{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:19Z","timestamp":1788998419347,"version":"build-2803163510"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>VHL germline mutations are classically associated with von Hippel-Lindau syndrome, but their role in hematological malignancies remains underexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed a pedigree with acute myeloid leukemia (AML) proband and two offspring: primary immune thrombocytopenia (ITP) and acute T-cell lymphoblastic leukemia (T-ALL) via targeted sequencing and familial validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetic analysis revealed: (1) the proband carried concurrent VHL, ASXL3, and CCR7 germline mutations along with acquired BCOR\/NF1 variants; (2) the ITP-affected offspring inherited ASXL3\/CCR7 mutations only; and (3) the T-ALL case exhibited solely the VHL mutation. Acquired mutations (e.g., BCOR\/NF1) in the proband suggest a \u2018two-hit\u2019 model for leukemogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study identifies VHL as the principal predisposing mutation in a familial hematologic malignancy pedigree presenting with heterogeneous phenotypes, where ASXL3\/CCR7 variants may serve as phenotypic modifiers. These findings advocate for genotype-driven surveillance strategies in familial hematological disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1630715","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T08:05:26Z","timestamp":1753776326000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: A familial hematological pedigree reveals VHL germline mutation as a principal predisposition factor with additional mutations modulating phenotypic 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