Recent insights into inherited bone marrow failure syndromes.
OBJECTIVE
Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in recent years and their impact on the understanding of IBMFS.


RESULTS
Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development.


CONCLUSIONS
The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS is likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.
Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Shefali
S
Parikh
Monica
M
Bessler
D000741:Anemia, Aplastic; D001855:Bone Marrow Diseases / Q000235:genetics*; D000080983:Bone Marrow Failure Disorders; D002648:Child; D002675:Child, Preschool; D019317:Evidence-Based Medicine; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000151:congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D008068:Lipomatosis / Q000235:genetics*; D008297:Male; D018832:Molecular Chaperones; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D011379:Prognosis; D000081003:Shwachman-Diamond Syndrome; D019098:Telomerase / Q000235:genetics
D051856:Fanconi Anemia Complementation Group Proteins; D018832:Molecular Chaperones; D019098:Telomerase; C535133:WRAP53 protein, human