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    ABSTRACT: Prompt and accurate diagnosis is required for optimal treatment and genetic counseling of patients with inherited bone marrow failure syndromes (IBMFS). However, the diverse clinical picture of these syndromes and their rareness is often associated with diagnostic difficulties. Recently, an improved diagnostic approach is possible by the cloning of many of the causative genes. Fanconi anemia (FA) patients belong to at least 12 complementation groups, of which 11 genes have been cloned. An approach combining an induced chromosomal breakage test, detection of FANCD2-L by Western blot analysis, complementation group analysis, and detailed mutation analysis enables unraveling the causative mutation in the majority of patients. With the use of such strategies, genotype/phenotype correlations in FA are evolving. In dyskeratosis congenita mutations in DCK1, TERC, and TERT genes have been identified, but mutations have been found in less than half of these patients. In patients with Shwachman-Diamond syndrome, mutations in the SBDS gene were found in approximately 90% of patients. In Diamond-Blackfan anemia the RSP19 gene is mutated in 20-25% of patients. Heterozygote ELA2 mutations are found in 60-80% of severe congenital neutropenia patients. All patients with congenital amegakaryocytic thrombocytopenia have mutations in the thrombopoietin receptor gene c-Mpl.
    Pediatric Hematology and Oncology 04/2007; 24(2):87-99. DOI:10.1080/08880010601123240
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    ABSTRACT: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined "very short" telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA+/CD20- naive T cells, and CD20+ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA- memory T cells and CD57+ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management.
    Blood 10/2007; 110(5):1439-47. DOI:10.1182/blood-2007-02-075598