The very rare association between T-cell acute lymphoblastic leukemia and down syndrome: a case report and review of the literature

Background – Children with Down syndrome (DS) show a higher incidence of acute lymphoblastic leukemia (ALL) compared to general population. They are almost entirely affected by B-cell precursor ALL, linked to the constitutional chromosome 21 trisomy and associated with recurrent mutational patterns. The occurrence of T-cell ALL (T-ALL) is extremely rare in DS patients, with only few reports described. This entity remains poorly characterized either genetically and clinically, and there are no standardized guidelines for the treatment of these rare and fragile patients. Here we describe the case of a child with DS and T-ALL and provide comprehensive genetic characterization of his disease. Case report – A previously well 7-year-old boy with DS was diagnosed with T-ALL presenting with leukocytosis, mediastinal mass and central nervous system involvement (CNS2). Genetic studies showed a complex karyotype with the translocation t(1;14)(p32;q11) and deletion of chromosome 9p. RNA sequencing was negative for fusion transcript. Next-generation sequencing analysis for somatic mutations on DNA material showed pathogenic variants in NOTCH1 and FBXW7. Chemotherapy was started according to AIEOP-BFM ALL 2017 study. During induction phase, the patient suffered from multiple severe complications, requiring significant treatment modifications and an anthracycline-free induction. However, the patient presented favorable response achieving minimal residual disease negativity. He is currently on maintenance therapy 15 months from the diagnosis. Conclusion – This case provides the first detailed genetic characterization of T-ALL in a child with DS. The findings of typical T-ALL somatic mutations and genetic alterations suggest a sporadic leukemogenesis origin, distinct from the specific pathway associated with B-cell precursor ALL. We confirm the rarity of this entity and the extreme susceptibility to treatment complications. An improved knowledge and characterization of DS T-ALL might be helpful to inform clinicians about treatment decision making for this very rare disease.