Acute myeloid leukemia with germline NPM1 mutation in twin sisters: First case report

Mutations in the Nucleophosmin 1 (NPM1) gene define a well-established subtype of acute myeloid leukemia (AML) with distinct clinical and molecular characteristics. While somatic NPM1 mutations are frequent, germline involvement remains exceedingly rare and largely unreported in the context of AML.[6] This report details the case of genetically identical twin sisters who were both diagnosed with AML harboring NPM1 mutations. Twin A presented at age 4 with fever and weakness, while Twin B presented 3 years later at age 7 with fever and gastrointestinal bleeding. Both had high leukocyte counts, thrombocytopenia, and >95% marrow blast involvement on aspirate smears. Flow cytometry confirmed myeloid lineage blasts, and multiplex PCR identified NPM1 mutations in both siblings. Conventional cytogenetics showed normal female karyotype (46,XX). Both had pulmonary infiltrates suggestive of fungal infection at baseline. Twin B had additional complications including central nervous system involvement and cardiac vegetations. Both were treated with the berlin frankfurt munster (BFM) 2004 protocol. Twin A remains in remission after 3.5 years of follow-up. Twin B is currently on maintenance with negative measurable residual disease by flow cytometry. This is the first reported case of germline NPM1-mutated AML in twin sisters, suggesting a potential inherited predisposition.[6,9,10] It emphasizes the importance of molecular diagnostics and consideration of germline mutations in familial pediatric AML.