Abstract: SA-PO697
Renal Complication and Mineral Ion Abnormalities in Patients with Jansen Metaphyseal Chondrodysplasia
Session Information
- Bone and Mineral Metabolism: Clinical - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 402 Bone and Mineral Metabolism: Clinical
Authors
- Saito, Hiroshi, Massachusetts General Hospital, Boston, Massachusetts, United States
- Jüppner, Harald, Massachusetts General Hospital, Boston, Massachusetts, United States
Background
Jansen metaphyseal chondrodysplasia (JMC) is a rare disease that is caused by heterozygous, activating mutations in the PTH/PTHrP receptor (PTHR1). Expression of PTHR1 mutants in growth plate chondrocyte impairs their maturation leading to marked skeletal abnormalities. Because the PTHR1 is also expressed in kidney and bone, JMC patients can develop PTH-independent hypercalcemia, hypophosphatemia, and high bone turnover, and thus nephrocalcinosis and impaired renal function. Long-term outcome of multiple JMC patients was recently reported (Saito et al., JCEM, 2018). We now emphasize the renal abnormalities associated with JMC.
Methods
Clinical and laboratory findings in 24 patients with JMC due to five different PTHR1 mutations (H223R, T410P, T410R, I458R, and I458K).
Results
During the first 2 weeks of life, calcium levels were normal in most patients. During childhood hypercalcemia was severe (11.8±1.4 mg/dL), but improved by adulthood (10.0±1.0 mg/dl). Phosphate and PTH levels were at the lower end of normal ranges. Urinary Ca/Cr (mg/mg) were consistently elevated (children, 0.8±0.4; adults, 0.3±0.2; normal:<0.2). Growth was severely impaired resulting in adult heights well below the 3rd percentile; furthermore, scoliosis and other skeletal deformities were noted. Most young JMC patients had nephrocalcinosis, but normal renal function. Two middle-aged patients revealed continuously worsening renal function, probably secondary to stag horn renal calculi, recurrent UTIs, and urinary tract obstructions.
Conclusion
Activating PTHR1 mutations are associated with persistently increased urinary calcium excretion, which is caused by the PTH-independent hypercalcemia. Hypercalciuria contributes early in life to nephrocalcinosis, which leads in adults to a decline in renal function. Treatment with bisphosphonates to reduce bone resorption may limit calcium excretion to slow the progression of chronic kidney disease. Although an inverse PTH agonist, namely [L11,dW12,W23,Y36]PTHrP(7–36), reduced basal cAMP signaling of the mutant PTHR1s in vitro, it remains to be determined whether such peptides have therapeutic potential.
Funding
- Other NIH Support