Hereditary Predisposition to Acute Myeloid Leukemia: A Novel Germline CEBPA Mutation in a Multigenerational Family

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven by the accumulation of genetic alterations in hematopoietic progenitor cells. CEBPA variants have been linked to familial AML, although multigenerational cases have been infrequently reported. We describe the case of a 6-year-old boy referred for hematologic abnormalities, with a history of idiopathic thrombocytopenic purpura at age 3. His family history revealed 11 cases of AML in four maternal generations, suggesting autosomal dominant inheritance. Diagnostic evaluation revealed AML with 40% bone marrow blasts, a normal karyotype, and a negative multiplex RT-PCR panel for 28 common chromosomal translocations. Next-generation sequencing (NGS) identified a novel heterozygous pathogenic variant in the CEBPA gene (c.273_309delinsGGCCAGGGTCT; p.Lys92Alafs∗7), which was predicted to generate a truncated protein. Given the patient's medical history, genetic screening was performed on the patient's first-degree relatives. Genetic testing subsequently identified the same variant in the patient's mother, supporting its germline origin, while his sister showed no alterations in the CEBPA gene sequence. The presence of the variant in the patient´s mother, who is asymptomatic, is consistent with autosomal dominant transmission and age-dependent or incomplete penetrance. In this case, the patient carried a heterozygous variant, achieved complete remission after chemotherapy, and remains under surveillance. We present a pathogenic germline deletion-insertion variant in the CEBPA gene, not previously described in the literature, associated with hereditary predisposition to AML in a four-generation family, highlighting the variable expressivity characteristic of this syndrome and the relevance of considering a hereditary predisposition disorder in pediatric patients with AML.