Calcium-Sensing Receptor (CASR) Mutations in Hypercalcemic States: Studies from a Single Endocrine Clinic Over Three Years

Guarnieri, Vito; Canaff, Lucie; Yun, Francisco; Scillitani, Alfredo; Battista, Claudia; Muscarella, Lucia Anna; Wong, Betty; Notarangelo, Angelo; D’Agruma, Leonardo; Sacco, Michele; Cole, David E. C.; Hendy, Geoffrey N.

doi:10.1210/jc.2008-2430

Cited by 74 publications

(64 citation statements)

References 39 publications

(36 reference statements)

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“…6,16 However, in follow-up studies, approximately one-third of patients with confirmed PHPT had a clearance ratio in the range of 0.01-0.02. 4,5,14,17,18 The Ca/Cr clearance ratio is also used as a marker of hypercalciuria, where hypercalciuria cannot be excluded if the urinary creatinine concentration exceeds 40 mg/100 mL. 19,20 In the evaluation of PHPT, it is recommended that FHH be ruled out, even though this condition is very rare.…”

Section: Discussionmentioning

confidence: 99%

“…However, this should be reserved for cases in which treatment would be significantly altered based on the diagnosis. 5,7,14,15,19 Hypercalcemia increases eGFR; however, tubular resorption of calcium is altered by many other factors such as age, medications, and hormones. While the volume of urine collected can affect the urinary creatinine and calcium levels and could be affected by diuretic use, we did not specifically analyze these factors.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with FHH typically present with hypercalcemia, normal to mildly elevated PTH, and hypocalciuria. [4][5][6] If there is a strong suspicion for FHH, the presence of the mutation in the CaSR gene can be detected using readily available polymerase chain reaction techniques. FHH is an asymptomatic, benign disease; thus, it is important to make the distinction from PHPT, since parathyroidectomy is not indicated in this condition.…”

Section: 3mentioning

confidence: 99%

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24-Hour Urinary Calcium in Primary Hyperparathyroidism

Black

Berg

Urquhart

2013

Clinical Medicine & Research

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Objective: To establish whether urinary and serum calcium levels are correlated in patients with primary hyperparathyroidism (PHPT) and to evaluate related factors including serum levels of parathyroid hormone (PTH) and vitamin D, age, gender and renal function. Design:Retrospective review on patients undergoing a parathyroidectomy for PHPT from 2000-2008. Data collected included: age, sex, preoperative serum calcium (ionized and total), creatinine, PTH, postoperative ionized calcium, vitamin D, and 24-hour urine calcium and creatinine. Data were evaluated by standard descriptive statistics. Results:Of the 214 patients evaluated, preoperative 24-hour urinary calcium was available for 150 patients (70%). 24-hour urine calcium levels did not correlate significantly with preoperative total serum or ionized calcium, PTH, vitamin D, or postoperative serum ionized calcium. There were significant correlations (P < 0.0001) of 24-hour urinary calcium with age, serum creatinine, and urine creatinine. Secondary analysis grouped subjects by urinary calcium level greater or less than 400 mg/24 hours. Age and urinary creatinine were significantly different between the two groups. Conclusions:In patients with PHPT who underwent parathyroidectomy, there was little correlation between preoperative 24-hour urine calcium and preoperative serum calcium, PTH, or vitamin D levels. 24-hour urine calcium levels were correlated with renal function and age, but these correlations are likely to occur in the general population and are not specific to this disease group. The normal physiology of calcium metabolism is complex and depends on many factors such as renal function, diet, and age. When this normal metabolism is disrupted, it can acutely lead to hypercalcemia, which causes an increase in urinary calcium excretion through mediation of the calcium sensing receptor (CaSR) in the kidney. Hypercalciuria has been used as a diagnostic marker and indicator for parathyroidectomy in patients with primary hyperparathyroidism (PHPT). Urinary calcium excretion as a function of serum calcium was demonstrated more than 50 years ago.1 However, it is not clear if 24-hour urine calcium levels correlate with preoperative total serum or ionized calcium, parathyroid hormone (PTH), and vitamin D in patients with primary hyperparathyroidism.The 24-hour urinary sample, in addition to serologic studies, has historically been part of the standard diagnostic evaluation for patients suspected of PHPT. The use of 24-hour urine studies in PHPT has served two primary functions: elevated urinary calcium was thought to be a risk factor for

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: 3mentioning

confidence: 99%

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24-Hour Urinary Calcium in Primary Hyperparathyroidism

Black

Berg

Urquhart

2013

Clinical Medicine & Research

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“…The majority of patients with FHH are asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroid glands [11,12]. However, some individuals with FHH develop symptomatic HPT [13,14]. Inactivating mutations of the CASR may lead to atypical phenotypic features including hypercalcemia, inappropriately high serum PTH and magnesium levels, and relative hypercalciuria, with nephrolithiasis in a subset of patients which resembles PHPT [10,15].…”

Section: Introductionmentioning

confidence: 99%

Frequent Germ-Line Mutations of the MEN1, CASR, and HRPT2/CDC73 Genes in Young Patients with Clinically Non-familial Primary Hyperparathyroidism

et al. 2011

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Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

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“…CASR testing, with functional analysis, provides valuable evidence in the differential diagnosis of hypercalcaemic states, as recently published (20). New technologies such as denaturing HPLC provide a rapid and effective tool to screen for CASR mutations (21).…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

Al‐Salameh

Cetani²,

Pardi³

et al. 2011

European Journal of Endocrinology

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Objective: The calcium-sensing receptor (CASR) has an important role in calcium homoeostasis by controlling PTH secretion and renal calcium handling. Inactivating mutations in the CASR gene (HGNC ID: 1514) cause familial hypocalciuric hypercalcaemia (FHH). We present a case of FHH patient to describe a novel mutation in the CASR. Subjects and methods: A 34-year-old patient was referred because of recurrent hypercalcaemia after resection of two hyperplastic parathyroids. Extensive evaluation found elevated PTH and low calcium/creatinine clearance ratio. One of her three children had high serum calcium concentrations. Genetic studies were performed by PCR amplification of CASR coding exons and direct sequencing of PCR products. Transient transfection of the wild-type (WT) CASR and the mutant CASR into COS-7 was performed to assess functional impact of the mutation and the capacity of either protein to mediate increases in cellular levels of inositol phosphates (IPs). Results: CASR sequencing found a previously undescribed heterozygous base substitution, determining a change of threonine to isoleucine at codon 550 (p.T550I) in the sixth exon. In contrast to those transfected with WT CASR, which showed a five-to eightfold increase in total IPs at high levels of calcium, COS-7 cells transfected with the (p.T550I) mutant showed no increase confirming to the inactivating nature of the mutation. COS-7 cells co-transfected with the WT and the (p.T550I) mutant showed an intermediate response suggesting a possible dominant negative effect. Conclusion: This case report presents a not-yet-described mutation in the cysteine-rich region of the CASR extracellular domain, a mutation with a possible dominant negative effect.

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Calcium-Sensing Receptor (CASR) Mutations in Hypercalcemic States: Studies from a Single Endocrine Clinic Over Three Years

Abstract: CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states.

Cited by 74 publications

References 39 publications

24-Hour Urinary Calcium in Primary Hyperparathyroidism

24-Hour Urinary Calcium in Primary Hyperparathyroidism

Frequent Germ-Line Mutations of the MEN1, CASR, and HRPT2/CDC73 Genes in Young Patients with Clinically Non-familial Primary Hyperparathyroidism

A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

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