Predisposition to ALL and Solid Tumors Rather Than Bone Marrow Failure in <i>FANCM</i>-Associated Fanconi Anemia.

Abstract

Fanconi anemia (FA) is a genetic disorder typically characterized by progressive bone marrow failure (BMF) during childhood, leading to diagnosis at that stage. In adolescence or adulthood, patients are predisposed to myelodysplastic syndrome (MDS), acute myeloid leukemia, and solid tumors. However, some individuals present atypically, delaying FA recognition and resulting in life-threatening complications. This study describes the distinctive phenotype associated with biallelic <i>FANCM</i> pathogenic variants. Clinical and biologic data were analyzed from eight patients carrying biallelic germline <i>FANCM</i> pathogenic variants within a French cohort of 411 patients with FA (2.0%). Clinical outcomes were compared with those of patients with FA carrying non-<i>FANCM</i> variants. None of the eight <i>FANCM</i> patients developed BMF, contrasting with a 93.5% cumulative incidence among other FA genotypes (<i>P</i> < .0001). This absence of marrow failure resulted in delayed FA diagnosis (median age 23.5 <i>v</i> 6.8 years, <i>P</i> < .01). Instead, six patients initially presented with malignancy and exhibited marked toxicity to conventional cancer therapies, prompting FA testing. Malignancies included four oral cancers and, unexpectedly, two ALL: a ZNF384-rearranged B-cell precursor ALL and a BCL11B::HOXA13 early T-cell precursor ALL. No ALL cases occurred among the 403 non-<i>FANCM</i> patients with FA (<i>P</i> < .0001). The treatment courses of the two <i>FANCM</i>-related ALL cases are reported. Biallelic <i>FANCM</i> variants define a distinct FA subtype lacking early BMF, leading to missed diagnoses and severe toxicity upon malignancy. Recognizing this presentation is crucial for timely FA detection and for implementing adapted therapeutic and follow-up strategies.