Elsevier

Bone

Volume 64, July 2014, Pages 102-107
Bone

Case Report
Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism—lack of effect of cinacalcet

https://doi.org/10.1016/j.bone.2014.04.010Get rights and content

Highlights

  • We describe a difficult case of Neonatal Severe Hyperparathyroidism.

  • We identified a novel homozygous inactivating CASR mutation in the proband.

  • The totally nonfunctional receptor rendered cinacalcet pharmacotherapy ineffective.

  • The success or failure of treatment with cinacalcet depends upon the CASR genotype.

  • In such cases, parathyroid surgery is the treatment of choice.

Abstract

Background

NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.

Objective

To describe a case of NSHPT unresponsive to cinacalcet.

Patient and Results

A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10–2.62), P: 0.83 mmol/l (1.55–2.64), PTH: 1096 pg/ml (9–52) and urinary Ca/Cr ratio: 0.5 mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5 mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion–frameshift mutation.

Conclusion

The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Introduction

Neonatal severe hyperparathyroidism (NSHPT) is a rare clinical entity caused by homozygous inactivating mutations in the calcium-sensing receptor (CASR) gene [1], [2], [3], [4]. NSHPT results in severe hypercalcemia, metabolic bone disease and potential neurodevelopmental deficits, all of which may be life-threatening [5]. The CaSR protein is a G-protein-coupled receptor expressed most abundantly in parathyroid chief and renal tubular cells [2]. The activity of the parathyroid CaSR regulates parathyroid hormone (PTH) secretion and PTH synthesis and parathyroid cell proliferation [2]. The relationship between extracellular ionized calcium and PTH concentrations is best modeled as an inverse sigmoidal curve [2]. The activity of the CaSR determines the calcium set point—that is, the extracellular calcium concentration at which PTH secretion is half-maximally inhibited. [2]. While individuals with familial hypocalciuric hypercalcemia (FHH) due to heterozygous inactivating CASR mutations usually exhibit a modest rightward shift in the Ca-PTH response curve, in NSHPT with homozygous CASR inactivation, there is a dramatic rightward shift and a greatly elevated calcium set point [6], [7].

Hypercalcemia in such cases is usually severe, and immediate medical and/or surgical treatment may be needed if a favorable outcome is to be assured [8]. Therapeutic options for NSHPT infants with symptomatic hypercalcemia and hyperparathyroidism include intravenous fluid hydration and loop diuretic therapy (albeit with careful monitoring of volume status), calcitonin and, more recently, bisphosphonates and calcimimetics [9], [10], [11], [12], [13]. However, medical management of such cases is often difficult and complex.

Herein, we present a case of NSHPT caused by homozygous mutation in the CASR gene and review the challenging clinical course that reveals the difficulties in management of this condition. The study suggests the benefits of an empiric trial of a calcimimetic as monotherapy and early mutation identification.

Section snippets

Case report

Protocols were approved by Institutional Ethics Committees. The parents of the proband provided informed consent. The proband (individual V-1; Fig. 1) is a 3240-g (50th percentile) female infant born by spontaneous vaginal delivery at term. The parents are first-degree cousins once removed (Fig. 1). The neonate required ventilatory support for respiratory distress on day 2 of life. Unresolving pneumonia and hypercalcemia (day 21) prompted referral to Marmara University Hospital Neonatal

Discussion

This case of NSHPT caused by homozygous truncating mutations in the CASR gene highlights the difficulties of medical management and the challenge to resolve the hyperparathyroid disease as soon as possible. Therapy for hypercalcemia was initiated with hydration using normal saline and a loop diuretic. Calcitonin that decreases bone resorption by interfering with osteoclast maturation and activity was given, but it is not effective in all cases, including this one. Bisphosphonates that inhibit

Acknowledgments

We thank all family members for their participation. The work was supported by grants from the Canadian Institutes of Health Research (MOP-86581 to GNH) and NSERC/Dairy Farmers of Canada (DECC).

Database linking

CASR-OMIM: 601199, 145980 (FHH), 239200 (NSHPT); GenBank: X81086, www.casrdb.mcgill.ca (CASRdb), www.genetests.org (Genetests), http://genetics.bwh.harvard.edu/pph2/ (Polyphen), http://sift.jcvi.org/ (SIFT), http://evs.gs.washington.edu/EVS/ (Exome Variant Server, NHLBI Exome Sequencing

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