MON-LB72 Multicentric Carpotarsal Osteolysis Syndrome (MCTO) Has a Generalized High Turnover Bone Phenotype, High S RANKL and Responds to Denosumab

Background:MCTO is a rare disorder, caused by mutations in the MABF gene, a negative regulator of RANKL. Manifestations include carpal tarsal osteolysis and subsequent renal failure in some. Pathophysiology is poorly understood, and no effective treatment is available. Clinical case:A 5y old boy presented (2011) with R wrist pain and diffuse swelling. MRI showed pan-carpal synovitis with joint effusion. He did not respond to different anti-inflammatory medications. Plain films showed central loss of the proximal row of carpal bones. His mother was followed as an adolescent with presumed juvenile rheumatoid arthritis. Genetic testing confirmed MAFB gene mutation (c.206C>T,p.Ser69Leu) in both patient and mother.At 7y, skeletal survey showed diffuse osteopenia and mild height loss in T1. DXA (L1-4) Z-score was -0.7. Calcium phosphate metabolism indices were within reference ranges. Bone Specific Alk Pi was modestly increased and C-telopeptide markedly increased.He received Denosumab (0.5-0.75 mg/Kg) 4-monthly for two years and experienced less pain and increased daily activities with improved R wrist function. Osteolysis stabilized and none was noted in the L wrist or ankles. BMD Z-score was -0.2. A year following treatment (2016) he received two more injections of Denosumab following pain and movement restriction of R elbow, R knee and L ankle. In 2019 (13y) he fell and radiology showed, R knee osteopenia, R wrist almost complete destruction of the carpal bones. Neither ankle nor L wrist showed osteolysis. R upper limb musculature was wasted when compared with the left. Shoulder and elbow strength were preserved. BMD Z-score was -1.2. Serum calcium, 25(OH)Vitamin D and PTH were normal. Bone specific alkaline phosphatase and C-Telopeptide were elevated. Serum creatinine was normal, eGFR 150 ml/min/1.73m2, ACR (6.6 [normal< 3.5] mg/mmol)) with no hypercalciuria or nephrocalcinosis. He was normotensive.High resolution peripheral quantitative computerized tomography (HRpQCT) of the L distal radius and distal tibia compared with 7 age-matched healthy males showed reduced total volumetric BMD (186.4;198.2-306.4), normal trabecular volumetric BMD and markedly reduced cortical volumetric BMD (320.4;636.5-792.5). Cortical thickness was below the expected range. HRpQCT measurements of the R wrist and tibia were similar. sRANKL, 6 weeks after Denosumab were markedly increased in both undiluted (35.4 pmol/L) and averaged diluted samples (83.73 pmol/L) when compared with healthy age-matched children (0.21-0.41pmol/L). Conclusions/Clinical Lessons:MCTO (MAFB, mutation c.206C>T,p.Ser69Leu), has a generalized high turnover skeletal phenotype (osteoporosis), likely driven by very high levels of sRANKL. Denosumab is a targeted treatment for the osteoporosis, which may help stabilize the osteolysis.