Inherited Failure Syndromes.

Abstract SCI-10

Global and lineage-restricted bone marrow failure syndromes can be acquired or inherited. Each of the known inherited disorders was initially described by observant clinicians before the field had access to modern tools of molecular biology and genetics. Consequently until recently, diagnosis had depended entirely on a clinical context drawn from the medical and family history, careful physical examinations and a few laboratory tests, none of which were pathognomonic. Today, many of the mutated genes responsible for these phenotypes have been identified and diagnostic tests of good reliability are emerging. This presentation will review the advantages and pitfalls associated with the application of newer diagnostic tests for many of these diseases. The molecular genetic insights have provided additional clinically relevant lessons. For example, the diseases are not limited to patients with the “classic” phenotype and can be diagnosed initially in adulthood. A substantial fraction of patients with Fanconi anemia (FA), for example, does not exhibit the cutaneous or skeletal manifestations of the disease. Some FA patients have entirely normal hematopoiesis, including the responses of hematopoietic cells to mitomycin C or diepoxybutane (abnormalities of which are considered to be the diagnostic standard for this disease). Such patients are “mosaics” in which a single hematopoietic stem cell has corrected the defect on one mutant FA allele and gives it and its progeny such a competitive advantage that they repopulate the entire marrow. Establishing the diagnosis in such cases is essential because the patients remain at high risk for squamous cell carcinoma and because their non-hematopoietic cells remain hypersensitive to cross-linking agents. Between these syndromes there are some shared genetic dysfunctions. For example, cells from patients with dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia have genetic lesions that directly perturb ribosome biogenesis. Few of these disorders are caused by the inactivation of only one gene. There are at least 13 FA genes, more than 6 dyskeratosis congenita genes, more than one Shwachman-Diamond gene, more than 6 Diamond-Blackfan genes, and at least 7 genes for congenital neutropenia. Not surprisingly, some of these genes encode mutually interacting proteins (the most widely studied of these form a nuclear Fanconi interactome). While the identification of involved genes has advanced our levels of diagnostic certainty, the discoveries have posed many challenges and the list of unanswered questions is growing longer. The most cost-effective approaches to diagnosis are not perfectly defined and although mutation analysis is of profound research importance and required for certain management strategies (e.g. in vitro fertilization and pre-implantation genetic diagnosis) the clinical value of assigning patients to specific complementation groups or mutations has not yet been clearly demonstrated. Leading research questions for hematologists focusing on these disorders include: How do these disparate genetic lesions influence the function of hematopoietic stem cells so profoundly? What environmental influences play a role in marrow failure progression and do the mutant gene products interact biochemically with signals evolving from environmental cues? What accounts for the high relative-risk of myelodysplasia and acute leukemia in all of these disorders? Will effective gene therapy reduce the relative risk of MDS and AML? Hypotheses centering on each of these points are now being tested in a number of laboratories and some of them will be summarized in this presentation.