Regulation of calcium metabolism in pseudohypoparathyroidism type 1b. From genotype to physiopathology

Abstract

ObjectivePseudohypoparathyroidism type 1b (PHP1b) results from methylation defects in the maternal GNAS locus. It is implied that the observed hypocalcemia results from impairment of renal vitamin D 1α hydroxylase. This study was undertaken to clarify: (1) How serum concentrations of calcium, phosphate, PTH and 1,25 dihydroxy vitamin D (1,25OH2D) relate to each other in patients with PHP1b; (2) how a mathematical model of calcium metabolism could reproduce the observed findings. PatientsThe study included 139 untreated patients, retrieved from the literature, with simultaneous measurements of Ca, P and PTH of whom 25 had measurements of 1,25OH2D. ResultsMean values and standard errors of the mean (SEM) were: PTH=43pM (3.66); P=2.16mM (0.056); Ca=1.69mM (0.038); 1,25OH2D=84pM (10.9). Phosphate correlated negatively with calcium (R=−0.590; p<0.001) and with age (R=−0.623; p<0.001). No other correlations were observed. The mathematical model simulated closely the biochemical pattern of PHP1b when the clearance of phosphate was reduced to 20%, the clearance of calcium was doubled and the response of 1α hydroxylase was reduced to 30%. Conclusions(1) In PHP1b the concentrations of 1,25OH2D are mostly normal. Therefore, they cannot explain the observed hypocalcemia; (2) hypocalcemia can only be explained by increased fractional excretion of calcium resulting from GNAS haplo-insufficiency at the level of the distal tubule; (3) the use of mathematical models to simulate complex metabolic systems allows the extraction, from clinical data, of insights onto physiopathology that are not accessible to intuition alone.