Summary

Neonatal severe primary hyperparathyroidism (NSHPT) is characterized by severe hypercalcemia (> 3.5 mM) from birth and associated with major hyperparathyroidism.

The prevalence is unknown.

The clinical manifestations are early (with onset occurring during the first days of life) and severe, including respiratory distress due to hypotonia and rib cage deformities, bone under mineralization, and multiple fractures, all of which influence the immediate vital prognosis.

NSHPT is associated in most cases with homozygous inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling parathyroid hormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels.

Biologically, children present with extremely high serum calcium and serum PTH levels and a relative hypocalciuria, but in some cases they present with a markedly elevated calciuria.

Familial hypocalciuric hypercalcemia (FHH; see this term) is a differential diagnosis. Hypercalcemia is usually milder and PTH levels are lower in FHH than in NSHPT and FHH is asymptomatic in most cases.

Prenatal diagnosis might be proposed to parents if they are both suffering from FHH.

NSHPT represents the homozygous form of FHH and is transmitted as an autosomal recessive trait. However, sporadic forms of NSHPT occur and are associated with a heterozygous de novo mutation in the CASR gene.

The control of hypercalcemia is often obtained through progressive therapeutic intervention involving the use of bisphosphonates and dialysis. If this is unsuccessful, a total parathyroidectomy is required. After parathyroidectomy, life-long treatment with 1-alpha hydoxylated vitamin D is required.

Most patients die from complications of hypercalcemia during the neonatal period from respiratory distress and dramatic hypercalcemia. Survivors can live normally.

Expert reviewer(s)

• Pr Anne LIENHARDT-ROUSSIE