The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with singlelineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multilineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant. | INTRODUCTIONAn accurate diagnostic work-up of children with bone marrow failure (MF) is a critical step for clinical management of the disease. In particular, the differential diagnosis between constitutional and acquired forms is a key way to identify specific treatment strategies 1-3 and a M Miano and A. Grossi equally contributed to this work. This study was approved by local ethical committee. Patients' consent form was obtained. No material from other sources was used. Data are

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

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