Expanding the molecular and phenotypic spectrum of MMP2-related multicentric osteolysis, nodulosis, and arthropathy: two brothers with marked intrafamilial variability and a review of the literature.
Reza Hajati, Sharareh Kamfar, Abolfazl Movafagh et al.
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Case in brief
Two brothers, aged 14 and 8 years, from a consanguineous family had molecularly confirmed MMP2-related multicentric osteolysis, nodulosis, and arthropathy (MONA), with the same homozygous c.1648 C > T (p.Arg550Ter) variant. Both had osteopenia, progressive distal osteolysis, hand and foot deformities, and joint contractures, but severity differed. The elder had extensive plantar nodules, severe foot and ankle deformity, and impaired ambulation; the younger had optic nerve involvement with raised intracranial pressure. Both had neonatal hepatobiliary abnormalities, with biliary atresia confirmed in the elder. Zoledronic acid was associated with improved bone mineral density, while established deformities persisted.
What made this case unusual
Despite sharing the same homozygous MMP2 variant, the brothers had markedly different skeletal severity and extraskeletal findings, including optic nerve involvement with raised intracranial pressure in the younger brother and confirmed biliary atresia in the elder.
Diagnostic / clinical pearl
MONA can involve systems beyond the skeleton, and substantial phenotypic differences may occur between siblings with the same MMP2 variant. Variant type or protein-domain location alone did not predict extraskeletal manifestations in the reviewed cases.
Why it matters
The relationship of the hepatobiliary, endocrine, and ophthalmologic findings to MMP2 deficiency remains uncertain; larger longitudinal, molecularly confirmed cohorts are needed to clarify genotype–phenotype correlations.