Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations

Abstract

Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome is a rare genetic skeletal dysplasia. Its diagnosis can be deceptively similar to childhood-onset genetic skeletal dysplasias and juvenile idiopathic arthritis. We aimed to report the syndrome’s clinical and radiologic features with emphasis on skeletal manifestations. And establish relevant phenotype-genotype correlations. We evaluated two boys, 4-and-7-years-old with MONA syndrome. Both patients had consanguineous parents. We verified the diagnosis by correlating the outcomes of clinical, radiologic and molecular analysis. We specifically evaluated the craniofacial morphology and clinical and radiographic skeletal abnormalities. We contextualized the resultant phenotype-genotype correlations to publications on MONA and its differential diagnosis. Skeletal manifestations were the presenting symptoms and mostly restricted to hands and feet in terms of fixed extension deformity of the metacarpophalangeal and flexion deformity of the interphalangeal joints with extension deformity of big toes. There were arthritic symptoms in the older patient especially of the wrists and minute pathologic fractures. The skeletal radiographs showed osteopenia/dysplastic changes of hands and feet. Both patients had variants in the matrix metalloproteinase2 gene which conformed to phenotype of previously reported literature in one patient while the other had a novel variant which conformed to MONA phenotype. Craniofacial abnormalities were present. However, minimal extra-skeletal manifestations. Overall, there is an emerging distinctive skeletal pattern of involvement in terms of both clinical and radiographic features. This includes age of onset and location of presenting skeletal manifestations, chronological order of joint affection, longitudinal disease progression, specifics of skeletal radiographic pathology and craniofacial features. Nevertheless, physicians are cautioned against differential diagnosis of similar genetic skeletal dysplasias and juvenile idiopathic arthritis.

Multicentric Osteolysis Nodulosis Arthropathy Syndrome Simulating Juvenile Idiopathic Arthritis in an Adult Female: A Case Report and a Literature Review

“…2000 [5] and it seems that the intelligence level generally remains normal in the MMP2 gene mutation. The link between MMP2 gene mutation and cardiac pathology was first described by Tuysuz et al [16] in a Turkish family and literature reported many cases of congenital cardiac anomalies linked to MMP2 gene mutation from Middle Eastern regions including current cases [16][17][18]. Bone resorption, osteopenia, osteolysis, and hand deformities were the characteristic findings in all cases and very few cases showed fracture incidence [8,17].…”

“…The treatment of osteopenia and osteoporosis using bisphosphonates increases bone mineral density and decreases pain but has no impact on osteolysis [5,17,19,20]. Overall, no improvement was observed in osteolysis, skeletal deformities, or delay in disease progression after using immunosuppressive treatment including methotrexate, etanercept, intravenous methylprednisolone, and oral corticosteroids [8,16,18,19].…”

Association of MMP-2 and MMP-9 Polymorphisms with Diabetes and Pathogenesis of Diabetic Complications

“…Protein expression shows a pattern in cytoplasmic expression in trophoblastic and decidual cells of placenta, macrophages and alveolar cells of the respiratory epithelium, urothelial cells of the urinary bladder, ciliated cells of the Florian tube, stromal cells of the endometrium as well as the endothelial and stromal cells in most tissues [19]. The disorder in which the coding gene is directly involved is multicentric osteolysis-nodulosis-arthropathy (MONA) disorders [20,21]. The functional polymorphism of this gene is also suspected to influence the risk of the metabolic syndrome.…”

Clinical, radiographic and molecular characterization of two unrelated families with multicentric osteolysis, nodulosis, and arthropathy

“…Another related disorder, Winchester syndrome (MIM# 277,950) is caused by variants of MMP14 but some of the patients have variants in MMP2 [5,6]. MONA is a rare genetic disease with only 52 patients and 23 variants reported in the literature for the osteolysis syndrome [1][2][3][4][7][8][9][10][11][12][13][14][15][16][17][18][19]. No epidemiological statistics of MONA have been reported.…”