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Neonatal severe primary hyperparathyroidism (NSHPT) is a life-threatening autosomal recessive disorder characterized by marked hypercalcemia, hyperparathyroid bone disease, and multiorgan dysfunction. Infants present in the first weeks of life with respiratory distress, hypotonia, feeding difficulties, and failure to thrive, often requiring emergency parathyroidectomy. Genetic analyses have established that biallelic inactivating mutations in the calcium-sensing receptor gene (CASR) underlie NSHPT by impairing calcium-mediated feedback on parathyroid hormone secretion (PMID:18751724).
Multiple case reports describe unrelated NSHPT probands with homozygous or compound heterozygous CASR loss-of-function variants. A de novo heterozygous missense mutation, c.554G>A (p.Arg185Gln), produced an unusually severe neonatal presentation requiring subtotal and then total parathyroidectomy in the fourth month of life (PMID:18751724). Two siblings with homozygous c.2303G>T (p.Gly768Val) had classic NSHPT with craniosynostosis and severe hypercalcemia, segregating in an autosomal recessive pattern within one family (PMID:24854525). Further homozygous variants such as c.740C>T (p.Ser247Phe) in unrelated neonates confirm recurrence of biallelic CASR defects in NSHPT (PMID:24735972).
The spectrum of CASR mutations in NSHPT spans missense, frameshift, and splice-site changes, predominantly clustering in the extracellular calcium-binding venus flytrap domain. Multi-patient studies of families with both familial hypocalciuric hypercalcemia and NSHPT demonstrate that homozygous loss-of-function alleles yield the most severe phenotypes, while heterozygotes have milder hypercalcemia or asymptomatic carriers (PMID:12412776). No common founder alleles have been reported, underscoring allelic heterogeneity.
Mechanistically, in vitro expression of mutant CaSR in HEK293 or Xenopus oocytes consistently shows right-shifted dose-response curves and reduced cell-surface expression, confirming loss-of-function. Truncating and misfolded receptors are retained in the endoplasmic reticulum, preventing normal calcium sensing (PMID:9109436). Allosteric activation with calcimimetics (e.g., cinacalcet) can partially restore signaling in some extracellular domain mutants, although surgical parathyroidectomy remains definitive in most NSHPT cases (PMID:18796518).
No studies have refuted the role of CASR in NSHPT; rather, abundant concordant genetic and functional data strengthen the disease association. Additional evidence from population screening and model organisms exceeds ClinGen scoring caps but further supports a loss-of-function haploinsufficiency mechanism.
Key Take-home: Biallelic CASR mutations cause NSHPT through severe loss of calcium-sensing function; early genetic diagnosis enables urgent management and informs family counseling.
Gene–Disease AssociationStrongAt least 5 unrelated probands with biallelic CASR loss-of-function mutations; functional assays concordant; multiple families Genetic EvidenceStrongAutosomal recessive inheritance; ≥6 probands; sibling segregation in multiple families; diverse LoF alleles Functional EvidenceStrongMultiple in vitro studies show loss-of-function, impaired receptor trafficking and signaling; partial rescue by calcimimetics |