Secretory Dysfunction in Parathyroid Cells from a Neonate with Severe Primary Hyperparathyroidism

Abstract

We report a patient with neonatal severe primary hyperparathyroidism whose parathyroid cells were markedly refractory to regulation by calcium in vitro. He showed life-threatening hypercalcemia (4.8-5.2 mM vs. normal of 2.1-2.7 mM). A sibling had been treated previously for an identical disorder. At age 6.5 months, four hyperplastic parathyroid glands were removed, and portions of one were immediately grafted into the forearm. Serum calcium again became elevated post-operatively and then fall to the normal range after excision of grafted parathyroid tissue. Dispersed parathyroid cells from the first operation showed no suppression of PTH secretion by 2 mM calcium; however, there was normal maximal suppressibility at 4 mM calcium with half-maximal suppression at 2.53 mM (the calcium set point). This contrasts with much lower set points previously established for suppressible cells from normal (1.02 +/- 0.10 mM, mean +/- 1 SD), from primary hyperplastic (1.10 +/- 0.14 mM), or from adenomatous (1.26 +/- 0.14 mM) parathyroid glands. The strikingly high set point may not be unique because a small number of glands previously classified as nonsuppressible (by the criterion of failing to suppress below 50% maximum at calcium concentration up to 2-3 mM) might have shown similarly high set points if tested at higher calcium concentrations. We conclude that an unusual abnormality of PTH secretory control accounts, in large part, for both the marked hypercalcemia and for its refractoriness to surgical treatment in this patient.

Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

“…Consent was obtained from all participants or their guardians in accordance with local institutional guidelines. The three families (D, Qu, and S) with affected FHH and NSHPT members harboring the Alu insertion have been described previously (5,13,17,22,23). Measurement of serum total calcium concentration was carried out by colorimetric assay, and measurement of serum ionized calcium was performed using a Nova 7 Analyzer (Nova Biomedical, Waltham, MA).…”

Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

“…While we can not exclude the possibility that some individuals with NSHPT may be heterozy- Recent studies (24) have suggested that heterozygous individuals with FHH exhibit a mild increase in the set point of their parathyroid glands for calcium (the Ca"+ concentration producing half of the maximal inhibition of parathyroid hormone release). In two cases (25,26) in which the parathyroid tissue from individuals with NSHPT was studied in vitro, there was a much more marked increase in the set point for Ca"+.…”

Neonatal severe hyperparathyroidism: further clinical and molecular delineation

“…We reported on two women from the Nova Scotia kindred who had undergone parathyroidectomy as infants for their NSHPT and went on to have children as young adults [5]. At last contact, two other males, also with the same frameshift mutation [5,20], were said to be healthy into their third decade (Cole DEC: personal communication). Regular follow-up to ensure optimal vitamin D and calcium supplementation and avoid undue vitamin D insufficiency are important considerations in ongoing management of this infant and the family members with FHH.…”