MTHFR, Pneumonia, and Thrombosis in Children: A Gene-Infection Interaction

Severe pediatric pneumonia associated with thromboembolism is notable, yet its pathogenic mechanism remains elusive, suggesting a potential nonnegligible role of genetic susceptibility. Five previously healthy children were admitted with severe pneumonia, primarily caused by Mycoplasma pneumoniae and other pathogens. All patients exhibited markedly elevated inflammatory markers and D-dimer levels. Crucially, whole-exome sequencing identified the methylenetetrahydrofolate reductase (MTHFR) c.665C>T mutation in all patients (2 homozygous, 3 heterozygous). Computed tomographic angiography confirmed pulmonary embolism in 4 cases, 2 of which had intracardiac thrombi, and also revealed 1 case of splenic infarction. A universal finding was the presence of transient lupus anticoagulant and other autoantibodies, suggesting an infection-induced prothrombotic autoimmune state. All patients were successfully treated with a combination of antibiotics, systemic corticosteroids, and anticoagulation therapy. Follow-up imaging demonstrated complete or significant resolution of thrombotic lesions, although some immunological abnormalities persisted. This case series strongly suggests that the MTHFR c.665C>T mutation may represent a critical genetic predisposition that, when compounded by the severe inflammatory and autoimmune response triggered by pneumonia, can lead to a potent prothrombotic state and overt thrombosis in children. Early recognition of this potential interplay, including prompt genetic and thrombophilia screening, and immediate initiation of anticoagulation alongside anti-infective and anti-inflammatory therapy are essential for managing such cases and preventing catastrophic outcomes.