Progression of mineral ion abnormalities in patients with jansen metaphyseal chondrodysplasia

Hiroshi Saito, Hiroshi Noda, Philippe Gatault, Detlef Bockenhauer, Kah Yin Loke, Olaf Hiort, Caroline Silve, Erin Sharwood, Regina Matsunaga Martin, Michael J. Dillon, David Gillis, Mark Harris, Sudhaker D. Rao, Richard M. Pauli, Thomas J. Gardella, Harald Jüppner*

*Corresponding author for this work
5 Citations (Scopus)


Context Five different activating PTH/PTH-related peptide (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 24 patients with JMC 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 and 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) were 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 patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and 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 [L 11,dW 12,W 23,Y 36 ]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 toward therapy.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
Pages (from-to)2660-2669
Number of pages10
Publication statusPublished - 01.07.2018

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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