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An autosomal dominant disease associated with osteolysis, amyotrophy, and nephropathy.
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Multicentric Osteolysis and Nephropathy; Multicentric Carpotarsal Osteolysis Syndrome with Nephropathy; Hereditary Osteolysis of Carpal Bones with Nephropathy; Idiopathic Carpotarsal Osteolysis and Nephropathy; Idiopathic Multicentric Osteolysis Type 3.
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Autosomal dominant inheritance has been described, but many cases seem to be de novo mutations. The defect seems to be caused by mutations in the v-MAF (musculoaponeurotic fibrosarcoma oncogene family, protein B; [MAFB]) gene, which has been mapped to chromosome 20q12. MAFB is expressed in myeloid cells in the bone marrow and is essential for normal hematopoiesis, but also plays a critical role in the differentiation and activation of osteoclasts as well as in renal development (glomerular and podocyte differentiation). Osteoclasts derive from hematopoietic stem cells of the myeloblast-monocyte-macrophage lineage.
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Based on the clinical and radiological findings.
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The diagnosis can often be made within the first year of life, although the clinical appearance is variable. Onset of the osseous changes initially manifest as arthritis-like episodes with painful swelling and rubor, primarily affecting the previously normal ankles (tarsal bones) and wrists (carpal bones). Radiological examinations show osteolytic changes resulting in progressive and severe deformities and later complete osteolysis with disappearance of the carpal and tarsal bones that lead to variable degrees of disability secondary to limited joint mobility. Additional skeletal features may include narrowing of the diaphysis of all tubular bones, erosion of the proximal ends of radii and ulnae with radioulnar synostosis, resorption of the distal radial and ulnar epiphyses, carpal deviation of the hands, radial deviation of the fingers, metacarpal anomalies, camptodactyly, fused sacroiliac joints, irregular femoral condyles, reduced joint spaces of the knees, and pes cavus. The destructive osseous process is usually progressive until puberty when it often subsides spontaneously. The gait is often wide based and unsteady, which is most likely due to pain and joint deformities. Biopsies of bone synovium and cartilage show increased osteoclastic activity, no signs of inflammation, and fibrofatty bone metaplasia during the course of the disease. Mild facial dysmorphism with triangular face, exophthalmos, corneal clouding, slim nose, maxillary hypoplasia, micro- and retrognathia with limited range of motion of the jaw, and prominent chin have been described as typical for these patients. The characteristic skeletal changes often precede renal failure by 5 to 15 years (although the interval may be much shorter). The cause of renal failure has yet to be determined; however, immunofluorescence studies on kidney biopsy specimens revealed focal granular deposits of immunoglobulin M along the glomerular capillary wall. Electron microscopy showed fusion of pseudopods of the visceral epithelial cells with discrete abnormalities (thinning and thickening of the lamina densa) of the glomerular basement membrane. ...