**Background:** Multicentric osteolysis, nodulosis, and arthropathy (MONA) is a rare autosomal recessive disorder caused by MMP2 deficiency, characterized by progressive bone loss, joint destruction, and skeletal deformities. Only 52 patients and 23 MMP2 variants have been reported. This study describes clinical, radiographic, and molecular findings in four patients from two unrelated families (Pakistani and Finnish).
**Methods:** Clinical evaluations, radiography, and blood sample collection were performed. DNA was extracted from all available family members. For Family 1 (Pakistani, consanguineous parents), whole-exome sequencing was conducted on both affected siblings using the xGen Exome Research panel v2 and NovaSeq 6000. Variants were filtered based on allele frequency <0.01 in gnomAD and 1000 Genomes, and prioritized by pathogenicity scores (REVEL, SIFT, PolyPhen2, MutationTaster, DANN, SpliceAI). Sanger sequencing confirmed segregation. RNA was extracted from blood for cDNA analysis but MMP2 amplification failed. For Family 2 (Finnish, non-consanguineous), Sanger sequencing of MMP2 was performed on the index patient and affected sister. In silico analyses included Human Splice Finder, Clustal Omega for conservation, and HOPE for structural modeling.
**Key Results:** In Family 1, both patients (male age 33, female age 31) had onset at age 16 years with progressive hand/foot deformities, knee immobility, and wheelchair dependence. Radiographs showed progressive osteolysis of carpal/tarsal bones, pencil-in-cup deformities, and joint destruction. A novel homozygous MMP2 splice donor variant c.1336+2T>G was identified, segregating with disease. In silico tools predicted mis-splicing leading to a premature stop codon. The variant had a gnomAD frequency of 0.000016 with no homozygotes. In Family 2, the index male (age 36) had onset at age 2 years with wrist swelling, osteoporosis, and progressive osteolysis; height −7 SDS. His sister (age 32) had onset at age 4 years with finger contractures, subcutaneous nodules, and corneal opacities; height −2.0 SDS. Both were homozygous for MMP2 missense variant c.1188C>A, p.(Ser396Arg). This variant had a Finnish-specific allele frequency of 0.0017 (gnomAD) and was predicted damaging by multiple tools. HOPE analysis indicated the mutation disrupts the collagen-binding domain. The male patient had a lumbar spine BMD Z-score of −6.0 at age 17, improving to −1.5 at age 36 after bisphosphonate therapy.
**Clinical Implications:** This study expands the MMP2 mutational spectrum and demonstrates that MONA can present with onset in late adolescence (age 16 in Family 1), later than previously reported (birth to 11 years). Significant intrafamilial variability was observed, including differences in height, subcutaneous nodules, and ophthalmologic findings. The p.Ser396Arg variant may be a founder mutation in Finland. Genetic testing is crucial for diagnosis, as anti-rheumatic treatments were ineffective. Bisphosphonates may improve BMD but do not halt osteolysis. The findings underscore the need for long-term multidisciplinary management.