, and management. Pediatr Nephrol. 1999; 13(6):542-7. DOI: 10.1007/s004670050654. View

Reh C, Hendy G, Cole D, Jeandron D . Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. J Clin Endocrinol Metab. 2011; 96(4):E707-12. DOI: 10.1210/jc.2010-1306. View

10.

Law Jr W, Heath 3rd H . Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med. 1985; 102(4):511-9. DOI: 10.7326/0003-4819-102-4-511. View

11.

Breitwieser G, Gama L . Calcium-sensing receptor activation induces intracellular calcium oscillations. Am J Physiol Cell Physiol. 2001; 280(6):C1412-21. DOI: 10.1152/ajpcell.2001.280.6.C1412. View

12.

Eastell R, Brandi M, Costa A, DAmour P, Shoback D, Thakker R . Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014; 99(10):3570-9. DOI: 10.1210/jc.2014-1414. View

13.

Dershem R, Gorvin C, Metpally R, Krishnamurthy S, Smelser D, Hannan F . Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population. Am J Hum Genet. 2020; 106(6):734-747. PMC: 7273533. DOI: 10.1016/j.ajhg.2020.04.006. View

14.

Ritter A, Vargas-Poussou R, Mohebbi N, Seeger H . Recurrent Nephrolithiasis in a Patient With Hypercalcemia and Normal to Mildly Elevated Parathyroid Hormone. Am J Kidney Dis. 2021; 77(6):A13-A15. DOI: 10.1053/j.ajkd.2020.09.022. View

15.

Bertocchio J, Tafflet M, Koumakis E, Maruani G, Vargas-Poussou R, Silve C . Pro-FHH: A Risk Equation to Facilitate the Diagnosis of Parathyroid-Related Hypercalcemia. J Clin Endocrinol Metab. 2018; 103(7):2534-2542. DOI: 10.1210/jc.2017-02773. View

16.

Nesbit M, Hannan F, Howles S, Reed A, Cranston T, Thakker C . Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2012; 45(1):93-7. PMC: 3605788. DOI: 10.1038/ng.2492. View

17.

Forman T, Niemi A, Prahalad P, Shi R, Nally L . Cinacalcet therapy in an infant with an R185Q calcium-sensing receptor mutation causing hyperparathyroidism: a case report and review of the literature. J Pediatr Endocrinol Metab. 2019; 32(3):305-310. DOI: 10.1515/jpem-2018-0307. View

18.

Zajickova K, Vrbikova J, Canaff L, Pawelek P, Goltzman D, Hendy G . Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status. J Clin Endocrinol Metab. 2007; 92(7):2616-23. DOI: 10.1210/jc.2007-0123. View

19.

Volpe A, Guerriero A, Marchetta A, Caramaschi P, Furlani L . Familial hypocalciuric hypercalcemia revealed by chondrocalcinosis. Joint Bone Spine. 2009; 76(6):708-10. DOI: 10.1016/j.jbspin.2009.02.001. View

20.

Sperlongano P, Sperlongano S, Foroni F, De Lucia F, Pezzulo C, Manfredi C . Postoperative hypocalcemia: assessment timing. Int J Surg. 2014; 12 Suppl 1:S95-7. DOI: 10.1016/j.ijsu.2014.05.042. View