PF354 HOW TELOMERE LENGTH SCREENING CAN BE HELPFUL FOR THE DIAGNOSIS OF CYTOPENIC PATIENTS?

Abstract

Background: Telomere-related disorders are a clinically and genetically heterogeneous group of diseases characterized by premature telomere shortening and proliferative failure of a variety of tissues.The main organs subject to failure of function and fatty or fibrotic replacement are the bone marrow, the lung, and the liver. All 3 may be affected in an individual or a pedigree, with variable severity.Screening for telomeropathies is of particular importance in cytopenic young patients as the disorders encompass a wide spectrum and clinical presentation can therefore be subtle. Aims: To evaluate lymphocyte and granulocyte telomere length (TL) in cytopenic patients and its correlation withphenotypical and hematological features. Methods: TL in lymphocytes and granulocytes was measured using flow fluorescence in situ hybridization (flow FISH) and compared to percentiles (p) of reference ranges. All patients underwent bone marrow evaluation and for some patients genetic tests were performed (NGS or Sanger sequencing). Furthermore, we recorded for all patients somatic and hematological features (see table). Somatic abnormalities and grade of cytopenia were scored according to scores published in other genetic marrow failure syndromes (Fanconi Anemia, from Svahn et al. Am J Hematol 2016). Dyskeratosis congenita (DC) phenotype was considered as established when one of the typical symptoms/signs was present (skin,nails, leuko/erythrtoplakia, lung, liver fibrosis). Results: During the timespan from april 2015 to February 2019 we studied 36 cytopenic patients, M/F 1.25, median age 12.5 years (range 1–51 years). Based on the evaluation of telomere lenght, we divided our patients into 3 groups - Group 1: no telomere lenght abnormalities: 25 patients - Group 2: telomere lenght between 1st and 5thp in at least one of cells subsets analyzed (lymphocytes or granulocytes): 3 patients - Group 3: telomere lenght <1st p in at least one of cells subsets analyzed (lymphocytes or granulocytes): 8 patients Patients hematological and phenotypic features are summarized in table 1 Patients with phenotypic abnormalities were 20/36, including 4 with established DC features. Patients with cytopenia of central origin were 23/36, 17 with Bone Marrow Failure, 5 with Myelodysplasia and 1 with Juvenile Myelomonocytic Leukemia. In 20 patients we performed genetic tests (NGS or Sanger sequencing) and we identified in 14/20 patients a pathogenic mutation (3 Fanconi Anemia mutations, 1 Blackfan Diamond Anemia, 1 LIG4 mutation, 2 TACI mutations, 1 PI3K mutation, 1 NFKB mutation, 1 GATA mutation, 1Ohdo syndrome, 3 DC mutations −1 DKC1, 1 TERT,1 TERC-). In patients with TL <5°p (group 2 and 3) we found that established DC phenotype was more frequent (p = 0.0011).According to the data available in the literature, all patients with genetically confirmed DC had a telomere <1st centile. Furthermore, the following combinations: phenotypic abnormalities+cytopenia and cytopenia+ established DC phenotype (with or without genetic confirmation) had excellent concordance with telomere shortening (Cohen's kappa coefficient >0.81).Summary/Conclusion: Our findings suggest that in patients with cytopenia, telomere shortening is more likely to be detected in those who have established DC phenotype and/ or other somatic abnormalities. Based on this it might be advisable to test telomere length in these categories in order to detect telomere disease subject that might be otherwise missed.