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International audience; Parathyroid hormone (PTH) is a hypercalcemic hormone acting on kidneys, bone and intestine. PTH promotes calcium release from the bone, renal calcium reabsorption and phosphate excretion, and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D-3. Hyperparathyroidism consists in PTH elevation, which may be adapted (secondary hyperparathyroidism) or non-adapted to calcemia levels (primary hyperparathyroidism, familial hypercalcemia/hypocalciuria, tertiary hyperparathyroidism). Primary hyperparathyroidism (PHP) features hypercalcemia and elevated or inappropriate PTH elevation. PHP may be revealed by biological abnormalities such as hypercalcemia and can be accompanied by renal complications (hypercalciuria, nephrolithiasis, nephrocalcinosis) and/or osteoporosis. However, it can also be normocalcemic and calcium loading will be necessary to diagnosis it. The differential diagnosis of PHP is familial hypocalciuric hypercalcemia (FHH), a dominant autosomal disease implicating a calcium sensing receptor-inactivating mutation. It impairs parathyroid cell sensitivity to calcemia elevation and thus induces excessive PTH stimulation, leading to hypercalcemia. Secondary HP (SHP) consists in PTH elevation secondary to a stimulus that needs to be corrected. 25 OHvitD deficiency, kidney failure, renal hypercalciuria, malabsorption and some drugs can induce SHP. Tertiary HP (THP) consists in autonomous PTH secretion by the parathyroid glands after prolonged stimulation under SHP, of whatever cause. This parathyroid autonomy results from the polyclonal hyperplasia observed in SHP progressing toward monoclonal nodular proliferation, leading to nodular hyperplasia or parathyroid adenoma (or, exceptionally, carcinoma), with reduced expression of CaSR and vitamin D receptor. In patients under dialysis, the frontier between SHP and THP is a matter of debate. This review will focus on the pathophysiology of calcium, diagnosis, and management of hyperparathyroidism.

We present a case of a 50-year-old woman with familial hypocalciuric hypercalcemia type 1 (FHH-1) that was missed during an initial evaluation of hypercalcemia in the setting of normal serum parathyroid hormone (PTH), leading to unnecessary parathyroidectomy. She subsequently reported years later with an inappropriately elevated PTH in the setting of hypercalcemia. Sequencing of the calcium-sensing receptor (CASR) gene revealed a known inactivating variant associated with FHH-1. We assessed the clinical utility of the recently reported pro-FHH (Probability of having familial hypocalciuric hypercalcemia) score at the time of her surgery and subsequent re-evaluation years later. This case highlights the diagnostic challenges in differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism (PHPT).

Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α(11), or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.

Familial hypocalciuric hypercalcemia is a benign cause of hypercalcemia of autosomal dominant inheritance that does not normally require treatment. The case is presented on a 21 year-old male with a typical familial hypocalciuric hypercalcemia biochemical profile: mild hypercalcaemia, normal PTH levels, and hypocalciuria. A genetic study was requested on the CASR gene, which showed a heterozygous variant not previously described in the literature. The father, with mild hypercalcaemia, was also a carrier of this variant. Although it is a disease with no significant clinical repercussions, it is useful to perform genetic confirmation of familial hypocalciuric hypercalcemia to differentiate it from primary hyperparathyroidism and to provide adequate genetic counselling to patients.

Primary hyperparathyroidism is a common endocrine disorder and the most prevalent cause of hypercalcemia worldwide. While most cases are sporadic, 5–10% of cases are inherited as part of a familial syndrome: multiple endocrine neoplasia (MEN-1, MEN-2A, MEN-4), hyperparathyroidism jaw-tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), autosomal dominant moderate hyperparathyroidism (ADMH), or familial isolated hyperparathyroidism (FIHPT). Recent developments in molecular pathology identified specific germline mutations ( MEN1 , RET , CDKIs , CDC73/HRPT2 , CaSR , GNA11 , AP2S1 ) implicated in their pathogenesis. In contrast to sporadic primary hyperparathyroidism which is usually caused by a solitary parathyroid adenoma, hereditary hyperparathyroidism tend to present with multiglandular parathyroid disease, with variable penetrance according to the genetic syndrome. As a result, the clinical severity of each familial condition varies tremendously, resulting in distinct prognosis and treatment strategies. With the advent of molecular testing, genetic subtyping has become an integral part of treatment decision making, requiring correlation with clinical and pathologic findings. This review provides an update on the current knowledge of hereditary hyperparathyroidism and its associated genetic syndromes.

Objective To discuss the unusual occurrence of both familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism in the same patient and to explore potential mechanisms of association and issues related to clinical management. Methods We discuss the diagnosis, compare the clinical presentations of FHH and primary hyperparathyroidism, review the literature regarding patients who have presented with both disorders, and discuss management considerations. We also describe 2 patients who have both FHH (confirmed by genetic testing for a mutation in the gene encoding the calcium-sensing receptor [CASR]) and primary hyperparathyroidism. Results The occurrence of both FHH and primary hyperparathyroidism in the same patient has been reported in a few cases, including 2 patients described here, one of whom was documented to have a novel CASR mutation. In those with clinical sequelae of hyperparathyroidism, parathyroidectomy has led to reduction, but not normalization, of serum calcium levels. Conclusions The coexistence of FHH and primary hyperparathyroidism should be considered in patients with hypercalcemia, hypophosphatemia, frankly elevated parathyroid hormone levels, and low urinary calcium excretion. Genetic testing for inactivating CASR gene mutations can confirm the diagnosis of FHH. Although surgical intervention does not resolve hypercalcemia, it may be beneficial by reducing the degree of hypercalcemia, alleviating the symptoms, and preventing potential complications of hyperparathyroidism. (Endocr Pract. 2012;18:412-417)

Objectives Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. Patients and methods A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-h urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. Results One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C>T (Pro55Leu) in exon 2 in heterozygosis. Conclusions According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypical clinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs.

Objective To review the pathophysiology, clinical features, diagnosis, and management options for benign familial hypocalciuric hypercalcemia. Methods We present a systematic summary of benign familial hypocalciuric hypercalcemia after review of the current available literature. Results Benign familial hypocalciuric hypercalcemia is an autosomal dominant condition characterized by lifelong hypercalcemia, relative hypocalciuria, and inappropriately elevated parathyroid hormone. It is caused by a loss-of-function mutation in the calcium-sensing receptor gene (CASR). Benign familial hypocalciuric hypercalcemia is important clinically because it can be difficult to distinguish from primary hyperparathyroidism. It is a benign condition, and affected patients should be advised against parathyroidectomy. The incidence of complications associated with primary hyperparathyroidism, like osteopenia and nephrolithiasis, is not increased in persons with benign familial hypocalciuric hypercalcemia, and the rates are similar to those in the general population. Rarely, a severe form of this disease, namely neonatal severe primary hyperparathyroidism is seen in infants with homozygous CASR mutations. Conclusions Benign familial hypocalciuric hypercalcemia is a small but important cause of hypercalcemia, especially in the younger population. Hypercalcemia persists after subtotal parathyroidectomy. It is important to diagnose this condition, not only in the index case but also in family members, because these patients should be advised against surgical intervention. (Endocr Pract. 2011;17[Suppl 1]:13-17)

Resumen: La hipercalcemia hipocalciúrica familiar (FHH) es una de las causas de hipercalcemia; se hereda de forma autosómica dominante, y posee alta penetrancia. Es el resultado de una mutación inactivante en el gen del receptor sensible al calcio (CaSR). Los casos heterocigotos no suelen presentar síntomas y se diagnostican de forma incidental.Presentamos los casos de tres niñas afectas de una mutación inactivante en heterocigosis, p.Phe789del, en el exón 7 del gen del receptor sensible al calcio (gen CASR) localizado en el cromosoma 3q21 (Ensembl ENSG00000036828). En las muestras sanguíneas se constató hipercalcemia con calcio iónico elevado, hormona paratiroidea normal o elevada, y la calciuria disminuida.Es importante establecer el diagnostico-diferencial con el hiperparatiroidismo primario. Por lo tanto, en presencia de una hipercalcemia con hormona paratiroidea elevada o normal, se debe realizar el estudio familiar y determinar la calciuria. La aparición de algún miembro afecto en la familia o la aparición de hipocalciuria es suficiente para sospechar esta entidad e indicar el análisis mutacional, para establecer el diagnóstico diferencial con el hiperparatiroidismo primario y evitar tratamientos innecesarios. Abstract: Familial hypocalciuric hypercalcemia (FHH) is a cause of hypercalcemia with autosomal dominant pattern of inheritance and high penetrance. In most of the cases it can be shown to be due to an inactivating mutation on the gene coding for the calcium-sensing receptor (CaSR). Heterozygous cases usually do not present symptoms and they are diagnosed as an incidental finding.We report three affected children with an inactivating heterozygous mutation, p.Phe789del, in exon 7 of the calcium-sensing receptor gene (CASR gene), situated in chromosome 3q21 (Ensembl ENSG00000036828), which results in elevated serum calcium, normal o high level of parathyroid hormone (PTH) and reduced urinary excretion with hypocalciuria.It is very important to determine the difference between FHH and primary hyperparathyroidism. Therefore, in a mild to moderate PTH-dependent hypercalcemia we must perform a family study and determine the urinary excretion of calcium. The presence of any other affected family member or reduced urinary calcium excretion is enough to suspect FHH, and this should be confirmed by the mutational analysis of the CASR gene, in order to establish the correct diagnosis, differentiated from primary hyperparathyroidism, to avoid unnecessary investigations or operations.

An underrecognized side effect of long-term lithium carbonate therapy is hyperparathyroidism with associated hypercalcemia and hypocalciuria. Because cessation of lithium carbonate therapy usually does not correct the hyperparathyroidism and associated hypercalcemia, parathyroidectomy frequently is necessary. This is the initial report of 2 patients with lithium carbonate-induced hyperparathyroidism treated with cinacalcet hydrochloride (HCl), which normalized serum calcium levels and reduced intact parathyroid hormone (iPTH) secretion. The patients, both with bipolar disease and a 15- to 30-year history of lithium carbonate therapy, were evaluated for stage 3 chronic kidney disease, persistent hypercalcemia, and hyperparathyroidism. A 67-year-old woman was administered cinacalcet HCl, 30 mg/d, for 11 months. Mean serum calcium level decreased from 10.8 +/- 0.4 mg/dL (2.69 +/- 0.10 mmol/L) to 9.9 +/- 0.4 mg/dL (2.47 +/- 0.10 mmol/L; P0.001), and iPTH level decreased from 139 +/- 31 pg/mL (139 +/- 31 ng/L) to 114 +/- 39 pg/mL (114 +/- 39 ng/L; P = not significant). A 63-year-old man was administered 30 mg/d of cinacalcet HCl for 8 months, then 60 mg/d for another 2 months. Mean serum calcium and iPTH levels decreased from 11.0 +/- 0.5 mg/dL (2.74 +/- 0.12 mmol/L) to 10.3 +/- 0.4 mg/dL (2.57 +/- 0.10 mmol/L; P0.001) and 138 +/- 10 pg/mL (138 +/- 10 ng/L) to 73 +/- 7 pg/mL (73 +/- 7 ng/L; P = 0.03), respectively. Urinary fractional excretion of calcium was low for both patients before (0.026 and0.015) and after (0.026 and 0.008) treatment with cinacalcet HCl. These findings suggest that cinacalcet HCl can provide an alternative nonsurgical means to control this disorder in patients with hypercalcemia of variable severity for whom surgical treatment is not a consideration because of perceived mildness of disease or unsuitability of the patient for surgical intervention.

Hypercalcemia is frequently encountered in healthy outpatients. Reliable measurements of the mediators of hypercalcemia have improved diagnostic certainty about the etiology in most patients. Hyperparathyroidism is overwhelmingly the most common cause. Medical evaluation of the patient with hyperparathyroidism requires an understanding of the complications of the disorder and the associated syndromes. At present decreased bone mineral density and nephrolithiasis are the major sequelae of hyperparathyroidism. Most cases of primary hyperparathyroidism are sporadic; however, hereditary forms can occur in patients with the multiple endocrine neoplasia syndromes. Surgery is the only curative therapy. Results are excellent when an experienced endocrine surgeon performs parathyroid surgery.

Serum calcium is under tight physiological control, but it is also a quantitative trait with substantial genetic regulation. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia or autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, ligand binding to the receptor protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor. We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15.4%. Mean total serum calcium (Ca(T)) was significantly higher in the SS (9.88 +/- 0.29 mg/dL, P = 0.015) and AS groups (9.45 +/- 0.05 mg/dL, P = 0.002), than in the AA group (9.23 +/- 0.04 mg/dL). In multiple regression modeling, the A986S genotype remained an independently significant predictor of Ca(T) (P < 0.0001) when serum albumin, globulin, inorganic phosphate, and creatinine covariates were included. These data are the first to show significant association between a common polymorphism and concentrations of a serum electrolyte. The A986S polymorphism is also a potential predisposing factor in disorders of bone and mineral metabolism.

A 44-year-old female with familial hypocalciuric hypercalcemia (FHH) due to a homozygous missense mutation (Pro40Ala) in calcium sensing receptor (CaSR) gene has type 2 diabetes mellitus. The identical heterozygous mutation of CaSR gene was observed in consanguineous parents and all other family members examined except her two sisters. Many subjects with abnormal glucose tolerance were observed in this family, which is compatible with maternal inheritance. Mitochondrial function of complex I (NADH-coenzyme Q reductase) activity in cybrid cells between mitochondrial DNA (mtDNA)-deleted (rho(0)) HeLa cells and mtDNA from the proband was decreased by 35%. The proband has eight substitutions and among these 4833 A/G is a missense substitution in NADH dehydrogenase 2 gene and may probably be a major pathogenic mutation of impaired complex I activity. These results suggest that coexistence of nuclear gene and mtDNA mutations may have caused or modified the development of abnormal glucose tolerance in this family.

Cloning of the CaR has increased understanding of the normal control of mineral ion homeostasis and has clarified the pathophysiology of PTH-dependent hypercalcemia. Cloning of the CaR has enabled identification of FHH and NSHPT as inherited conditions with generalized resistance to Ca2+o, which is caused in many cases by inactivating mutations in the CaR gene. In most kindreds with FHH, there is resetting of Ca2+o to a mildly elevated level that does not require an increase in the circulating level of PTH above the normal range to maintain it. FHH is not accompanied by the usual symptoms, signs, and complications of hypercalcemia. The kidney participates in the genesis of the hypercalcemia in FHH by avidly reabsorbing Ca2+; consequently, there is no increased risk of forming urinary calculi in most cases. Generally, there is no compelling rationale for attempting to lower the level of Ca2+o in these patients to a nominal normal level. In contrast, in primary hyperparathyroidism, the Ca2+o resistance is limited to the pathologic parathyroid glands, and the rest of the body suffers the consequences of high circulating levels of calcium, PTH, or both. In this condition, removal of the offending parathyroid glands is often the treatment of choice. Parathyroidectomy may also be appropriate in disorders with generalized resistance to Ca2+o owing to inactivating CaR mutations in the following special circumstances: in selected families with FHH in which there is unusually severe hypercalcemia, frankly elevated PTH levels, or atypical features such as hypercalciuria; in cases of NSHPT with severe hypercalcemia and hyperparathyroidism; and in the occasional mild case of homozygous FHH owing to CaR mutations that confer mild-to-moderate resistance to Ca2+o that escapes clinical detection in the neonatal period. As discussed elsewhere in this issue, selective calcimimetic CaR activators are being tested in clinical trials, which potentiate the activation of the CaR by Ca2+o, thereby resetting the elevated set point for Ca2+o-regulated PTH release in primary and secondary hyperparathyroidism toward normal. It is hoped that these agents may become an effective medical therapy for the acquired Ca2+o resistance in primary and secondary hyperparathyroidism and perhaps for that present in the unusual cases of FHH and NSHPT, resetting the "calciostat" downward and thereby reducing Ca2+o and PTH toward normal.

The serum calcium level should be measured in all patients with stones. Although the vast majority has a normal value, those who have elevated serum calcium levels must be identified not only to prevent further urolithiasis but also because of the implications for other organ systems. In a patient with kidney stones, an elevated serum calcium level usually means hyperparathyroidism or, much less frequently, sarcoidosis. The milk-alkali syndrome as a cause of hypercalcemia and urinary calculi is unusual since the advent of H2 acid-blocking drugs, although one recent report 7 suggested that increased use of calcium carbonate supplements may be generating a new form of this syndrome. If kidney stones and serum calcium abnormalities occur in an unexpected situation, such as in an anorectic 15-year-old girl, overuse of the fat-soluble vitamins should be suspected. Hypercalcemia associated with malignancy does not result in stone formation ordinarily. These patients probably do not live long enough to form stones, and the renal damage that occurs reduces the excretion of other lithogenic substances. Familial hypocalciuric hypercalcemia (discussed further subsequently) also is not usually characterized by urolithiasis.

Calcium-sensing receptor and calcimimetic agents. Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependant fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

In vivo dynamic tests of parathyroid gland function have provided useful information about the secretory behavior of parathyroids in various clinical disorders, but the limitations of this approach must be recognized when applied to studies of parathyroid gland physiology. Set point abnormalities have been documented in vivo both in primary hyperparathyroidism and in familial hypocalciuric hypercalcemia. Such findings are consistent with in vitro results obtained in studies of dispersed parathyroid cells from patients with primary hyperparathyroidism and with recently described alteration in calcium receptor expression in patients with FHH. The assessment of parathyroid gland function in patients with end-stage renal disease presents distinct methodological problems, however, because of marked variation in the degree of parathyroid gland enlargement. Neither the four parameter model originally used to describe set point abnormalities both in vitro and in vivo or alternative approaches to the assessment of PTH secretion in vivo adequately address this important issue. Results from recent in vivo studies of patients with chronic renal failure do not support the view that the set point for calcium-regulated PTH release is abnormal in secondary hyperparathyroidism or that treatment with calcitriol lowers the set point for calcium-regulated PTH release in patients with uremic secondary hyperparathyroidism. The concept of set point disturbances has strongly influenced discussions about the pathogenesis of secondary hyperparathyroidism, and it has served as a focal point for examining the therapeutic response to calcitriol in patients with this disorder. This matter requires careful reconsideration, however, in light of recent clinical findings and the development of techniques to directly assess the molecular mechanisms responsible for regulating calcium-mediated PTH release in renal failure and other disorders of mineral metabolism. Although knowledge in this area remains limited, the extent of parathyroid hyperplasia and the role of factors that influence the development of parathyroid gland enlargement may ultimately prove to be particularly important modifiers of parathyroid gland function in chronic renal failure.

The recent cloning of an extracellular calcium (Ca 2+ o )-sensing receptor (CaR) from the parathyroid gland and the kidney has provided novel insights into the mechanisms that underlie the direct actions of (Ca 2+ o ) on various cells. The receptor is a member of the superfamily of G protein-coupled receptors, activating phospholipase C (PLC) and probably also inhibiting adenylate cyclase in target tissues. In the parathyroid gland it is a key mediator of the inhibition by high (Ca 2+ o ) of parathyroid hormone (PTH) secretion and, perhaps, PTH gene expression and parathyroid cellular proliferation. It also appears to represent the major mechanism through which Ca 2+ o stimulates the secretion of calcitonin from the thyroidal C-cells. In the kidney, the CaR directly inhibits tubular reabsorption of calcium and magnesium in the thick ascending limb, and may be responsible for the long-recognized, but poorly understood inhibition of urinary concentrating ability by hypercalcemia. The demonstration that activating and inactivating mutations of the CaR, respectively, are the proximate causes of the inherited hypo- calcemic disorder, autosomal dominant hypocalcemia (ADH) and the hypercalcemic diseases, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), has provided additional strong support for the physiologic importance of the CaR in human mineral ion homeostasis. Therefore, when Ca 2+ o acts through its own G protein-coupled cell surface receptor, it acts as an extracellular first messenger in addition to serving its better recognized role as a key intracellular second messenger.

A cDNA that encodes a putative Ca 2+ -sensing receptor (HuKCaSR) was cloned from human kidney with the use of the polymerase chain reaction. The predicted HuKCaSR protein consists of 1078 amino acids and shares 93.1 and 93.8% overall identity with the bovine parathyroid Ca 2+ -sensing receptor (BoPCaR1) and rat kidney Ca 2+ -sensing receptor (RaKCaR), respectively, with least similarity in the carboxyl-terminal regions. The HuKCaSR gene was mapped by fluorescence in situ hybridization to chromosome 3q21, at which region the gene responsible for familial hypocalciuric hypercalcemia has previously been localized by genetic linkage analysis. RNA blot analysis revealed HuKCaSR mRNA in human kidney, but not in brain, lung, liver, heart, skeletal muscle, or placenta.

The ability of the parathyroid cell to sense minute fluctuations in the extracellular ionized calcium concentration (Ca2+ o) is essential for maintaining mineral ion homeostasis. However, the mechanism(s) through which the parathyroid cell and other cells recognize and respond to changes in Ca2+ o has remained unclear. We recently isolated a cDNA encoding a Ca2+ o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The receptor shows pharmacologic properties that are almost identical to those of the receptor on the parathyroid cell and, like the latter, stimulates phospholipase C in a G-protein-dependent manner. The amino acid sequence of the cloned receptor deduced from this cDNA predicts a protein with a molecular mass of 121 kd, which has three principal structural domains. The first is a 613 amino acid, putatively extracellular amino terminus which has several regions rich in acidic amino acids that may potentially be involved in binding Ca2+ and other polycationic agonists. The second comprises seven membrane-spanning segments that are characteristic of the superfamily of G-protein-coupled receptors, and the third is a 222 amino acid cytoplasmic tail. Transcripts for this Ca2+ o-sensing receptor are present in the parathyroid as well as in the kidney, thyroid, and brain. We next investigated the hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, as possible examples of inherited abnormalities in this Ca2+ o-sensing receptor, since both disorders show abnormal Ca2+ o-sensing and/or handling in the kidney and parathyroid.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Low 24-hour urine calcium (uCa) levels in patients with primary hyperparathyroidism (pHPT) raise concern for familial hypocalciuric hypercalcemia. This study evaluated patients with a low 24-hour uCa level for potential differences that may guide the extent of preoperative evaluation needed. Methods A retrospective review was conducted of 1,139 sporadic pHPT patients who underwent parathyroidectomy between December 1999 and May 2011. Results Of the 54 (5%) patients with greater than or equal to one low 24-hour uCa ( P = .0011) and glomerular filtration rate ( P = .0007). Conclusion This study suggests that sporadic pHPT patients with low 24-hour uCa levels may not require further evaluation with genetic testing for familial hypocalciuric hypercalcemia, especially if previous eucalcemia is documented.

Serum calcium is under tight physiological control, but it is also a quantitative trait with a substantial genetic component. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia and autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, the activity of the protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor (Lancet 1999;353:112). We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15%. Mean total serum calcium (Car) was significantly higher in the SS (9.88 ± 0.29 mg/dL, p=.015) and AS groups (9.45 ± 0.05 mg/dL, p=.002), than in the AA group (9.23 ± 0.04 mg/dL). In multiple regression modelling, the A986S genotype remained an independently significant predictor of Car (p

The authors report a case of familial hypocalciuric hypercalcemia revealed by systematic measurement of calcemia in a patient treated ten years previously for a chest adenocarcinoma. Her mother and her sister had hypocalciuric hypercalcemia.

The relatives of 25 index patients with primary parathyroid hyperplasia were tested for hypercalcemia. At least 13 of these patients had one or more first degree relatives with hypercalcemia. Two familial syndromes each with autosomal dominant transmission were recognized. Two index patients were part of large kindreds categorized as having familial hypocalciuric hypercalcemia (FHH). Manifestations of multiple endocrine neoplasia type I were present in the kindreds of at least four other index patients (FMEN I). In seven other kindreds there were too few affected members to allow definitive classification. Differences between manifestations of FHH and FMEN I were described. Among offspring of affected persons in kindreds with FHH, as distinct from FMEN I, the prevalence of hypercalcemia approached the theoretic maximum of 50 per cent during the first two decades. In FHH, nephrolithiasis and peptic disease were unusual; moderate hypercalcemia occurred without hypercalciuria; and subtotal parathyroidectomy did not abolish hypercalcemia. Concentrations of peptide hormones other than parathyroid hormone (PTH) were normal in those with FHH; in FMEN I high concentrations of glucagon in plasma were found in five of six patients tested, and high concentrations of gastrin were found in three of 12 patients. Hypergastrinemia generally accompanied obvious peptic disease. Distinction of the two conditions is important since patients with FHH may not benefit from subtotal parathyroidectomy, but they generally have a better clinical prognosis than do patients with FMEN I.

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3. Orwoll E, Silbert J, McClung M. Asymptomatic neonatal familial hypercalcemia. Pediatrics 1982;69:109-11. 4. Matsuo M, Okita K, Takemine H, Fujita T. Neonatal primary hyperparathyroidism in familial hypocalciuric hypercalcemia. Am J Dis Child 1982;136:728-31. 5. Marx S J, Attie MF, Spiegel AM, Levine MA, Laska RD, Fox M. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med 1982;306:257-64. 6. Fujita T, Watnabe N, Fukase M, et al. Familial hypocalciuric hypercalcemia involving four members of a kindred including a girl with severe neonatal primary hyperparathyroidism. Miner Electrolyte Metab 1983;9:51-4. 7. Sopwith AM, Burns C, Grant DB, Taylor GH, Wolf E, Besser GM. Familial hypocalciuric hypercalcemia: association with neonatal primary hyperparathyroidism, and possible linkage with HLA haplotype. Clin Endocrinol (Oxf) 1984;21:57-64. 8. Marx S J, Fraser D, Rapoport A. Familial hypocalciuric hypercalcemia: mild expression of the gene in heterozygotes and severe expression in homozygotes. Am J Med 1985;76:1522. 9. Harrison HE, Harrison HC. Familial hyperparathyroidism. In: Lifshitz F, ed. Pediatric endocrinology: a clinical guide. New York: Marcel Dekker, 1985;333-47. 10. Lillquist K, Ilium N, Jacobsen BB, Lockwood K. Primary hyperparathyroidism in infancy associated with familial hypocalciuric hypercalcemia. Acta Paediatr Scand 1983; 72:625-9. 11. Foley TP, Harrison HC, Arnaud C, Harrison HE. Familial benign hypercalcemia. J PEDIATR 1972;81:1060-7. 12. Attie MF, Gill JR Jr, Stock JL, et al. Urinary calcium excretion in familial hypocalciuric hypercalcemia: persistence of relative hypocalciuria after induction of hypoparathyroidism. J Clin Invest 1983;72:667-76.

To determine whether familial benign hypercalcemia, or familial hypocalciuric hypercalcemia (FHH), has adverse effects on the skeleton, we measured bone mineral density (BMD) in 31 affected persons from 14 families (16 women and 15 men), ranging in age from 19 to 68 years. Forearm BMD was measured by single-photon absorptiometry, and spinal BMD was measured by dual-photon absorptiometry. In addition, we systematically queried 82 hypercalcemic and 52 normocalcemic family members about skeletal fractures. Both men and women with FHH had normal BMD (expressed as grams per square centimeter) in the lumbar spine, distal radius, and midradius. Osteoporotic-type fractures (vertebrae, hip, and distal radius) were virtually absent in both affected and unaffected family members. Detailed evaluation of larger numbers of of older affected persons may be necessary to resolve this issue definitively, but we conclude provisionally that FHH has no important adverse effects on skeletal health.

We analyzed, by light microscopy, specimens obtained at parathyroid surgery from 18 members of eight kindreds with familial hypocalciuric hypercalcemia. For comparison, similar analyses were performed with normal parathyroid glands (surgical or postmortem specimens) and with glands from patients with typical primary parathyroid hyperplasia. The average parathyroid parenchymal area in familial hypocalciuric hypercalcemia was 300 per cent of that in normal subjects (0.049 versus 0.15 sq. cm., p less than 0.0005) but significantly less than that in typical primary parathyroid hyperplasia. Thirteen of the 18 subjects with familial hypocalciuric hypercalcemia had one or more enlarged glands. Enlarged parenchymal areas were noted at all ages in familial hypocalciuric hypercalcemia, but there was a spectrum of histologic findings among the glands in each case, within most families, and between families. Mild parathyroid hyperplasia was a feature in most patients with familial hypocalciuric hypercalcemia who had undergone neck surgery. Simple quantitative analyses were useful in identifying parathyroid hyperplasia in the group with familial hypocalciuric hypercalcemia.

Renal calcium handling in familial hypocalciuric hypercalcemia. We have determined calcium and sodium excretion rates in three members of a kinship with familial hypocalciuric hypercalcemia (FHH) and in four patients with primary hyperparathyroidism (PHP) under control conditions and following the intravenous administration of chlorotluazide or furosemide. The characteristic hypocalciuria of FHH, evidenced by a significantly reduced urinary calcium/creatinine ratio compared with that of PHP, is present under control conditions (0.08 vs. 0.26mg calcium/mg creatinine, respectively, P < 0.05), and after chlorothiazide (0.14 vs. 0.53, respectively, P < 0.01). However, after furosemide infusion the calcium/creatinine ratio is no longer lower in FHH than in PHP (1.12 vs. 1.14, respectively, P > 0.05). These data suggest that, in FHH, tubular calcium reabsorption is enhanced in the thick ascending limb of Henle's loop, the site of action of furosemide. However, the data do not exclude the presence of an abnormality at a more distal site in the nephron.Elimination rénale du calcium dans l'hypercalcémie hypocalciurique familiale. Nous avons déterminé les débits d'excrétion de calcium et de sodium chez trois membres d'une famille avec une hypercalcémie hypocalciurique familiale (FHH) et chez quatre malades avec un hyperparathyroïdisme primitif (PHP) dans des conditions contrôle et après l'administration intra-veineuse de chlorothiazide de furosémide. L'hypocalciurie caractéristique de la FHH, mise en évidence par une diminution significative du rapport calcium/créatinine urinaire par rapport à celui de PHP, est présente pendant les conditions contrôles (0.08 contre 0.26mg calcium/mg créatinine, respectivement, P < 0.05), et après chlorothiazide (0.14 contre 0.53, respectivement, P < 0.01). Cependant, après perfusion de furosémide, le rapport calcium/créatinine ne demeure pas plus faible dans la FHH par rapport à PHP (1.12 contre 1.14, respectivement, P > 0.05). Ces données suggèrent que, dans la FHH, la réabsorption tubulaire du calcium est augmentée dans la branche ascendante large de l'anse de Henlé, le site d'action du furosémide. Cependant ces données ne permettent pas d'exclure la présence d'une anomalie située à un site plus distal du néphron.

The histologic characteristics of the parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia) are disputed, some finding parathyroid hyperplasia and others finding no abnormalities. To further investigate this issue, the histologic appearance of 82 parathyroid glands from 47 control patients (surgical and autopsy) were compared with those of 28 glands from 23 patients with familial hypocalciuric hypercalcemia who had undergone surgery for suspected primary hyperparathyroidism. Median and mean weights of 23 parathyroid glands from 12 patients with familial hypocalciuric hypercalcemia were 50 mg and 60 mg, respectively, with a range from 5 to 181 mg. Eighty-three percent of individual glands were within extreme normal limits for weight (less than 75 mg). Percent parenchymal area in familial hypocalciuric hypercalcemia was slightly but significantly less than control values (62 +/- 2 versus 71 +/- 2 percent, respectively; (p = 0.009). Conversely, percent fat was higher in familial hypocalciuric hypercalcemia than control values (30 +/- 3 versus 21 +/- 2 percent, respectively; p = 0.015). Stromal area was 8 +/- 1 percent in each group. Although 15 to 20 percent of parathyroid glands in familial hypocalciuric hypercalcemia exceeded normal size, most were indistinguishable from normal by size, weight, and microscopic appearance. The significantly reduced percent parenchyma in glands from patients with familial hypocalciuric hypercalcemia further suggests that the condition is not uniformly accompanied by typical parathyroid hyperplasia and should not be thought of as merely a variant of the latter.