Sage Journals: Discover world-class research

Abstract

Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by mild to moderate hypercalcemia, mild hypermagnesemia, and normal or inappropriately elevated parathyroid hormone levels. Familial hypocalciuric hypercalcemia 1 is the most prevalent form of familial hypocalciuric hypercalcemia and is typically caused by heterozygous loss-of-function mutations in the calcium-sensing receptor (CaSR) gene. Homozygous CaSR mutations are more commonly associated with neonatal severe primary hyperparathyroidism. We report the case of a female patient in her early 40s harboring a novel homozygous frameshift mutation in the CaSR gene (c.2603_2604insTT), resulting in familial hypocalciuric hypercalcemia 1. The patient presented with persistent hypocalciuria, hypercalcemia, and primary hyperparathyroidism, along with a family history of consanguinity. This case highlights the phenotypic variability associated with CaSR mutations and broadens the clinical spectrum of homozygous CaSR-related disorders. Increased clinical awareness of atypical genetic presentations is essential to avoid misdiagnosis and to ensure appropriate management of patients with familial disorders of calcium homeostasis.

Keywords

Familial hypocalciuric hypercalcemia calcium-sensing receptor homozygous mutation hyperparathyroidism frameshift mutation

Introduction

Familial hypocalciuric hypercalcemia (FHH), also known as familial benign hypercalcemia, is an autosomal dominant disorder. FHH is categorized into three types, FHH1, FHH2, and FHH3, based on loss-of-function of the calcium-sensing receptor (CaSR), Gα11 protein, or AP2σ protein, respectively.¹ FHH1 accounts for approximately 65% of FHH cases and is characterized by persistent hypercalcemia, hypocalciuria, and normal or elevated serum parathyroid hormone (PTH) concentrations. FHH1 results from germline loss-of-function variants in the CaSR gene. More than 230 distinct mutations have been identified; of them, majority (>85%) are missense substitutions, whereas a smaller proportion (<15%) consists of nonsense, deletion, insertion, and splice-site alterations that result in a truncated receptor.^2–4

Germline homozygous mutations in the CaSR gene are typically associated with neonatal severe hyperparathyroidism (NSHPT), and adult-onset presentations are exceedingly rare.⁵ Herein, we present a case that does not conform to the expected genotype–phenotype correlation. A Chinese female patient developed FHH1 caused by a novel pathogenic homozygous loss-of-function CaSR mutation, with disease onset in adulthood accompanied by severe hypercalcemia. Additionally, we conducted a review of previously reported FHH1 cases with homozygous CaSR mutations.

Methods

Laboratory tests

Serum creatinine levels were measured using the sarcosine oxidase method. Calcium concentrations in 24-h urine samples and serum were determined using a dry chemistry colorimetric assay, whereas phosphorus levels were measured using the xylidyl blue colorimetric method. Intact PTH concentrations were quantified using a full-length PTH assay based on chemiluminescent microparticle immunoassay technology. Serum 25-hydroxyvitamin D levels were measured using an electrochemiluminescence-based assay. All biochemical and immunological analyses were performed using a fully automated biochemical immunoassay analyzer (Beckman Coulter, Brea; CA, USA). The normal reference ranges were as follows: 41–73 µmol/L for creatinine, 0.85–1.51 mmol/L for phosphate, 2.11–2.52 mmol/L for serum calcium, 15.0–68.3 pg/mL for serum PTH, >20 ng/mL for serum 25-hydroxyvitamin D, and 2.4–7.5 mmol/24 h for the 24-h urinary calcium level.

High-throughput exome sequencing

Whole-exome high-throughput sequencing was performed using Berry Genomics’ proprietary Verita Trekker® mutation-detection system. Sequence data were annotated and interpreted using the Enliven® variant annotation and interpretation system. Variants identified as suspicious or dynamically evolving using whole-exome sequencing were confirmed by targeted polymerase chain reaction (PCR), followed by capillary electrophoresis and comprehensive downstream analysis.

Literature searching strategy

A comprehensive literature search was conducted in the PubMed database using the following keywords: hypercalcemia, hypocalciuric hypercalcemia, calcium-sensing receptor, hyperparathyroidism, thyroid, cinacalcet, familial hypocalciuric hypercalcemia, and primary hyperparathyroidism.

Case presentation

A woman in her early 40s was admitted to The First Hospital of Jilin University in August 2024 with a 3-month history of hypercalcemia accompanied by recurrent headaches. Recently, she had experienced a 3-day episode of nausea. She had previously been hospitalized for dizziness and headaches, during which elevated serum calcium (3.68 mmol/L) and glucose levels were noted. Her symptoms improved with rehydration, intravenous (IV) furosemide, calcitonin, and zoledronic acid. She was discharged on 70 mg alendronate weekly and 20 mg furosemide daily. Despite treatment, intermittent follow-up evaluations showed persistent calcium levels of 3.8 mmol/L. Three days before admission, she again developed headaches and nausea, and a local hospital recorded a serum calcium level of 3.84 mmol/L.

Her medical history was notable. Eight months earlier, she had been diagnosed with diabetes mellitus, which was managed with insulin. She was born to consanguineous parents (first cousins) and had exhibited delayed motor development compared with her peers, achieving sitting, standing, or walking only at approximately 3 years of age. She reported no family history of hypercalcemia or related disorders. Physical examination revealed a height of 158 cm, weight of 56.5 kg, and body mass index (BMI) of 22.63 kg/m² along with dry tongue, reduced skin turgor, and bilateral knee valgus deformities.

Laboratory testing at admission showed an elevated serum calcium of 3.86 mmol/L (normal reference range: 2.11–2.52 mmol/L), low creatinine at 35.1 µmol/L (normal reference range: 41–73 µmol/L), and low phosphate at 0.41 mmol/L (normal reference range: 0.85–1.51 mmol/L). During hospitalization, serum calcium levels ranged from 2.96 to 3.30 mmol/L (3.30, 3.18, 3.10, 2.96, 2.98, 3.11, 3.20, 3.21, and 3.10 mmol/L). Serum PTH was markedly elevated at 230.20 pg/mL (normal reference range: 15.0–68.3 pg/mL), whereas serum 25-hydroxyvitamin D was deficient at 10.04 ng/mL (normal reference range: >20 ng/mL). The 24-h urinary calcium level was low at 1.95 mmol/24 h (reference range: 2.4–7.5 mmol/24 h), with a calcium-to-creatinine clearance ratio (CCCR) of 0.003 (<0.01), supporting a diagnosis of hypocalciuric hypercalcemia. Other hormone levels, diabetes-related autoantibodies, and tumor markers were within normal limits.

Parathyroid scintigraphy demonstrated increased radiotracer uptake in the mid-posterior region of the left thyroid lobe, suggesting hyperfunctioning parathyroid tissue. Cervical computed tomography (CT) revealed a low-density nodule measuring 0.6 cm × 0.4 cm (CT value approximately 14 HU). Brain CT showed multiple calcifications involving the cerebellar tentorium, falx cerebri, and ocular globes. Abdominal Doppler ultrasonography revealed calcifications in the left kidney (Figure 1).

Figure 1.

Imaging findings of the patient. (a, b) Calcified nodules (red arrows) in the lower lobe, mediastinum, and right hilar region; (c, d) multiple calcifications (red arrows) in the cerebellar tentorium, falx cerebri, and ocular globes, suggestive of possible abnormal calcium deposition; (e, f) increased radiotracer uptake (red arrows) in the mid-posterior region of the left thyroid lobe, indicative of potential hyperfunction of the parathyroid tissue.

After obtaining written informed consent, whole blood samples were collected from the patient and her family members for high-throughput exome sequencing. A homozygous frameshift mutation (c.2603_2604insTT) in the CaSR gene was identified in the patient. Her mother and daughter were heterozygous carriers (Figure 2). This mutation introduces a premature stop codon in the final exon of the gene and is predicted to escape nonsense-mediated decay, affecting more than 10% of the protein sequence. This mutation was not identified in public population databases, including the 1000 Genomes Project, the China Genomics Database, the Exome Aggregation Consortium (ExAC), or the Genome Aggregation Database (gnomAD).

Figure 2.

Results of high-throughput exome sequencing. The patient (0F2X019137) had a homozygous frameshift mutation (c.2603_2604insTT) in the CaSR gene. The mother (0F2X019138) and daughter (0F2X019139) were both heterozygous for this mutation, which was inherited from the mother.

Based on the clinical, biochemical, and genetic findings, the patient was diagnosed with FHH type 1 due to a homozygous CaSR mutation, accompanied by primary hyperparathyroidism and diabetes mellitus. She was initially treated with 25 mg cinacalcet twice daily and 40 mg furosemide twice daily. One month later, she discontinued cinacalcet without medical advice. Serum calcium levels remained elevated at 3.52 and 3.38 mmol/L, and she required two additional hospitalizations for headaches and fatigue, during which she received symptomatic calcium-lowering therapy before discharge.

This study was reviewed and approved by the Ethics Committee of The First Hospital of Jilin University (Approval Number: AF-IRB-026-01). The requirement for written informed consent was waived. The reporting of this study conforms to the Case Report (CARE) guidelines.⁶

Literature search results

A literature search identified seven publications reporting seven cases of FHH type 1 attributed to homozygous loss-of-function mutations in the CaSR gene. Among these cases, three patients were female and four were male, with ages ranging from 2 to 59 years. The clinical characteristics of these cases are summarized in Table 1.^7–13

Table 1.

Reported cases of FHH1 associated with homozygous loss-of-function CaSR variants.

Study	Patient sex and age (years)	Typical clinical manifestations			Mutation site	Genetic status of the family
Study	Patient sex and age (years)	Hypercalcemia, hypocalcemia, and hypophosphatemia	Secondary hyperparathyroidism	PTH	Mutation site	Parent	Sibling
Chikatsu et al. 1999⁷	Female26	Yes	—	Increase	p.Gln27Arg	Homozygous mutation	—
Lietman et al. 2009⁸	Male11	Yes		Increase	c.1376.A→G Q459R		Homozygous mutation
Szczawinska et al. 2014⁹	Female16	Yes	Yes	Significantly increase	p.Q459R		Homozygous mutationQ459R homozygous mutation
Borsari et al. 2017¹⁰	Female59	Yes	—	Increase	c.2013G>C p.E671D		Homozygous mutation
Wang et al. 2020¹¹	Male32	Yes	—	—	c.1664 T>C p.I555T		Homozygous mutation
Li et al. 2021¹²	Male12	Yes	—	Normal	c.178T>G p.C60G		—
Koca 2023¹³	Male2	Yes	—	Slightly increased	c.1057G>A p.Glu353Lys		—
Parents’ next of kin marriage	Past medical history	Comment
Yes	Parathyroid hyperplasia with parathyroidectomy and autologous gland transplantation	—
Yes	4-month history of acute appendicitis; hypercalcemia was first diagnosed at the age of 2	No parathyroid adenoma; there was no renal calcinosis or calculi in the kidney.
Yes	Valgus deformity at the age of 1; fracture of the radius at the age of 12	Ultrasound of the parathyroid gland was normal; kidney ultrasound was normal.
Yes	—	Bone metabolite, bone mineral density, parathyroid function imaging, and abdominal color ultrasound were all normal.
Yes	Cognitive and motor retardation; 10-year history of diabetes; multiple stones of the pancreatic duct; craniocerebral CT: extensive meningeal calcification	Parathyroid imaging was normal; bone mineral density indicated reduced bone mass; abdominal CT: pancreatic atrophy with calcification.
Yes	At 14 months, he was diagnosed with cerebral palsy with bone pain	Bone X-ray scan was normal; kidney color ultrasound was normal.
No	—	Parathyroid imaging was normal; kidney color ultrasound was normal.

PTH: parathyroid hormone; FHH1: familial hypocalciuric hypercalcemia 1; CaSR: calcium-sensing receptor. CT: computed tomography.

Discussion

Herein, we report the case of a patient carrying a homozygous CaSR mutation who exhibited a relatively mild clinical phenotype of FHH1. The coexistence of mild hypercalcemia, hypocalciuria, widespread soft-tissue calcifications, and modest parathyroid radiotracer uptake suggests partial preservation of CaSR function as well as a mixed pathophysiology involving both FHH1 and primary hyperparathyroidism. Overall, this case represents an atypically mild presentation of a homozygous CaSR mutation.

CaSR, encoded by the CaSR gene located on chromosome 3q21.1, is a class C G protein–coupled receptor comprising a large extracellular domain, a transmembrane region, and an intracellular C-terminal tail. CaSR is highly expressed in tissues that regulate calcium homeostasis, particularly the parathyroid glands and kidneys.¹⁴ Loss-of-function CaSR mutations cause a rightward shift in the extracellular calcium concentration–response curve, thereby increasing the regulatory set point. This dysregulation manifests as hypercalcemia accompanied by reduced urinary calcium excretion.¹⁵ Pathogenic variants have been identified in all structural domains of the encoded protein; however, mutations are frequently located within the first 350 amino acids of the extracellular domain, which contains the calcium-binding sites and the venus flytrap domain.¹⁶ This region represents a mutational cluster region for FHH1, and approximately 50% of identified variants disrupt CaSR biosynthesis and subsequent post-translational processing in the endoplasmic reticulum or Golgi apparatus.¹⁷ In contrast, alterations affecting the cysteine-rich region or the transmembrane domain often impair coupling of CaSR to heterotrimeric G proteins and downstream signaling molecules, thereby disrupting signal transduction.¹⁸ In the kidneys, CaSR modulates calcium reabsorption by inhibiting PTH-induced activation of renal cyclic adenosine monophosphate (cAMP). The thick ascending limb of the loop of Henle reabsorbs approximately 25% of filtered calcium. Elevated serum calcium activates CaSR that reduces aquaporin-2 expression, thereby decreasing urine-concentration capacity. Consequently, loss-of-function mutations in CaSR result in increased tubular calcium reabsorption.¹⁹

In the present case, the patient’s clinical presentation were not consistent with the severe manifestations typically associated with homozygous CaSR mutations, which are commonly linked to NSHPT. NSHPT has been reported in offsprings from consanguineous families with FHH or in unrelated individuals harboring homozygous or compound heterozygous CaSR mutations. Typically, heterozygous pathogenic CaSR variants cause mild hypercalcemia, characteristic of autosomal dominant FHH, whereas biallelic mutations result in NSHPT.² The homozygous CaSR mutation identified in this patient was not associated with the severe clinical presentation of NSHPT. The relatively mild clinical manifestations may be attributable to the location of stop codon in the last exon of the gene, which truncates only approximately 10% of the protein and may allow partial preservation of CaSR function.

A review of the literature on FHH1 cases with homozygous CaSR mutations revealed a consistent pattern of heterozygous CaSR variants in the parents and a high incidence of consanguinity (Table 1). These findings suggest that consanguineous unions, in the context of parental heterozygosity, substantially increase the likelihood of transmitting homozygous loss-of-function alleles, resulting in FHH1. This observation may provide novel insights into the diagnosis and management of FHH1.

Additionally, although the current patient had no family history of diabetes, she was diagnosed with diabetes and reduced pancreatic function 8 months earlier, despite ultrasonographic findings demonstrating normal pancreatic morphology. These findings differ from those reported by Wang et al.¹¹ in 2021, in which diabetes was associated with pancreatic atrophy and calcification. One possible explanation is that chronic hypercalcemia may impair pancreatic endocrine function through metabolic or microvascular mechanisms before structural changes become detectable. However, a causal relationship cannot be established in this case. Alternatively, the diabetes may represent a coincidental comorbidity unrelated to CaSR dysfunction. Further studies are needed to clarify the potential association between long-standing hypercalcemia and pancreatic dysfunction.

Furthermore, the extensive calcifications observed at multiple sites in this patient suggest abnormal calcium deposition, likely reflecting long-standing hypercalcemia with relatively subtle clinical manifestations. This pattern is consistent with partial loss of CaSR activity resulting from the relatively limited proportion of the protein affected by the homozygous mutation.

FHH and primary hyperparathyroidism (PHPT) are both characterized by elevated serum calcium levels and elevated or inappropriately normal PTH levels. Despite these similarities, it is important to distinguish between these conditions for appropriate management.²⁰ CCCR is a useful biochemical marker for differentiation. A CCCR value of <0.01 is suggestive of FHH, whereas a value ≥0.02 supports a diagnosis of PHPT. However, CCCR values within the intermediate range (0.01–0.02) may be less reliable, making genetic testing advisable for definitive diagnosis.²¹ FHH is primarily caused by loss-of-function mutations in the CaSR gene, leading to impaired CaSR activity and an increased calcium set point. This results in hypercalcemia with reduced urinary calcium excretion. In contrast, PHPT is commonly caused by parathyroid gland hyperplasia or adenomas, resulting in excessive PTH secretion despite elevated serum calcium levels. In PHPT, reduced CaSR expression in parathyroid cells contributes to an altered PTH secretion set point and impaired negative feedback regulation, resulting in a rightward shift of the PTH secretion–calcium curve.¹⁴ Decreased CaSR expression has been demonstrated in adenomas and hyperplastic parathyroid glands, further contributing to increased PTH secretion in PHPT.²² Additionally, the formation of receptor complexes such as CaSR–GABAB1 has been associated with enhanced PTH secretion.²³ Evidence also suggests that CaSR influences parathyroid cell proliferation through mitogen-activated protein kinase (MAPK) pathways and interactions with the klotho protein.²⁴

Management of FHH is generally conservative, with observation recommended in most cases. Parathyroidectomy is reserved for severe cases, particularly in patients with homozygous CaSR mutations.²⁵ Pharmacological therapy may include CaSR agonists, which are classified as type I agonists (e.g. polyvalent cations) or type II allosteric modulators (e.g. cinacalcet).²⁶ Cinacalcet, a type II agonist, increases CaSR sensitivity to extracellular calcium, thereby reducing PTH secretion and serum calcium levels.²⁷ Clinical evidence supports the efficacy of cinacalcet in managing FHH, with 14 of 16 reported cases demonstrating favorable outcomes, including patients with AP2S1 mutations and heterozygous CaSR mutations.^28,29 Recent in vitro studies have also shown that cinacalcet can correct intracellular calcium and MAPK response impairments associated with FHH2 caused by Gα11 mutations.^28,30 In addition to medical therapy, interventional approaches have been explored for patients with refractory hypercalcemia who are intolerant of or unresponsive to pharmacological treatment. Hao et al.³¹ reported successful radiofrequency ablation of hyperfunctioning parathyroid tissue in a patient with hypercalcemia due to an inactivating CaSR mutation. This minimally invasive procedure achieved sustained normalization of serum calcium while avoiding surgical risks, suggesting that radiofrequency ablation may be a potential alternative in carefully selected cases. Although current evidence is limited to case reports, these findings indicate that radiofrequency ablation may serve as a useful adjunct in the management of CaSR-related refractory hypercalcemia.

Conclusions

This case highlights the diagnostic value of molecular analysis in distinguishing FHH1 from PHPT and in explaining atypical clinical presentations. Despite the presence of a homozygous CaSR mutation, the patient exhibited relatively mild hypercalcemia, likely due to partial preservation of CaSR function and long-standing compensatory mechanisms. Accurate interpretation of genetic findings, together with biochemical markers such as the CCCR, remains essential for differentiating FHH from other hypercalcemic disorders and for guiding appropriate management. This case underscores the phenotypic variability associated with CaSR mutations and reinforces the importance of incorporating molecular testing into the diagnostic workflow for suspected FHH.

Supplemental Material

sj-zip-1-imr-10.1177_03000605261429307 - Supplemental material for A novel homozygous inactivating mutation of the calcium-sensing receptor causing familial hypocalciuric hypercalcemia complicated with primary hyperparathyroidism due to parathyroid adenoma: A case report

Supplemental material, sj-zip-1-imr-10.1177_03000605261429307 for A novel homozygous inactivating mutation of the calcium-sensing receptor causing familial hypocalciuric hypercalcemia complicated with primary hyperparathyroidism due to parathyroid adenoma: A case report by Xiaoran Tao, Mengsha Yin and Xiaokun Gang in Journal of International Medical Research

Footnotes

Acknowledgments

We gratefully acknowledge the trust and collaboration of the patients and families in this study and commend the research team members for their essential contributions and relentless commitment.

Author contributions

Conceptualization: Mengsha Yin

Data curation: Xiaoran Tao

Investigation: Mengsha Yin

Methodology: Xiaoran Tao

Supervision: Xiaokun Gang

Writing – original draft: Xiaoran Tao

Writing – review & editing: Xiaokun Gang

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Declaration of conflicting interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics statement

This study was reviewed and approved by the Ethics Committee of The First Hospital of Jilin University, with the batch number AF-IRB-026-01. The requirement for patient informed consent was waived.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No. 82272993 to X.G.).

Patient perspective

After receiving the diagnosis, the patient actively participated in the decision-making process regarding the treatment plan and provided preventive advice to their family members. The patient also focused on identifying any potential clinical phenotypes and informed their family about the importance of early prevention and intervention.

ORCID iD

Xiaoran Tao

References

Nesbit

Hannan

Howles

, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med 2013; 368: 2476–2486.

Hannan

Thakker

RV.

Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract Res Clin Endocrinol Metab 2013; 27: 359–371.

Vargas-Poussou

Mansour-Hendili

Baron

, et al. Familial hypocalciuric hypercalcemia types 1 and 3 and primary hyperparathyroidism: similarities and differences. J Clin Endocrinol Metab 2016; 101: 2185–2195.

Hannan

Nesbit

Zhang

, et al. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet 2012; 21: 2768–2778.

Kerkhof

Van Der Linden

Sipkema

Role of myocardium and endothelium in coronary vascular smooth muscle responses to hypoxia. Am J Physiol Heart Circ Physiol 2002; 282: H1296–H1303.

Gagnier

Kienle

Altman

; CARE Groupet al. The CARE guidelines: consensus-based clinical case reporting guideline development. Headache 2013; 53: 1541–1547.

Chikatsu

Fukumoto

Suzawa

, et al. An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor. Clin Endocrinol (Oxf) 1999; 50: 537–543.

Lietman

Tenenbaum-Rakover

Jap

, et al. A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. J Clin Endocrinol Metab 2009; 94: 4372–4379.

Szczawinska

Schnabel

Letz

, et al. A homozygous CaSR mutation causing a FHH phenotype completely masked by vitamin D deficiency presenting as rickets. J Clin Endocrinol Metab 2014; 99: E1146–E1153.

10.

Borsari

Marcocci

Cetani

Familial hypocalciuric hypercalcemia type 1 due to a novel homozygous mutation of the calcium-sensing receptor gene. J Endocrinol Invest 2017; 40: 1271–1272.

11.

Wang

Mei

, et al. Familial hypocalciuric hypercalcemia caused by homozygous CaSR gene mutation: a case report of a family. Medicine (Baltimore) 2020; 99: e21940.

12.

, et al. A novel homozygous mutation of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. Chin Med J (Engl) 2021; 134: 1869–1871.

13.

Koca

SB.

Cinacalcet therapy in a child with novel homozygous CASR p.Glu353Lys mutation causing familial hypocalciuric hypercalcemia type 1: case report and review of the literature. Turk J Pediatr 2023; 65: 853–861.

14.

Brown

EM.

Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab 2013; 27: 333–343.

15.

Egbuna

Brown

EM.

Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008; 22: 129–148.

16.

Geng

Mosyak

Kurinov

, et al. Structural mechanism of ligand activation in human calcium-sensing receptor. Elife 2016; 5: e13662.

17.

White

McKenna

Cavanaugh

, et al. Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Mol Endocrinol 2009; 23: 1115–1123.

18.

Leach

Wen

Davey

, et al. Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. Endocrinology 2012; 153: 4304–4316.

19.

Riccardi

Valenti

Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol 2016; 12: 414–425.

20.

Shinall

Dahir

Broome

JT.

Differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism. Endocr Pract 2013; 19: 697–702.

21.

Christensen

Nissen

Vestergaard

, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008; 69: 713–720.

22.

Conigrave

Ward

DT.

Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 2013; 27: 315–331.

23.

Chang

Jean-Alphonse

, et al. PTH hypersecretion triggered by a GABAB1 and Ca²⁺-sensing receptor heterocomplex in hyperparathyroidism. Nat Metab 2020; 2: 243–255.

24.

Corbetta

Lania

Filopanti

, et al. Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells. J Clin Endocrinol Metab 2002; 87: 2201–2205.

25.

Arnold

Marx

SJ.

Familial primary hyperparathyroidism (including MEN, FHH, and HPT‐JT). In: Rosen

(ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed. Wiley, 2013, pp. 553–561.

26.

Hannan

Babinsky

Thakker

RV.

Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. J Mol Endocrinol 2016; 57: R127–R142.

27.

Khan

Bilezikian

Bone

, et al. Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery. Eur J Endocrinol 2015; 172: 527–535.

28.

Howles

Hannan

Babinsky

, et al. Cinacalcet for symptomatic hypercalcemia caused by AP2S1 mutations. N Engl J Med 2016; 374: 1396–1398.

29.

Mayr

Schnabel

Dörr

, et al. GENETICS IN ENDOCRINOLOGY: gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts. Eur J Endocrinol 2016; 174: R189–R208.

30.

Babinsky

Hannan

Gorvin

, et al. Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein α-11 mutations causing hypercalcemic and hypocalcemic disorders. J Biol Chem 2016; 291: 10876–10885.

31.

Hao

Lei

Shi

, et al. Radiofrequency ablation of parathyroid glands to treat a patient with hypercalcemia caused by a novel inactivating mutation in CaSR. Front Endocrinol (Lausanne) 2021; 12: 743517.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

8.87 MB