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) levels. Optimal therapy is unclear. Evidence acquisition We categorized genotype/phenotype pairings related to CASRs. For the 2 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 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal 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 pairings, 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 pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are 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.

Possible Health Implications and Low Vitamin D Status during Childhood and Adolescence: An Updated Mini Review

Vitamin D deficiency is common in the developing countries and exists in both childhood and adult life. The great importance of Vitamin D is the moderation of calcium (Ca) and phosphorus (P) homeostasis as well as the absorption of Ca. While insufficiency of vitamin D is a significant contributing factor to risk of rickets in childhood, it is possible that a more marginal deficiency of vitamin D during life span contribute to osteoporosis as well as potentially to the development and various other chronic diseases such as cardiovascular disease, cancer and diabetes. This paper reviews the metabolism, epidemiology, and treatment of vitamin D and calcium insufficiency as well as its relation to various diseases during childhood and adolescence.