SUN-747 PTH1R Mosaicism In Jansen Metaphyseal Chondrodysplasia

Abstract Disclosure: W. Abbas: None. C.R. Ferreira: None. N. Balatska: None. G. Grigelioniene: None. K. Baltzer Sollander: None. L. Bliss: None. M. Motevalli: None. H. Jüppner: None. A.M. Boyce: None. S. Jha: None. Background: Jansen Metaphyseal Chondrodysplasia (JMC) is an ultra-rare skeletal dysplasia caused by heterozygous variants in PTH1R resulting in constitutive activation of the parathyroid receptor type 1 (PTH1R). Patients present with severe short stature, bowing of the arms and legs, and hypercalcemia in most cases. We describe the first case of JMC caused by PTH1R mosaicism. Clinical Case: A 4-year-old boy presented with painless bilateral swelling above the knee joint. Parents denied history of trauma, mobility, developmental concerns or prior fractures. Physical examination showed no apparent facial abnormalities, no tenderness on palpation of the spine, normal gait with a tendency towards eversion, subtle bulging of bilateral wrists and distal ends of femur. Radiographs confirmed enlargement at the distal end of bilateral femur. Skeletal survey revealed flaring of the metaphyses of long bones. Laboratory assessment showed a slightly elevated serum ionized calcium at 1.30 [1.09-1.29] mmol/L; albumin corrected calcium of 9.7 [8.8-10.8] mg/dL; serum phosphorus of 5.6 [4.1-5.9] mg/dL and serum creatinine of 0.38 [0.31-0.61] mg/dL with a slightly reduced PTH of 14.2 [15.0-65.0] pg/mL. These findings prompted genetic testing for JMC which revealed the presence of a heterozygous pathogenic variant in PTH1R c.668A>G (p.His223Arg) at an allele frequency of 3-13% in DNA from peripheral leukocytes indicating PTH1R mosaicism. The variant was not detected in DNA from peripheral leukocytes from either of the two parents alluding to its de novo origin. Droplet digital PCR (ddPCR) of peripheral leukocyte and buccal DNA from the patient identified the heterozygous variant at an allele frequency of 6.73 % and 6.76%, respectively. However, the variant was not seen in DNA from an available bone biopsy sample. Given the skeletal phenotype, this is likely explained by technical challenges due to the poor DNA quality from the limited amount of available formalin-fixed paraffin-embedded decalcified bone sample. Patient’s 24-hour urinary calcium was 3.9 (< 4 mg/kg/day) and bone turnover markers were increased with osteocalcin at 165.8 [7.3-38.5] ng/mL, and C-telopeptide at 1827 [351-1532] pg/mL. Tubular reabsorption of phosphate was 92.2% with a serum intact FGF23 of 52 [≤52] pg/mL. CT scan of the skull did not identify any expansile lesion in the craniofacial skeleton. Ultrasound of the kidney revealed no nephrocalcinosis. Further evaluation revealed no vision or hearing deficits. Dental evaluation showed one tooth with enamel hypoplasia. Clinical Lesson: Variant PTH1R mosaicism can cause a relatively milder phenotype of JMC and should thus be considered in patients with high clinical suspicion for JMC and DNA sequencing data should be carefully reviewed for low frequency PTH1R variants. Acknowledgement: Intramural Research Program of NIDDK/NCATS/NICHD/NCATS and R01 DK113039. Presentation: Sunday, July 13, 2025