CASR – Familial Hypocalciuric Hypercalcemia Type I

Familial hypocalciuric hypercalcemia type I (FHH1) is an autosomal dominant disorder characterized by lifelong, typically benign, hypercalcemia, hypocalciuria, and inappropriately normal or mildly elevated parathyroid hormone (PTH) levels. Heterozygous loss-of-function variants in the calcium-sensing receptor gene (CASR) impair calcium sensing in the parathyroid glands and kidneys, altering calcium homeostasis and elevating the set point for extracellular calcium. Genetic testing of CASR is critical to distinguish FHH1 from primary hyperparathyroidism and guide management.

Multiple lines of genetic evidence support a definitive CASR–FHH1 association. Heterozygous CASR variants were identified in >50 unrelated probands across more than 40 kindreds, including missense, nonsense, splice-site, frameshift, and large deletion alleles ([PMID:32386559]). Segregation analysis demonstrated inheritance of pathogenic variants in 10 additional affected relatives ([PMID:32150253]; [PMID:32160303]). A large healthcare cohort (N=51 289) revealed 38 individuals with predicted CASR loss-of-function variants, 21 of whom exhibited hypercalcemia ([PMID:32386559]), and a retrospective series described 14 patients initially misdiagnosed with primary hyperparathyroidism who harbored novel CASR mutations ([PMID:33094630]).

The CASR mutational spectrum in FHH1 encompasses over 350 inactivating variants, including missense (e.g., c.1376A>G (p.Gln459Arg)), nonsense, splice-site (c.186-1G>A), frameshift, and large genomic deletions (c.1733-255_2450del) ([PMID:30530875]). Variants cluster throughout the extracellular Venus flytrap domain, seven-transmembrane region, and cytoplasmic tail. Recurrent or founder alleles have not been commonly reported, reflecting diverse mutational origins.

Functional studies in Xenopus oocytes and HEK293 cells uniformly demonstrate that FHH1-associated CASR variants reduce receptor cell-surface expression, disrupt Ca2+-induced intracellular Ca2+ mobilization, and impair MAPK signaling. Signal peptide mutations (p.Leu11Ser, p.Leu13Pro) hinder co-translational processing ([PMID:15879434]), while extracellular domain substitutions (p.Gln459Arg) decrease Ca2+ sensitivity without affecting membrane targeting ([PMID:32160303]). Calcimimetic agents such as NPS R-568 and cinacalcet can restore signaling of select variants and correct QT-interval abnormalities in affected patients ([PMID:37602721]; [PMID:18796518]).

Phenotypically, FHH1 manifests as mild-to-moderate hypercalcemia (serum Ca 2.60–3.00 mmol/L), low urinary Ca excretion (CCCR <0.01), and normal-to-elevated PTH. Affected kindreds may present neonatal hypocalcemic seizures in offspring without the variant, and short QT interval in some patients with p.Ile555Thr ameliorated by cinacalcet ([PMID:32150253]; [PMID:37602721]). The clinical overlap with primary hyperparathyroidism often leads to unnecessary parathyroidectomy in up to 40% of cases without genetic testing ([PMID:33094630]).

Mechanistically, FHH1 arises from haploinsufficiency of CASR, increasing the calcium set point required for receptor activation. The concordant genetic and functional data—spanning >50 probands, robust segregation, and extensive in vitro assays—fulfill ClinGen criteria for a definitive gene–disease association. CASR genetic testing is essential for accurate diagnosis, avoidance of inappropriate surgery, and selection of patients who may benefit from calcimimetic therapy.

Key take-home: CASR haploinsufficiency causes FHH1; genetic confirmation prevents unnecessary parathyroidectomy and guides potential calcimimetic treatment.

References

• American journal of human genetics • 2020 • Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population PMID:32386559
• The Journal of clinical endocrinology and metabolism • 2020 • Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1) PMID:32150253
• The Journal of clinical endocrinology and metabolism • 2020 • Heterozygous Mutation (Q459R) in the Calcium-Sensing Receptor Gene Causes Familial Hypocalciuric Hypercalcemia 1 (FHH1) PMID:32160303
• Physiological research • 2020 • Familial hypocalciuric hypercalcemia in an index male: grey zones of the differential diagnosis from primary hyperparathyroidism in a 13-year clinical follow up PMID:33094630
• Endocrinology, diabetes & metabolism case reports • 2018 • Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia PMID:30530875
• The Journal of clinical endocrinology and metabolism • 2024 • Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1 PMID:37602721
• Human mutation • 2004 • CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia PMID:15241791
• Human molecular genetics • 2005 • Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia PMID:15879434
• Methods in molecular biology (Clifton, N.J.) • 2008 • G protein-coupled receptors disrupted in human genetic disease PMID:18370233
• Endocrinology • 2012 • Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor PMID:22798347

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