A clinical and molecular characterization of a Pakistani family with multicentric osteolysis, nodulosis and arthropathy (MONA) syndrome.

Multicentric osteolysis nodulosis and arthropathy (MONA) is a rare skeletal dysplasia characterized primarily by progressive osteolysis, particularly affecting the carpal and tarsal bones, accompanied by osteoporosis. In addition, it features subcutaneous nodules on the palms and soles, along with the progressive onset of arthropathy, encompassing joint contractures, pain, swelling and stiffness. It is caused by a deficiency of the Matrix Metalloproteinase-2 (MMP2). In the current study we present a comprehensive clinical, radiological, genetic and in silico analysis of MONA in a consanguineous Pakistani family. Clinical and radiological examinations of the three severely affected siblings demonstrated a progressive MONA syndrome with phenotypic variability. The patients presented unusual facial appearance, thickened skin, severe short stature, short hands and feet. Radiographs revealed extensive bone deformities affecting upper and lower arms, legs, vertebrae and hip. Genetic analysis revealed a homozygous missense variant [c.539 A > T p.(Asp180Val)] in the MMP2 gene. In silico findings suggested a mutant MMP2 protein with a decreased stability and an altered pattern of interactions. Our findings add to the existing literature on the skeletal phenotype of MONA syndrome, including the specific clinical and radiological patterns observed. Moreover, the study will aid in genetic counseling and accurate diagnosis of families affected by the same disorder within the Pakistani population.