Abstract Context Five different activating PTH/PTHrP receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia. Objectives Assess the natural history of clinical and laboratory findings in twenty-four JMC patients and characterize the disease-causing mutant receptors in vitro. Patients and Methods The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate. Results Postnatal calcium levels were normal in most patients, but elevated between 0.15-10 years (11.8±1.37 mg/dL) and tended to normalize in adults (10.0±1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) was consistently elevated (children: 0.80±0.40; adults: 0.28±0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most JMC patients had undergone orthopedic surgical procedures, most had nephrocalcinosis, two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L11,dW12,W23,Y36]PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant. Conclusions Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path towards therapy. Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: May 16, 2018
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