A Familial Case of Multicentric Carpotarsal Osteolysis Syndrome and Treatment Outcome

Abstract

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder caused by heterozygous mutations in the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B). This is an autosomal dominant condition with a high frequency of sporadic cases. MCTO is characterized by osteolysis of the carpal, metacarpal, and tarsal bones beginning in early childhood with musculoskeletal rheumatologic symptoms such as pain and disability. Renal involvement can be seen in more than half of the patients; from ages 16 months to 42 years and manifests from proteinuria to end-stage renal failure requiring renal transplantation. The association of MAFB gene mutations with this genetic condition has aided in understanding the pathophysiology of the disease. We report here a 7-year-old Caucasian boy and his 33-year-old mother diagnosed with MCTO, with the boy having concomitant juvenile idiopathic arthritis. He was initially diagnosed with arthritis at age 5 years based on bilateral wrist synovial swelling, morning stiffness, and weakness with family history of his mother being diagnosed with erosive psoriatic arthritis leading to limb deformities. Initial therapy for the boy included methotrexate and infliximab with moderate response. Later, during the course of his disease, he underwent a genetic evaluation at age 7 years for history of learning disabilities and dysmorphic features. Maternal evaluation and radiographic examination led to a clinical diagnosis of MCTO in the mother, and subsequent testing for MAFB gene in the son revealed a mutation at c.206C > T (p.Ser69Leu), the most commonly reported genetic change in MCTO. Nevertheless, further imaging still confirmed ongoing arthritis, and therapy was adjusted based on its progression including abatacept, tocilizumab, and pamidronate. Our report highlights the possibility of concomitant inflammatory arthropathy in MCTO.

Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab

“…Therefore, MafB acts as a key modulator of RANKL-induced osteoclastogenesis by means of its ability to attenuate the expression of NFATc1 and OSCAR ( Kim et al, 2007 ). In turn, reduced MafB expression results in increased RANKL levels, excessive activation of osteoclasts and bone resorption ( Upadia et al, 2018 ).…”

“…Some cases of MCTO have been treated with a TNF-α monoclonal antibody, methotrexate, salicylates, and non-steroidal anti-inflammatory agents. None of these agents have proven to be effective ( Upadia et al, 2018 ; Klein et al, 2018 ).…”

“…MCTO is caused by an autosomal dominant mutation in the MafB gene encoding the MafB protein. It is an autosomal dominant condition with high frequency of sporadic cases ( Upadia et al, 2018 ). The MafB protein negatively regulates the receptor activator of nuclear factor-кB ligand (RANKL).…”

“…The MafB protein negatively regulates the receptor activator of nuclear factor-кB ligand (RANKL). Reduced MafB expression consequently results in excessive RANKL stimulation of osteoclasts and increased bone resorption ( Upadia et al, 2018 ). It is unclear why mutations in MafB predominantly impact carpal and tarsal bones.…”

Zebrafish mafbb Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients

“…Currently, there are no effective treatments for MCTO patients [ 48 ]. Bisphosphonates may be effective by interrupting the osteoclast activity and formation [ 49 ].…”