Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel inactivating mutation of the calcium-sensing receptor

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are consequent to inactivating mutations of the calcium-sensing receptor (CaR) gene. FHH is usually associated with heterozygous inactivating mutations of the CaR gene, whereas NSHPT is usually due to homozygous inactivation of the CaR gene. FHH is generally asymptomatic and is characterized by mild to moderate lifelong hypercalcemia, relative hypocalciuria, and normal intact PTH, whereas individuals with NSHPT frequently show life-threatening hypercalcemia. In this study, we report a novel inactivating mutation of the CaR gene, identified in a 9-yr-old Brazilian girl who was found to be severely hypercalcemic during investigation of a 6-month history of headaches and vomits. Direct sequencing of the CaR gene from this patient showed a novel homozygous mutation (L13P) in exon 2. Functional characterization by intracellular calcium measurement by fluorometry showed that the mutant receptor had a dose-response curve shifted to the right relative to that of wild type. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, showed the same mutation in the heterozygous form. The mutation described in this study is the inactivating missense mutation present at the most N-terminal end among the known CaR missense mutations. This study reinforces the fact that patients with homozygous inactivation of the CaR gene may present with severe hypercalcemia in different phases of life.     

Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.     

A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor

Antibodies to cell surface receptors can cause endocrine dysfunction by mimicking or blocking the actions of their respective hormones. We sought patients with autoantibodies to the extracellular calcium (Ca(2+)(o))-sensing receptor (CaR), which sets the normal level of blood calcium, that mimic the genetic disorder, familial hypocalciuric hypercalcemia, caused by heterozygous inactivating mutations of the CaR. Four individuals from two kindreds were identified with PTH-dependent hypercalcemia, who had other autoimmune manifestations: one with sprue and antigliadin and antiendomyseal antibodies and three with antithyroid antibodies. Three of the patients also had relative or absolute hypocalciuria. The patients' sera contained antibodies that reacted with the cell surface of bovine parathyroid cells in a manner similar to an authentic polyclonal anti-CaR antibody, stained bands on Western analysis of sizes similar to those labeled by the anti-CaR antiserum, and reacted with several synthetic peptides derived from sequences within the CaR's extracellular amino terminus. The patients' sera also stimulated PTH release from dispersed human parathyroid cells compared with the effect of sera from normocalcemic control subjects. This stimulation could be blocked by preabsorbing serum with membranes from CaR-transfected, but not nontransfected, human embryonic kidney (HEK293) cells. Finally, in two of the patients, antibodies affinity-purified using a synthetic peptide from within the CaR's extracellular domain inhibited high Ca(2+)(o)-stimulated, CaR-mediated accumulation of inositol phosphates and activation of mitogen-activated protein kinase in CaR-transfected HEK293 cells. DNA sequencing revealed no mutations within the index patients' CaR genes in the two families. Therefore, a biochemical phenotype of PTH-dependent hypercalcemia resembling that caused by heterozygous inactivating mutations of the CaR in familial hypocalciuric hypercalcemia can be observed in patients with antibodies to the CaR's extracellular domain that stimulate PTH release, probably by inhibiting activation of the CaR by Ca(2+)(o). Autoimmune hypocalciuric hypercalcemic is an acquired disorder of Ca(2+)(o) sensing that should be differentiated from that caused by inactivating mutations of the CaR.     

Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism

Heterozygous inactivating mutations of the calcium-sensing receptor (CaR) cause familial hypocalciuric hypercalcemia, whereas homozygous or compound heterozygous inactivating mutations normally cause neonatal severe hyperparathyroidism. In a case of neonatal severe hyperparathyroidism characterized by moderately severe hypercalcemia and very high PTH levels, coupled with evidence of hyperparathyroidism and effects on brain development not previously demonstrated, we detected point mutations on separate alleles of the CaR, resulting in premature stop codon substitutions at G94 and R648. This led to severely truncated receptors and an effective so-called knockout of functional CaR. FLAG-tagged, truncated receptors were expressed in HEK293 cells for functional analysis. Confocal microscopy demonstrated cytoplasmic localization of the G94stop receptor, whereas the R648stop receptor was present both in the cytoplasm and associated with the cell membrane. Only the R648stop receptor could be detected by Western analysis. Functional assays in which R648stop and wild-type receptor were cotransfected into HEK293 cells demonstrated a reduction in wild-type Ca(2+)-responsiveness by the R648stop receptor, even at physiological Ca(2+) levels, thus simulating familial hypocalciuric hypercalcemia in relatives of the infant who were heterozygous for the R648stop mutation. The R648stop receptor alone was nonresponsive to Ca(2+). This case contributes to our understanding of the clinical manifestation of a CaR knockout.     

Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population

CONTEXT: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene. OBJECTIVE: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations. DESIGN AND PARTICIPANTS: A total of 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype-phenotype relationships were established in 66 mutation-positive index patients and family members. MAIN OUTCOME MEASURES: We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4), and PTH were measured. RESULTS: We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F, and p.G553R. CONCLUSIONS: The present data add 19 novel mutations to the catalog of inactivating CASR mutations and illustrate a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.     

New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT)

A loss of calcium-sensing receptor (CASR) function due to inactivating mutations can cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). NSHPT represents the most severe expression of FHH and courses as a life-threatening condition. The aim of this study was to identify and characterize a CASR mutation in a female infant brought to the health service due to dehydration, apathy, lack of breast feeding and severe hypercalcemia. Molecular analysis was performed on genomic DNA of the index case and her parents. A novel homozygous mutation (p.E519X) in CASR was identified in the proband; both mother and father had the same mutation in heterozygous state, confirming their FHH condition. The mutation results in a truncated and inactive protein due to the lack of transmembrane and intracellular domains. The identification of this novel CASR gene mutation established the basis of hypercalcemia in this family and allowed a genetic counseling.     

An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor

Inactivating mutations in the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcaemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Earlier investigations showed patients with FHH are heterozygous, and NSHPT are homozygous for inactivating mutations. However, one adult patient with severe hypercalcaemia and hypocalciuria has been reported to have a homozygous inactivating mutation in CaSR (Pro39Ala). This suggested that mutant CaSR in this patient had some residual activity and hypercalcaemia was not so severe as to be fatal. However, the function of this mutant CaSR was not evaluated. In the present study, we describe a novel homozygous mutation in an adult patient with severe hypercalcaemia and hypocalciuria, and evaluate the function of the mutant CaSRs. The DNA sequence of CaSR gene was determined by direct sequencing of the polymerase chain reaction product. The function of mutant CaSR was analysed by creating mutant cDNAs by in vitro mutagenesis, transfection of mutant cDNAs into HEK293 cells and measuring intracellular ionized Ca in response to changes in extracellular Ca. A 26-year-old Japanese woman showed marked hypercalcaemia with an elevated parathyroid hormone (PTH) level. Her consanguineous parents had asymptomatic hypercalcaemia with relative hypocalciuria. The proband had a homozygous mutation at codon 27 of CaSR gene (CAA-->CGA, Gln27Arg). Her parents were heterozygous for this mutation. EC50 for Ca of this mutant CaSR (GIn27Arg) was 4.9 mM. EC50 of another mutant CaSR (Pro39Ala) whose homozygous mutation was discovered in an adult patient was 4.4 mM. These EC50s were significantly higher than that of wild-type CaSR (3.7} 0.1 mM), but were the lowest among the reported EC50s for inactivating mutations of CaSR. These results indicate that serum Ca and PTH levels are determined by residual function of mutant CaSR in patients with homozygous mutation in CaSR, and that patients having homozygous mutant CaSRs with mild dysfunction do not suffer from fatal hypercalcaemia in infancy and can survive into adulthood.     

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

CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a benign condition associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CASR) gene. OBJECTIVE: The objective of the study was to identify and characterize a CASR mutation in a moderately hypercalcemic, hyperparathyroid individual and his family and assess the influence of vitamin D status on the clinical expression of the defect. SUBJECTS: We studied a kindred with FHH, in which the proband (a 34-yr-old male) was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. METHODS: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The mutant CASR was functionally characterized by transient transfection studies in kidney cells in vitro. RESULTS: A novel heterozygous mutation (F180C, TTC>TGC) in exon 4 of the CASR gene was identified. Although the mutant receptor was expressed normally at the cell surface, it was unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. The baby daughter of the proband presented with neonatal hyperparathyroidism with markedly elevated PTH. Vitamin D supplementation of both the proband and the baby resulted in reduction of serum PTH levels to the normal range. The serum calcium level remained at a constant and moderately elevated level. CONCLUSION: The identification of a novel CASR gene mutation established the basis of the hypercalcemia in the kindred. Concomitant vitamin D deficiency modulates the severity of the presentation of FHH.     

Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis.

Calcium-sensing receptor gene (CASR) mutations that alter the function of the G protein coupled Ca (2+)-sensing receptor are reported in patients with familial hypocalciuric hypercalcemia (FHH), autosomal dominant hypocalcemia (ADH), and neonatal severe hyperparathyroidism (NSHPT). In search for novel disease causing mutations in the CASR gene, we screened exons 2 - 7 of the CASR gene of a family with FHH using single-strand conformation polymorphism analysis. We identified a novel CASR mutation (c.518 T > C; L173 P) in exon 4 encoding for the extracellular domain of the Ca (2+)-sensing receptor. This region seems to represent a hot spot within the CASR gene with at least 13 reported disease causing mutations thus far.     

Vitamin D metabolism in familial benign hypercalcemia (hypocalciuric hypercalcemia) differs from that in primary hyperparathyroidism

We compared serum concentrations of immunoreactive PTH and plasma levels of vitamin D metabolites in 11 patients with adenomatous primary hyperparathyroidism and 32 individuals with the syndrome of familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH). Serum immunoreactive PTH was elevated in the hyperparathyroid group but indistinguishable from control in FHH, despite comparable degrees of hypercalcemia. Plasma 25-hydroxyvitamin D concentrations were normal in both groups, but plasma 1,25-dihydroxyvitamin D levels in FHH were significantly lower than control (P less than 0.0025) or hyperparathyroid (P less than 0.01) values. FHH is pathogenetically distinct from primary hyperparathyroidism and should not be thought of simply as a variant of that condition.     

Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia

OBJECTIVE: Heterozygous inactivating mutations of the calcium-sensing receptor (CaR) gene cause familial hypocalciuric hypercalcaemia (FHH), a generally benign disorder characterized by mild to moderate PTH-dependent hypercalcaemia. We aimed to identify the causative CaR mutations in three families with FHH and examine the correlation between type of mutation and biochemical and/or functional phenotypes. PATIENTS, DESIGN AND MEASUREMENTS: The CaR gene from FHH family members was assessed for mutations by direct DNA sequencing and mutations were confirmed by restriction enzyme analysis. Functional studies on two missense mutations were conducted by introducing them by site-directed mutagenesis into the CaR cloned into a mammalian expression vector, and assessing calcium responsiveness using an inositol phosphate (IP) assay in HEK293 cells. Biochemical data from patients heterozygous for each type of mutant were correlated with functionality. RESULTS: Two novel nonsense mutations (R25stop and K323stop) and one novel missense mutation (G778D) were identified. The G778D mutant receptor and another mutation identified in an earlier study (L174R) demonstrated a complete lack of Ca2+ responsiveness using the IP assay. When cotransfected with wild-type receptor, the mutant receptors demonstrated a dominant-negative effect on wild-type receptor response, with L174R having a more pronounced effect than G778D. Significantly more severe hypercalcaemia and a trend towards higher PTH levels were observed in patients heterozygous for CaR mutants with a stronger dominant-negative effect. CONCLUSIONS: Naturally occurring CaR mutations with differences in dominant-negative effect on wild-type receptor demonstrate differences in biochemical severity in FHH.     

Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.     

Physiology and pathophysiology of the extracellular calcium-sensing receptor

The system governing extracellular calcium (Ca2+o) homeostasis maintains near constancy of Ca2+o so as to ensure continual availability of calcium ions for their numerous intracellular and extracellular roles. In contrast to the intracellular ionized calcium concentration (Ca2+i), which varies substantially during intracellular signaling via this key second messenger, Ca2+o remains nearly invariant. Yet there must be a mechanism that senses small changes in Ca2+o so as to set into motion the homeostatic responses that return Ca2+o to its normal level. The recent identification and molecular cloning of the mechanism through which parathyroid cells and a number of other cell types sense Ca2+o, a G protein-coupled Ca2+o-sensing receptor (CaR), has proven unequivocally that extracellular calcium ions serve in an informational capacity. The CaR permits Ca2+o to function in a hormone-like role as an extracellular first messenger through which parathyroid, kidney, and other cells communicate with one another via the CaR. The identification of inherited human hypercalcemic and hypocalcemic disorders arising from inactivating and activating mutations of the CaR, respectively, has provided additional proof of the essential, nonredundant role of the CaR in mineral ion homeostasis. Moreover, CaR-active drugs are currently in clinical trials for the treatment of primary and uremic hyperparathyroidism, disorders in which there are acquired, tissue-specific reductions in CaR expression and, in turn, defective Ca2+o-sensing by pathological parathyroid cells. No doubt further studies of Ca2+o-sensing by the CaR will reveal additional functions of Ca2+o, not only as a systemic "hormone" but also in local, paracrine, and autocrine signaling through this novel Ca2+o-sensing receptor.     

Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor

Familial benign hypocalciuric hypercalcaemia (FHH) results from a heterozygous inactivating mutation of the calcium-sensing receptor (CaR) and is characterized by hypercalcaemia, hypocalciuria and inappropriately normal plasma levels of parathyroid hormone. In a minority of patients, a loss of function mutation of the CaR results in severe hypercalcaemia associated with complications for which no effective surgical or medical treatment is available. We investigated the effects of the calcimimetic agent cinacalcet, an allosteric modulator of the CaR, in a 26-year-old man presenting with hypercalcaemia due to a de novo inactivating mutation of the CaR. Complicating features were recurrent psychosis and progressive severe osteoporosis. A single dose of either 30 or 60 mg of cinacalcet resulted in a 63-88% decline in plasma parathyroid hormone levels within 2 h of administration of the agent, reverting to baseline levels after 12 h. Normalization of serum calcium was more gradual but sustained for up to 12 months of treatment with a maintenance twice-daily oral dose of 60+30 mg cinacalcet. In addition to its beneficial effects in primary and secondary hyperparathyroidism, cinacalcet may open new therapeutic avenues in the management of a subset of patients with severe hypercalcaemia due to inactivating mutations of the CaR.     

Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

Familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and autosomal dominant hypocalcemia (ADH), in which calcium homeostasis is disordered, are associated with mutations in the calcium-sensing receptor (CASR). Six unrelated kindreds with FHH and/or NSHPT and two unrelated kindreds with ADH were studied. Direct sequence analysis of the exons of the CASR gene identified heterozygous mutations in six of the kindreds with FHH and in one of those with ADH. We performed functional analyses on the novel missense and insertion/frameshift mutants by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. All mutant receptors were expressed at a similar level to that of the wild type; however, whereas mutants R220W and A835T (the ADH mutant) were fully glycosylated and were visualized on the cell surface, glycosylation of mutants G549R and C850-851 ins/fs was impaired, resulting in reduced cell surface staining. In fura-2-loaded HEK293 cells expressing the wild-type or mutant receptors, the inactivating R220W mutant produced a significant shift to the right relative to the wild-type CASR in the cytosolic calcium response to increasing extracellular calcium concentrations and the G549R and C850-851 ins/fs mutants were without detectable activity. The activating A835T mutation resulted in a shift to the left in the cytosolic calcium response to extracellular calcium concentrations relative to the wild type. Our studies have identified novel CASR mutations that alter the function of the CASR in several different ways.     

Familial hypocalciuric hypercalcemia. Report of a new family

We report a new family with familial hypocalciuric hypercalcemia (FHH) composed by 55 living members. Of 38 studied, 10 have been found to be affected by FHH. Differences between FHH and primary hyperparathyroidism are emphasized; lack of clinical features, relative hypocalciuria for the concomitant hypercalcemia and low phosphate excretion index. The PTH and urinary cAMP are normal. It is noteworthy that the disease is benign. None of our patients have undergone surgery, and all of them are asymptomatic.     

Calcium-sensing receptor induces messenger ribonucleic acid of human securin,pituitary tumor transforming gene,in rat testicular cancer

Pituitary tumor transforming gene (PTTG), the human ortholog of securin, is an oncogene. Few normal tissues express PTTG, although in the testis, it is more abundantly expressed. In cancer, however, its wide expression has been directly correlated with the proliferation and angiogenesis, although very little is known about the overall regulation of the PTTG gene. In this study, we investigate the role of the calcium-sensing receptor (CaR), a G protein-coupled receptor (GPCR), in regulating PTTG in a widely used model of humoral hypercalcemia of malignancy, the rat H-500 Leydig cell testicular cancer. We show that extracellular calcium (Ca2+o) up-regulates PTTG mRNA. This up-regulation has a rapid onset, starting at 0.5 h, and remains up-regulated until 40 h. The up-regulation was also Ca2+o concentration dependent, with increases (mean +/- se) of 4.22 +/- 1.61-fold, 5.11 +/- 1.11-fold, and 5.64 +/- 1.92-fold at 5, 7.5, and 10 mm calcium, respectively, compared with 0.5 mm Ca2+o. This effect was abolished by overexpression of a dominant-negative CaR (R185Q), thereby confirming that the effect of high Ca2+o is CaR mediated. Another GPCR agonist, ADP, had no effect on PTTG expression. Because PTTG has been reported to induce angiogenesis, we investigated the effect of elevated Ca2+o on vascular endothelial growth factor (VEGF) expression. Indeed high calcium up-regulated VEGF mRNA by 1.59 +/- 0.22-fold. In conclusion, we show for the first time that a GPCR, the CaR, stimulates the synthesis of PTTG mRNA in a nonmetastasizing model for humoral hypercalcemia of malignancy and, in the process, might induce angiogenesis via VEGF.     

Familial benign hypocalciuric hypercalcemia and neonatal hyperparathyroidism

Conclusion In summary, both FBHH and NSHPT represent the phenotypic expression of inactivating mutations of the CaSR in most cases, FBHH usually presenting with mild asymptomatic lifelong hypercalcemia and NSHPT with generally more severe, potentially lethal hypercalcemia, which, in cases of homozygous or compound heterozygous CaSR mutations, carries a high morbidity. Additional molecular studies should elucidate the basis for variations in the phenotypic and biochemical abnormalities observed with both FBHH and NSHPT and identify the disease genes on chromosome 19 that can also cause FBHH in rare cases.     

Hypercalcemia with low-normal serum intact PTH: a novel presentation of primary hyperparathyroidism

The diagnosis of primary hyperparathyroidism has rested on the finding of hypercalcemia coupled with an elevated serum parathyroid hormone (PTH) level. Over 300 consecutive patients with primary hyperparathyroidism have had elevated or high-normal serum PTH levels using a specific immunoradiometric assay. Here we present a patient who proved to have surgically documented primary hyperparathyroidism in whom PTH levels were completely normal in all assays used. In the immunoradiometric assay, his normal result was unprecedentedly low (17 to 28 pg/mL; normal, 10 to 60 pg/mL) for this condition, and in a range consistent with non-PTH-dependent hypercalcemia or familial hypocalciuric hypercalcemia. This rare biochemical presentation of primary hyperparathyroidism should be considered in the differential diagnosis of hypercalcemia.