The 4th WHO classification included three different groups that took germline predisposition into account: predisposition without pre-existing disorders or organ dysfunction (CEBPA, DDX41), predisposition with pre-existing platelet disorder (RUNX1, ANKRD26, ETV6), and predisposition with potential organ dysfunction (e.g., GATA2). While the WHO 5th edition classification now categorizes these germline predispositions as secondary myeloid malignancies (with the addition of SAMD9/SAMD9L and TP 53), the ICC classifies them under hematologic neoplasms with germline predisposition, as pathogenic variants in certain genes predispose individuals to both lymphoid and myeloid neoplasms (e.g., ETV6 and RUNX 1).

Approximately 100 genes have currently been identified as linked to germline predisposition to both IBMFS and MDS [15]. The spectrum of these diseases is continually broadening alongside the classical IBMFS, which include Fanconi anemia, Diamond–Blackfan anemia, severe congenital neutropenia, dyskeratosis congenita, Shwachman–Diamond syndrome, and congenital thrombocytopenias. One of these congenital thrombocytopenias is congenital amegakaryocytic thrombocytopenia (CAMT), characterized by severe thrombocytopenia progressing to pancytopenia and bone marrow failure in early childhood [16]. This condition results from mutations in either the MPL gene (CAMT-MPL), responsible for encoding the thrombopoietin receptor, or from mutations in the thrombopoietin gene itself (CAMT-THPO). While patients with CAMT-MPL should undergo hematopoietic stem cell transplantation (HSCT), those with CAMT-THPO respond effectively to thrombopoietin receptor agonists [17].

Genetic analyses in patients suspected of childhood MDS range from the targeted testing for specific genetic alterations, such as mutations in GATA2, SAMD9/SAMD9L and RUNX1, which are most commonly associated with childhood MDS, to more comprehensive yet time- and cost-intensive methods like whole-exome sequencing (WES) or even whole-genome analysis in suspected predisposition syndromes.

GATA2 deficiency stands out as the most prevalent germline predisposition for pediatric MDS, particularly prominent among adolescents with monosomy 7. As a zinc finger transcription factor, GATA2 plays a crucial role in hematopoiesis, which is reflected by the complex disorder, including immunodeficiency and autoimmunity, caused by its deficiency [18]. In a study on MDS in childhood conducted by EWOG [11] involving 508 pediatric MDS cases, germline GATA2 mutations were detected in 57 patients. Despite their high rate in advanced MDS cases (15%) and adolescents with monosomy 7, GATA2 mutations do not inherently predict a poor prognosis in childhood MDS. The management of patients with hematologic symptoms in combination with GATA2 deficiency depends on the severity of bone marrow failure and the presence of karyotypic abnormalities. In cases with a normal karyotype, no transfusion requirement and a neutrophil count above 1.0 G/L, regular monitoring of the patients is recommended. For more severe cytopenia, certain karyotypic abnormalities, or the presence of blasts, HSCT is indicated (EWOG MDS 2017 guidelines).

Recent research has underscored the benefits of comprehensive genomic analysis in diagnosing IBMFS and conditional MDS, facilitating the resolution of yet unresolved cases and yielding effective outcomes in treatment and family monitoring [15]. Blombery et al. [19] conducted an extensive analysis of 115 pediatric and adult patients (median age 24 years, range 3 months–81 years), utilizing various genomic techniques including whole exome sequencing, targeted gene panels, RNA sequencing, and droplet digital PCR (ddPCR). This analysis led to a change of the diagnostic category for 26% of the cohort, notably identifying germline causes in 3 of 47 patients initially diagnosed with SAA/acquired MDS and 16 of 45 patients with clinically unclassifiable BMF. An Israeli nationwide study of 189 children with refractory cytopenias identified pathogenic or likely pathogenic germline variants in almost one-third of the patients of whom 80% had germline predisposition to leukemia [20]. Similar results were found in studies on young adults, with causative germline mutations identified in 19% (13/68) of patients with MDS or AML [21]. Regarding the genomic profile of somatic mutations, pediatric MDS patients differ from adult patients, notably in the absence of mutations linked to epigenetic regulation or RNA splicing. Instead, somatic abnormalities in the RAS/MAPK pathway or somatic driver mutations in SETBP1, ASXL1, and RUNX1 are prevalent in cMDS [12]. This spectrum is continuously broadening, as highlighted by the recent identification of UBTF-tandem duplications in one-third of patients with advanced primary cMDS within a cohort of 104 individuals [22].

As demonstrated in the following two cases presented below, the differentiation between the disorders IBMFS, SAA, and cMDS presents a well-recognized challenge, with significant implications for treatment.