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Multiple pre- and postreceptor defects in pseudohypoparathyroidism (a multicenter study with twenty four patients)
Abstract:
Three different pathophysiological mechanisms are probably responsible for hereditary pseudohypoparathyroidism: 1) a defect at the prereceptor-level, 2) a defective membrane N-protein accounting for diminished second messenger production, and 3) a defect in the cytosolic response to the hormone. In a cooperative, study 24 patients (mean age, 13 yr; range, 3-23 yr, 8 girls, 16 boys) receiving vitamin D metabolites (5,000-80,000 U/day) were examined and compared to a control group of 36 normal children. Immunoreactive N-terminal PTH (N-PTH), mid-C-regional PTH (mid-C-PTH), intact PTH and bio-PTH, vitamin D metabolites, and serum calcium and phosphate, alkaline phosphatase activity, and the N-protein activity of erythrocyte membranes were measured in each subject. By clinical and biochemical criteria three groups were differentiated. Eight patients had the completely expressed features of Albright's Hereditary Osteodystrophy (AHO+), including brachydactyly and/or sc calcifications, and increased N-PTH, mid-C-PTH, and alkaline phosphatase activity. Bio-PTH, intact PTH, and N-protein were normal. Nine additional patients with complete (AHO+) had elevated levels of bio-PTH, N-PTH, and mid-C PTH, normal hydroxylation of vitamin D, but decreased N-protein activity. Seven patients with pseudohypoparathyroidism had no features of AHO (AHO-), no increase of urinary cAMP excretion after exogenous PTH, normal PTH peptide levels and N-protein activity, but elevated 25-hydroxyvitamin D and decreased 1,25-dihydroxyvitamin D concentrations. In conclusion, we identified three subpopulations of PsHP: group a had a dissociation of N-PTH and bio-PTH suggesting a defective N-PTH causing renal resistance, whereas their bones respond to PTH. Group b had defective N-protein causing generalized PTH resistance. Group c was characterized by high 25-hydroxyvitamin D and relatively low 1,25-dihydroxyvitamin D levels, thus providing evidence for a defect in the cytosolic interaction of the two different second messengers for PTH, cAMP, and calcium.
Insights
Hereditary pseudohypoparathyroidism involves three distinct mechanisms. This study identified three patient subpopulations with varying parathyroid hormone (PTH) resistance and vitamin D metabolite levels, aiding in diagnosis.
Area of Science:
- Endocrinology
- Genetics
- Biochemistry
Background:
- Hereditary pseudohypoparathyroidism (PsHP) is a rare genetic disorder characterized by resistance to parathyroid hormone (PTH).
- Pathophysiological mechanisms are complex, involving prereceptor defects, impaired G-protein signaling, or cytosolic response abnormalities.
- Understanding these mechanisms is crucial for accurate diagnosis and management.
Purpose of the Study:
- To differentiate pathophysiological mechanisms in hereditary pseudohypoparathyroidism.
- To identify distinct subpopulations of PsHP patients based on clinical and biochemical markers.
- To investigate the roles of PTH metabolites, vitamin D, and N-protein activity in PsHP.
Main Methods:
- Studied 24 patients with PsHP and 36 healthy children.
- Measured serum levels of various PTH fragments (N-PTH, mid-C-PTH, intact PTH, bio-PTH), vitamin D metabolites (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D), calcium, phosphate, and alkaline phosphatase.
- Assessed N-protein activity in erythrocyte membranes and urinary cAMP excretion after PTH administration.
Main Results:
- Identified three patient groups: AHO+ with elevated N-PTH/mid-C-PTH, AHO+ with elevated bio-PTH/N-PTH/mid-C-PTH and decreased N-protein activity, and AHO- with normal PTH/N-protein but altered vitamin D metabolite levels.
- Group a showed dissociation of N-PTH and bio-PTH, suggesting renal PTH resistance.
- Group b exhibited generalized PTH resistance due to defective N-protein.
- Group c displayed high 25-hydroxyvitamin D and low 1,25-dihydroxyvitamin D, indicating cytosolic interaction defects.
Conclusions:
- Three distinct pathophysiological subtypes of PsHP were identified.
- Subtype 1 (Group a) involves defective N-PTH leading to renal resistance.
- Subtype 2 (Group b) is characterized by defective N-protein causing generalized PTH resistance.
- Subtype 3 (Group c) suggests a cytosolic defect in second messenger interaction, linked to vitamin D metabolism.