Case ReportNovel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism—lack of effect of cinacalcet
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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2021, Bone ReportsCitation Excerpt :Other described cases have not responded well, and have required parathyroidectomy (Murphy et al., 2016; Garcia Soblechero et al., 2013; Atay et al., 2014; Capozza et al., 2018; Ahmad et al., 2017; Savas-Erdeve et al., 2016). Osteopenia at the time of parathyroidectomy increases the risk of hungry bone disease characterized by hypocalcemia, hypophosphatemia and hypomagnesemia due to excessive bone remineralization (Atay et al., 2014; Capozza et al., 2018). Hypocalcemia after parathyroidectomy due to postoperative hypoparathyroidism is more commonly described however (Stokes et al., 2017; Murphy et al., 2016; Capozza et al., 2018; Ahmad et al., 2017).
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2019, Principles of Bone BiologyNeonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia
2016, European Journal of Medical GeneticsCitation Excerpt :CaSR gene mutations often decrease the receptor's sensitivity to extracellular calcium. An elevated calcium homeostasis set point (the point at which serum calcium concentration halfmaximally inhibits parathyroid hormone secretion)results, and parathyroid gland stimulation and chief cell proliferation follows (Atay et al., 2014). Increased synthesis and secretion of PTH leads to skeletal demineralization and decreased renal calcium excretion yielding severe hypercalcemia.
Familial hyperparathyroidism syndromes
2016, Diagnostic HistopathologyCitation Excerpt :Neonatal severe hyperparathyroidism (NSHPT) is regarded as the extreme phenotypic variant of FHH-1, caused by homozygous germline inactivating mutations in the CaSR gene (3q21.1), although a single abnormal allele has been reported in rare cases.1,5,8,18,19,30,63,91 Unlike the milder heterozygous form (FHH-1), the homozygous form (NSHPT) presents with severe and almost complete penetrance for hyperparathyroidism.1,5,8,18,19,30,63,91 The clinical presentation of NSHPT is quite characteristics as patients generally present shortly after birth (in the first 6 months of life) with extreme hyperparathyroidism, hypocalciuria and life-threatening hypercalcemia, complicated by hypotonia, failure to thrive, bone demineralization, fractures and respiratory distress.1,5,8,18,19,30,32,63,91,92
Severe neonatal hypercalcemia in 4-month-old, presented with respiratory distress and chest wall deformity
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