Neonatal Severe Hyperparathyroidism: Novel Insights from Calcium, PTH, and the CASR Gene.

CONTEXT: Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH). Optimal therapy is unclear.

EVIDENCE ACQUISITION: We categorized genotype/phenotype pairings related to CASRs. For the two pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant.

EVIDENCE SYNTHESIS: Homozygous and heterozygous NSHPT are two among a spectrum of nine genotype/phenotype pairings relating to CASRs and NSHPT. For the two NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of materno-fetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high grade CASR variants in vitro were more pathogenic in vivo than low grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme, hypercalcemia (above 4.5 mM; normal 2.2-2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week.

CONCLUSIONS: In NSHPT, the homozygotes for pathogenic CASR variants show higher calcium and PTH than heterozygotes. Calcium above 4.5 mM among NSHPT is frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes.