Acquired RhD positivity loss mediated by promoter hypermethylation is associated with adverse outcome in Myelodysplastic Syndrome: a case report and literature review

Background The RhD antigen is a critical immunogenic protein on red blood cells. Acquired loss of RhD expression in individuals with a previous positive phenotype is a rare event, most often reported in hematological malignancies. Case presentation A 58-year-old woman with intermediate-risk myelodysplastic syndrome (MDS) was admitted with fever. Routine blood typing revealed a discrepant RhD-negative result, contradicting her documented positive status from three months prior. This was confirmed by a reference serological method. Results Genetic analysis identified a heterozygous RHD genotype, comprising one allele with a complete deletion and the other carrying a weak D allele ( RHD*01W.33 ). Quantitative methylation analysis demonstrated significant hypermethylation (75.20%) of RHD promoter in the current sample, compared to both her prior sample (64.65%;) and healthy control (67.08%). Despite supportive care, the patient died, reflecting her disease's aggressive course. A review of the literature confirmed the rarity of this phenomenon and highlighted that epigenetic dysregulation is a plausible, yet under-investigated mechanism. Conclusions This report directly implicates RHD promotor hypermethylation in acquired RhD antigen loss in MDS. Such epigenetic regulation may mark disease progression and herald a poor prognosis, justifying evaluation for hypomethylating therapy upon its detection.