Clinical and genetic characteristics of multicentric carpotarsal osteolysis syndrome

Abstract

BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) syndrome is a rare autosomal dominant disease of skeletal dysplasias caused by heterozygous missense variants in MAFB. Clinical manifestations of the disease are characterized by pain, swelling, and hand and foot deformities as a result of progressive osteolysis of the carpal and tarsal bones. Kidney insufficiency also developed in some patients. CLINICAL CASES: Three Russian patients aged 2–39 years with MCTO syndrome caused by pathogenic variants c.176CT, c.184AG, c.203CT in MAFB are presented. All cases were sporadic. Two of our patients with MCTO were typically observed for several years with a diagnosis of juvenile idiopathic arthritis. All patients underwent phenotypic analysis using standard methods, radiography of the upper and lower extremities, ultrasonography of the kidneys, blood and urine tests to assess renal function, and molecular tests to clarify the diagnosis. Molecular genetic analysis included direct automatic Sanger sequencing of MAFB (NM_005461.5). DISCUSSION: The clinical manifestations of the disease in the patients included deformities and shortening of the hands and feet and typical signs of osteolysis of the metacarpal and metatarsal bones on radiographs. One of the examined patients had proteinuria in early childhood. Considering the rarity of MCTO syndrome, a description of the clinical and radiological characteristics of newly identified cases of the disease will help optimize its diagnosis and multidisciplinary observation of patients and improve the quality of medical and genetic counseling for affected families. CONCLUSIONS: The first clinical manifestations of MCTO syndrome are characterized by significant similarities with those of juvenile arthritis. For their differential diagnosis, a thorough radiographic analysis of the hands and feet for osteolysis is necessary. Early diagnosis of MCTO syndrome is essential because in recent years intensive research aimed at developing therapy for diseases caused by dysfunction of the RANK/RANKL signaling pathway, in which the protein product of MAFB functions.