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IntroductionFamilial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder caused by an inactivating mutation in the CASR gene, while Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder resulting from a pathogenic mutation in the SLC12A3 gene. Both genetic disorders are relatively rare. This report presents a patient with both FHH and GS, exhibiting unique clinical and genetic complexities.Case summaryWe report a case of a 69-year-old Asian female patient who had previously presented to the hospital on multiple occasions with complaints of joint stiffness, fatigue, dizziness, or other symptoms. The patient was readmitted to the hospital at the age of 66, presenting with the following clinical findings: hypocalciuria, hypercalcemia, normal or mildly elevated parathyroid hormone (PTH) levels, hypokalemia, hypomagnesemia, hypophosphatemia, normal blood pressure, chondrocalcinosis (CC), and diabetes mellitus. Our careful analysis suggested that the patient might have the co-occurrence of GS and FHH. Genetic testing revealed a novel heterozygous CASR p.Tyr161* mutation and a homozygous SLC12A3 p.Thr60Met mutation, which ultimately confirmed the diagnosis of familial hypocalciuric hypercalcemia type 1 (FHH1) combined with GS.ConclusionFor the first time, we report a case of FHH combined with GS. The novel CASR mutation in this patient expands the variant spectrum of FHH, provides new genetic evidence for its pathogenesis, and underscores the importance of genetic counseling for consanguineous families. This case also suggests a potential association between FHH and CC, the mechanism of which warrants further investigation. In addition, this report highlights possible potential interactions between FHH and GS. Clinically, hypokalemia and hypomagnesemia associated with GS are more detrimental than hypercalcemia linked to FHH and should be prioritized in management. Finally, genetic testing and molecular diagnostics are crucial for pediatric and adolescent populations with FHH and/or GS, and further studies are needed to clarify the genotypic and phenotypic relationships between FHH and GS comorbidities.

Primary hyperparathyroidism is the main cause of hypercalcemia while familial hypocalciuric hypercalcemia is a rare one. We report a case of a 39-year-old woman followed at our rheumatology outpatient center with the diagnosis of ankylosing spondylitis in which the routine laboratorial analysis demonstrated hypercalcemia with high levels of parathyroid hormone. The ultrasound, scintigraphy, and histology findings confirmed the diagnosis of primary hyperparathyroidism and parathyroid hyperplasia as the underlying cause. After surgery, given the persistence of hypercalcemia in association with a low urinary calcium excretion, a genetic study was carried out which led to the diagnosis of familial hypocalciuric hypercalcemia type 1. The patient had no symptoms or familiar history of hypercalcemia. The authors highlight the rarity of the association of these two conditions in the same patient and the importance of considering familial hypocalciuric hypercalcemia as a possible diagnosis even in patients with an established diagnosis of primary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Familial hypocalciuric hypercalcemia (FHH) is marked by mild to moderate hypercalcemia, normal-elevated serum PTH levels, and relative hypocalciuria. Cinacalcet, a calcimimetic therapy, has been reported to reduce symptom burden and serum calcium levels in FHH. We report 2 adult males with chronic hypercalcemia, with initial concerns for primary hyperparathyroidism. Urine calcium screening and genetic testing confirmed FHH in both patients. Shortened QTc normalized while on cinacalcet in the first patient and reductions in serum calcium and PTH levels without symptomatic hypercalcemia were noted in the second patient. Calcimimetic therapy can potentially be offered to FHH patients, particularly those with hypercalcemia symptoms, serum calcium levels >1 mg/dL (0.25 mmol/L) above normal or at risk of cardiac arrhythmias. Cinacalcet treatment was overall well tolerated and significantly reduced serum calcium and PTH levels in 2 adult FHH patients over time. Calcimimetic therapy has shown promise in managing persistent hypercalcemia and potential adverse events in FHH patients. Potential barriers include indefinite treatment, cost, and possible adverse effects. [ABSTRACT FROM AUTHOR]

Context: Although a monoallelic mutation in the calcium-sensing receptor (CASR) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited. Objective: A 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+,) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and characterized the functional and pathophysiological mechanisms, and then linked the mutation to calcimimetics treatment in vitro. Design: Sanger sequencing of the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation model was used to predict the function of the identified mutant. In vitro studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte 520 Ca2+, detection, and half-maximal effective concentration (EC50), were examined. Results: This proband was found to carry a de novo heterozygous missense I554N in the cysteine-rich domain of CASR, which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that CASR I554N mutation decreased its binding energy with Ca2+,. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+, response to gradient extracellular Ca2+,(eCa2+,) concentration. The EC50 study also demonstrated the correctable effect of calcimimetics on the function of the CASR I554N mutation. Conclusion: This novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+, corrected by therapeutic calcimimetics. [ABSTRACT FROM AUTHOR]

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variantassociated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The occurrence of prolactinomas in sex hormone treated patients with central hypogonadism is extremely rare. Case presentation: We present a Caucasian male patient who was diagnosed with Kallmann syndrome (KS) at age 15 years. Testosterone treatment was started. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence of marked hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in a complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Genetic testing of genes associated with pituitary tumors, Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium receptor (CASR) gene which yielded a pathogenic inactivating variant. Discussion/conclusion: The presence of two separate prolactinomas in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The occurance of multiple prolactinomas in our patient suggests increased susceptibility. Although CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population, the relevance of the CASR gene variant in our patient for the KS phenotype is unclear at present. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. Methods: A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test. Results: Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. Conclusion: The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features. [ABSTRACT FROM AUTHOR]

ContextA germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ).ObjectiveTo evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management.MethodPatients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database.ResultsA total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%.ConclusionIn contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Background. Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia in childhood. Heterozygous Calcium-sensing receptor (CASR) gene mutations cause FHH, and homozygous CASR gene mutations cause neonatal severe primary hyperparathyroidism (NSHPT). Cinacalcet is an allosteric modulator of Calciumsensing receptor (CaSR), and has been used in the treatment of these clinical entities in recent years. Case. A 26-month-old boy was examined for a recurrent rash. During the evaluation, hypercalcemia (13.3 mg/dL), hypophosphatemia (2.3 mg/dL) and inappropriately normal PTH level (67 pg/mL) were observed. Neck and renal ultrasonography were normal. The parathyroid scintigraphy was unremarkable. The patient's family members were also evaluated, and hypocalciuria (fractional excretion of calcium were 0.01%, 0.04% on two separate tests) was detected concurrently with the patient's hypercalcemia. The mother's serum calcium was 10.2 mg/dL, the father's was 10.6 mg/dL, and the brother's was 12.8 mg/dL. CASR gene sequencing showed a novel homozygous mutation in exon 4 (c.1057G>A), which had generated a substitution of the amino acid glutamate to lysine at codon 353 (p.Glu353Lys). This mutation was homozygous in the children and heterozygous in the parents. Fluid hydration, furosemide, oral phosphorus, prednisolone, pamidronate and cinacalcet treatments were used in the management of hypercalcemia of the proband. A longer and more effective control was achieved with cinacalcet treatment. Conclusions. FHH can be seen in heterozygous as well as homozygous CASR gene mutations. Different clinical findings may occur in different individuals from the same family. Cinacalcet therapy can be used successfully in the treatment of individuals with FHH. [ABSTRACT FROM AUTHOR]

Background. Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia in childhood. Heterozygous Calcium-sensing receptor (CASR) gene mutations cause FHH, and homozygous CASR gene mutations cause neonatal severe primary hyperparathyroidism (NSHPT). Cinacalcet is an allosteric modulator of Calciumsensing receptor (CaSR), and has been used in the treatment of these clinical entities in recent years. Case. A 26-month-old boy was examined for a recurrent rash. During the evaluation, hypercalcemia (13.3 mg/ dL), hypophosphatemia (2.3 mg/dL) and inappropriately normal PTH level (67 pg/mL) were observed. Neck and renal ultrasonography were normal. The parathyroid scintigraphy was unremarkable. The patient`s family members were also evaluated, and hypocalciuria (fractional excretion of calcium were 0.01%, 0.04% on two separate tests) was detected concurrently with the patient`s hypercalcemia. The mother`s serum calcium was 10.2 mg/dL, the father`s was 10.6 mg/dL, and the brother`s was 12.8 mg/dL. CASR gene sequencing showed a novel homozygous mutation in exon 4 (c.1057G > A), which had generated a substitution of the amino acid glutamate to lysine at codon 353 (p.Glu353Lys). This mutation was homozygous in the children and heterozygous in the parents. Fluid hydration, furosemide, oral phosphorus, prednisolone, pamidronate and cinacalcet treatments were used in the management of hypercalcemia of the proband. A longer and more effective control was achieved with cinacalcet treatment. Conclusions. FHH can be seen in heterozygous as well as homozygous CASR gene mutations. Different clinical findings may occur in different individuals from the same family. Cinacalcet therapy can be used successfully in the treatment of individuals with FHH.

IntroductionThe occurrence of prolactinomas in sex hormone treated patients with central hypogonadism is extremely rare.Case presentationWe present a Caucasian male patient who was diagnosed with Kallmann syndrome (KS) at age 15 years. Testosterone treatment was started. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence of marked hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in a complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Genetic testing of genes associated with pituitary tumors, Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium receptor (CASR) gene which yielded a pathogenic inactivating variant.Discussion/conclusionThe presence of two separate prolactinomas in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The occurance of multiple prolactinomas in our patient suggests increased susceptibility. Although CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population, the relevance of the CASR gene variant in our patient for the KS phenotype is unclear at present.

Between 2% and 10% of patients with primary hyperparathyroidism (pHPT) are diagnosed with hereditary forms of primary hyperparathyroidism (hpHPT). They are more prevalent in younger patients before the age of 40 years, in patients with persistence or recurrence of pHPT and pHPT patients with multi-glandular disease (MGD). The various forms of hpHPT diseases can be classified into four syndromes, i.e., hpHPT associated with diseases of other organ systems, and four diseases that are confined to the parathyroid glands. Approximately 40% of patients with hpHPT suffer from multiple endocrine neoplasia type 1 (MEN-1) or show germline mutations of the MEN‑1 gene. Currently, germline mutations that lead to a specific diagnosis in patients with hpHPT have currently been described in 13 different genes, which enables a clear diagnosis of the disease; however, a clear genotype-phenotype correlation does not exist, even though the complete loss of a coded protein (e.g. due to frame-shift mutations in the calcium sensing receptor, CASR) often leads to more severe clinical consequences than merely a reduced function of the protein (e.g. due to point mutation). As the various hpHPT diseases require different treatment approaches, which do not correspond to that of sporadic pHPT, a clear definition of the specific form of hpHPT must always be strived for. Therefore, before surgery of a pHPT with clinical, imaging or biochemical suspicion of hpHPT, genetic proof or exclusion of hpHPT is necessary. The differentiated treatment approach for hpHTP can only be defined by taking the clinical and diagnostic results of all the abovenamed findings into account. [ABSTRACT FROM AUTHOR]

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gainof- function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calciumsensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. [ABSTRACT FROM AUTHOR]

Taking care of patients with parathyroid disorders during pregnancy requires consideration of the physiological fundamental changes in bone and mineral metabolism occurring in these women. Diagnostic and therapeutic procedures regarding primary hyperparathyroidism (PHPT) and hypoparathyroidism significantly differ from the nonpregnant population. PHPT should preferably be cured by parathyroidectomy before pregnancy since in women with hypercalcemic PHPT, maternal and fetal pregnancy complications seem to increase according to the degree of hypercalcemia. Parathyroidectomy, if needed during pregnancy, is preferentially performed in the second trimester. Conservative treatment is recommended for milder cases and is mainly restricted to hydration, with only limited evidence regarding drug treatment. Women with hypoparathyroidism can be informed that there are no major concerns regarding disease-associated infertility and that the risk of pregnancy complications is low if the disease is properly managed. Regular active surveillance is recommended, as requirements for calcium and active vitamin D may change during the course of pregnancy in either direction, with an overall trend for rather reduced doses. Any woman suffering from parathyroid disorders during pregnancy requires further surveillance in the postpartum period and during lactation, as there is an increased risk of hypercalcemia after delivery. Newborns of mothers with parathyroid diseases should, depending on disease severity, be carefully monitored for calcium levels in the first days (to weeks) after delivery since intrauterine exposure to hyper- or hypocalcemia may impact their postnatal regulation of calcium metabolism. [ABSTRACT FROM AUTHOR]

Abstract Background Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. Case presentation A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). Conclusion We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

Familial hypocalciuric hypercalcemia (FHH) is a benign disease associated with heterozygous inactivating mutations in the calcium-sensing receptor (CaSR) gene. This article presents a girl with heterozygous p.Cys575Tyr variation in the CaSR gene. The serum calcium level of a 9.2-year-old girl was 12.4mg/dl in incidental laboratory analysis. On the same occasion, the serum parathyroid hormone (PTH) level was 45 pg/ml, 25(OH) vitamin D level 24.2ng/ml, 1.25 dihydroxy vitamin D level 22pg/ml, and urinary Ca/creatinine ratio A) variation was detected in the patient's CaSR gene, which was reported before, but no clinical manifestations were specified. In children with asymptomatic hypercalcemia, the diagnosis of FHH should be considered if the PTH level is normal or high and the urinary calcium is low. [Med-Science 2022; 11(4.000): 1731-3]

Loss-of-function calcium-sensing receptor (CASR) mutations cause mineral metabolism disorders, familial hypocalciuric hypercalcemia, or neonatal severe hyperparathyroidism and increase the risk of femoral fracture, chronic kidney disease, coronary heart disease, and other diseases. In severe cases, CaSR mutations are lethal. Off-label use of the CaSRpositive allosteric modulator (PAM), cinacalcet, corrects hypercalcemia in some patients with CaSR mutations. However, other patients remain unresponsive to cinacalcet, attesting to the need for novel treatments. Here, we compared t he effects of cinacalcet to two other clinically approved synthetic CaSR activators, evocalcet and etelcalcetide, as well as a novel PAM, 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (MIPS-VD-836-108) on clinically relevant CaSR mutations. We assessed the compounds in CaSR-expressing HEK293 cells for correction of mutation-induced impairments in intracellular calcium (Ca2+i) mobilization and cell surface expression. While cinacalcet, MIPS-VD-836-108 and evocalcet rescued the signaling of cell surface-expressed mutants, albeit to varying degrees, etelcalcetide was ineffective. Cinacalcet and evocalcet, but not MIPS-VD-836-108 or etelcalcetide, restored the expression of a R680H mutant. However, no compound rescued expression of I81K and C582R mutants or a r eceptor missing 77 amino acids in the extracellular domain mimicking deletion of CASR exon 5, which impairs CaSR function. These data suggest specific compounds may be clinically effective in some patients with CaSR mutations, but other patients will r emain refractory to treatment with currently available CaSR-targeting activators, highlighting the need for new generation drugs to rescue both the signaling and expression of mutant CaSRs. [ABSTRACT FROM AUTHOR]

Background: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. Case presentation: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). Conclusion: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH. [ABSTRACT FROM AUTHOR]

Context In the clinic it is important to differentiate primary hyperparathyroidism (PHPT) from the more benign, inherited disorder, familial hypocalciuric hypercalcemia (FHH). Since the conditions may sometimes overlap biochemically, identification of calcium-sensing receptor (CASR) gene variants causative of FHH (but not PHPT) is the most decisive diagnostic aid. When novel variants are identified, bioinformatics and functional assessment are required to establish pathogenicity. Objective We identified 3 novel CASR transmembrane domain missense variants, Thr699Asn, Arg701Gly, and Thr808Pro, in 3 probands provisionally diagnosed with FHH and examined the variants using bioinformatics and functional analysis. Methods Bioinformatics assessment utilized wANNOVAR software. For functional characterization, each variant was cloned into a mammalian expression vector; wild-type and variant receptors were transfected into HEK293 cells, and their expression and cellular localization were assessed by Western blotting and confocal immunofluorescence, respectively. Receptor activation in HEK293 cells was determined using an IP-One ELISA assay following stimulation with Ca++ ions. Results Bioinformatics analysis of the variants was unable to definitively assign pathogenicity. Compared with wild-type receptor, all variants demonstrated impaired expression of mature receptor reaching the cell surface and diminished activation at physiologically relevant Ca++ concentrations. Conclusion Three CASR missense variants identified in probands provisionally diagnosed with FHH result in receptor inactivation and are therefore likely causative of FHH. Inactivation may be due to inadequate processing/trafficking of mature receptor and/or conformational changes induced by the variants affecting receptor signaling. This study demonstrates the value of functional studies in assessing genetic variants identified in hypercalcemic patients. [ABSTRACT FROM AUTHOR]

Familial hypocalciuric hypercalcemia (FHH) is a benign disease associated with heterozygous inactivating mutations in the calcium-sensing receptor (CaSR) gene. This article presents a girl with heterozygous p.Cys575Tyr variation in the CaSR gene. The serum calcium level of a 9.2-year-old girl was 12.4mg/dl in incidental laboratory analysis. On the same occasion, the serum parathyroid hormone (PTH) level was 45 pg/ml, 25(OH) vitamin D level 24.2ng/ml, 1.25 dihydroxy vitamin D level 22pg/ml, and urinary Ca/creatinine ratio <0.01. The ultrasonographic evaluation of the urinary system was unremarkable. The clinical and laboratory findings pointed towards FHD. A heterozygous p.Cys575Tyr (c.1724G>A) variation was detected in the patient's CaSR gene, which was reported before, but no clinical manifestations were specified. In children with asymptomatic hypercalcemia, the diagnosis of FHH should be considered if the PTH level is normal or high and the urinary calcium is low. [ABSTRACT FROM AUTHOR]

Familial Hypocalciuria Hypercalcemia (FHH) is an inherited disease with autosomal dominant transmission characterized by the presence of usually mild-to-moderate hypercalcemia, hypophosphatemia, hypocalciuria, and normal or moderately increased PTH values. Generally, FFH is asymptomatic although symptoms related to elevated plasma calcium values such as asthenia, intense thirst, polyuria, polydipsia or confusional state may occur. Three types of FHH, which differ in the genetic alterations underlying the condition, are described. The majority of FHH cases are classified as type 1 (about 65 percent of cases), due to mutation in the gene for the calcium-sensitive receptor CASR, expressed on chromosome (Chr) 3q13.3-21, which encodes for a calcium-sensitive receptor G-protein-coupled protein of the plasma membrane. FHH types 2 and 3 are due to GNA11 and AP2S1 mutations, respectively, and other genes involved in the pathogenesis of the disease have likely yet to be identified. Rarely, familial hypocalciuric hypercalcemia may not recognize a genetic cause but be caused by autoantibodies directed against CASR. The frequency of the disease is not known and is estimated, probably by default, because of paucisymptomatic presentation of the disease, to be around 1:80000 cases. Recognition of FHH is especially important for differential diagnosis with primary hyperparathyroidism, which has a much higher incidence, about 1:1000 cases. This allows for the identification of patients at risk for chondrocalcinosis and/or pancreatitis. Clinical suspicion must be raised in cases of hypercalcaemia associated with hypocalciuria, and genetic analysis is fundamental in the differential diagnosis toward forms of primary hyperparathyroidism that might result in unnecessary surgical interventions. We describe a clinical case in which a novel inactivating mutation of CASR leading to FHH type 1 was found., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

We present a case of a 75-year-old woman with persistent hypercalcemia (serum calcium 10.7 mg/dL, ionized calcium 1.37 mmol/L), elevated parathyroid hormone levels (86.6 pg/mL), and significantly low 24-hour urinary calcium excretion (<11 mg/24 hours). Genetic testing identified a novel heterozygous variant in the calcium-sensing receptor (CaSR) gene, c.3166G>C (p. Val1056Leu). The patient's biochemical profile and the identification of the CaSR variant support the diagnosis of familial hypocalciuric hypercalcemia (FHH). The novel c.3166G>C (p.Val1056Leu) variant has not been previously reported in FHH or other CaSR-associated conditions. Its presence in this patient suggests a potential role in the clinical manifestation of FHH. However, it is currently classified as a variant of undetermined significance (VUD) in the ClinVar database, necessitating further research on the clinical relevance of this variant in FHH. This case highlights the significance of genetic testing in diagnosing FHH and the potential clinical impact of discovering novel CaSR gene mutations. Further research on the genetics associated with FHH is necessary to better understand the condition, detect it early, and manage it effectively, thereby improving patient care and outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Al Kayed et al.)

Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the main differential diagnoses in a patient presenting with parathyroid hormone (PTH)-mediated hypercalcemia. PHPT is most often caused by a single-gland parathyroid adenoma and FHH is the result of an inactivating mutation of the calcium-sensing receptor (CaSR) gene. In this paper, we present a unique case of the co-existence of an inactivating CaSR gene mutation and PHPT due to a single-gland parathyroid adenoma. The patient is a 67-year-old female with a history of recurrent nephrolithiasis who presented with hypercalcemia, elevated PTH level, and hypocalciuria. As a result of the patient's hypocalciuria, familial hypocalciuric hypercalcemia was suspected, and genetic testing was pursued. CaSR gene analysis revealed a heterogeneous inactivating mutation of the CaSR gene. Additionally, nuclear imaging with technetium sestamibi revealed a large focus of activity on the right side of the neck suspicious of a parathyroid adenoma. This was resected and confirmed to be a hypercellular parathyroid adenoma. Two years after her surgery, the patient continues to have normal calcium levels with no further episodes of nephrolithiasis. She is currently undergoing treatment for osteoporosis and is being periodically monitored for recurrence of hypercalcemia due to the presence of the inactivating CaSR gene mutation. This case highlights an exceedingly rare case of a patient with both an inactivating CaSR gene mutation and PHPT due to a single parathyroid adenoma, and it underscores the importance of further research to determine any potential relationship between the two., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Russell et al.)