Inherited bone marrow failure in the pediatric patient

Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with one or more extra-hematopoietic abnormalities. BM failure, which can involve one or more cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how this is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways: DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. Additionally, as these disorders are usually associated with extra-hematopoietic abnormalities and increased cancer risk, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly for patients with FA and DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs (transforming growth factor (TGF)-beta inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC) that target disease-specific defects.