Chromosomal abnormalities play a crucial role in the pathogenesis and progression of myelodysplastic neoplasms (MDS). Mosaic loss of the Y chromosome (mLOY), a common cytogenetic event in elderly men, has been associated with an increased risk of age-related diseases, including cancer. Although frequently observed in the context of clonal hematopoietic disorders, mLOY may coexist with other genetic alterations, suggesting a more complex clonal evolution that remains poorly understood. In this context, we report an atypical case of clonal evolution in a patient with MDS, in which cytogenetic analysis revealed two distinct cell populations: one with Y chromosome nullisomy (mLOY) and another with trisomy of chromosome 14 — a rare aneuploidy typically considered lethal.

A 91-year-old male returned for follow-up reporting fatigue and general malaise. Hematological profile showed: hemoglobin 10.5 g/dL, leukocytes 6,280/ µL, platelets 158,000/µL, normocytic normochromic anemia, and protein electrophoresis with a monoclonal spike. In 2025, a new bone marrow aspirate revealed dyserythropoiesis, mild dysplasia, mild eosinophilia, and atypical myeloblasts. Classical cytogenetic analysis showed 45,X,-Y[3]/46,X,-Y,+14[9]/46,XY[8]. Molecular cytogenetic analysis by fluorescence in situ hybridization (FISH) revealed nuc ish(BCL2x2,IGHx3)[120/200], indicating the presence of three signals for the IGH gene (located on chromosome 14, region 14q32.33). Based on these findings, the patient was diagnosed with MDS with low blasts (MDS-LB).

Classical cytogenetics remains a fundamental tool for identifying chromosomal abnormalities in myelodysplastic neoplasms; however, in complex cases of clonal evolution, integration with molecular cytogenetic techniques such as FISH becomes essential for the accurate confirmation and characterization of the detected alterations. In this case, karyotypic analysis revealed two distinct cell populations: one with loss of the Y chromosome (nullisomy Y) and another with an additional chromosome of suggestive but uncertain morphology, possibly indicating a trisomy. Given the possibility of a marker chromosome, the use of FISH with a specific probe for the IGH gene, located on the long arm of chromosome 14, allowed confirmation of the origin of the extra chromosomal material by identifying a third IGH signal, thus confirming trisomy 14. This finding supports the hypothesis of clonal evolution, in which the mLOY-bearing clone later acquires chromosome 14 trisomy. In this context, FISH was crucial to rule out the presence of a marker chromosome from another origin and reinforces its value as a diagnostic complement, especially in cases where chromosome morphology prevents definitive identification by conventional banding. Therefore, the integration of classical and molecular cytogenetics offers greater accuracy in interpreting clonal-genetic alterations, with direct implications for prognosis assessment and clinical management of patients.