Importance of genetic clarification in cytopenia syndromes (childhood myelodysplastic syndrome forms)

Summary Childhood myelodysplastic syndrome (cMDS) is a rare clonal hematopoietic disorder characterized by peripheral cytopenia, with refractory cytopenia of childhood (RCC) being the most prevalent form. In children presenting with pancytopenia and significantly reduced bone marrow cellularity, RCC, severe aplastic anemia (SAA), and inherited bone marrow failure syndromes (IBMFS) are critical differential diagnoses, with accurate distinction being pivotal for effective treatment decisions. While histopathological analysis remains fundamental in differentiating these conditions, genetic and molecular testing are playing an increasingly important role. Reflecting this importance, two new classifications for cMDS were introduced in 2022: the WHO 5th edition and the International Consensus Classification (ICC). Both classifications have broadened the scope to include additional gene mutations, highlighting advances in understanding the genetic underpinnings of cMDS. However, significant differences in terminology persist: while the WHO 5th edition redefined RCC, replacing it with the term childhood MDS with low blasts (cMDS-LB), the ICC retained the RCC designation. This paper presents two cases that illustrate the current challenges in diagnosing and treating disorders in the spectrum of cMDS. One case describes a patient with germline GATA2 deficiency, highlighting the difficulties of distinguishing between SAA and cMDS in a timely manner. The other case underscores the importance of whole exome sequencing to differentiate between IBMFS and cMDS in the presence of a histomorphological RCC pattern.