A novel variant in MAFB in a patient with hereditary multicentric carpo-tarsal osteolysis

Multicentric carpo-tarsal osteolysis (MCTO) is a rare, progressive skeletal disorder that can be chall enging to diagnose due to its very low prevalence, with fewer than 60 genetically confirmed cases documented in the last decade. The disease has an autosomal dominant pattern of inheritance, although most cases arise sporadically. It occurs due to pathogenic variants in the MAFB gene that affect RANKL-mediated osteoclast differentiation, causing excessive bone remodeling. We present a patient with clinical skeletal features of MCTO who was found to have a novel missense variant in the MAFB gene, in a region where other pathogenic mutations have been described. Cases of MCTO have been frequently associated with renal dysfunction; however, significant renal disease was not notable in our patient or in affected relatives. Lay summary Rare skeletal disorders lend insights into the pathogenesis of bone disease, and study of their phenotype allows an appreciation of the spectrum of the disorder. One such disease is multicentric carpo-tarsal osteolysis (MCTO), which is a progressive skeletal disorder causing erosion and loss of bones of the hands and feet, and which has also been associated with kidney disease. It is inherited in an autosomal dominant manner, i.e., with a 50% chance of inheritance; however, cases mostly occur due to sporadic mutations. It has been found to occur due to pathogenic variants in the MAFB gene that is responsible for affecting signaling of RANKL, a protein that encourages osteoclasts to mature and cause bone loss. We present a patient with clinical features of MCTO and a strong family history of the disorder, who was found to have a novel variant in the MAFB gene.