Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder and represents a rare cause of hypercalcemia. It stems from variants in the calcium-sensing receptor gene (CaSR), G-protein subunit alpha11 gene (GNA11), or adaptor-related protein complex 2 gene (AP2S1), among which variants in the CaSR gene are the most prevalent. However, challenges in the current diagnosis of FHH persist, owing to the overlap in clinical features with primary hyperparathyroidism (PHPT). The three reported patients demonstrated similar clinical presentations such as hypercalcemia and relative hypocalciuria. In two of them, the parathyroid hormone (PTH) level was elevated, while in one, it was normal. Initially, all of them received conventional hypocalcemic treatment. After comprehensive medical history collection and auxiliary examination were conducted to exclude other causes of hypercalcemia, whole exome sequencing (WES) and sanger sequencing were carried out. The results showed that the three patients carried different variants sites in the CaSR gene, namely, c.887G>A, c.2027 > G, c.1608 + 3A>T and c.332C>T. In addition, c.887G>A was also found in the son and grandson of patient 1. The analysis of the conservation of homologous species and the prediction of protein structure for all variant sites demonstrated that due to the heterozygous variants in CaSR, relatively conserved amino acids were altered, affecting the interaction forces between adjacent amino acids, resulting in changes in the protein structure, which might affect the function of the protein. In conclusion, we report three cases of FHH1 with different heterozygous variant sites in the CaSR gene. This study has expanded the spectrum of variants. It is of great significance for the genetic screening, diagnosis, counseling, and research of hypercalcemia-related genes and become a key resource for enhancing clinicians' understanding of FHH1.

Familial 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. We 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. For 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.

Genetic testing of the calcium-sensing receptor (CASR) gene is crucial for confirming diagnoses of familial hypocalciuric hypercalcemia type I (FHH1) and autosomal dominant hypocalcemia type I (ADH1). Therefore, we created a publicly accessible comprehensive database of the disease-causing variants of the CASR gene. We used 2 sources for variant reports: (1) we conducted a systematic review in the Embase and PubMed databases from inception to March 2023, using search strategies associated with CASR. We identified all articles reporting CASR variants associated with disorders of calcium metabolism. (2) Additionally, data associated with pathogenic (P) or likely pathogenic (LP) variants in the ClinVar and LOVD databases were retrieved. Benign or likely benign variants were excluded. Variants of uncertain significance (VUS) were included only if they were reported in the literature. We generated a library of CASR variants associated with phenotypes, which has been made available on a website. We identified a total of 498 variants, of which 121 (24.3%) were associated with ADH1 and 377 (75.7%) with FHH1. Most included variants were identified from the literature (117 activating and 352 inactivating variants), and the majority of these were not documented in ClinVar/LOVD (73/117, 62.4% activating variants; 207/352, 58.8% inactivating variants). We developed CASRdb, a database that compiles information on all CASR variants associated with disorders of calcium metabolism from existing literature and genomic databases. Our database stands out due to the substantially higher number of disease-associated variants it contains, highlighting its comprehensive nature. The website is available at http://casrdb.mgh.harvard.edu.

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.

Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date. Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined. CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed. The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment. Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment.