A number of inherited bone marrow failure syndromes are associated with an increased risk of developing advanced myeloid malignancies. This may be due to the proliferative stress imposed by chronic cytopenias or defects in DNA repair that are hallmarks of several of these syndromes.
Fanconi anemia (FA) is the most common inherited bone mar row failure disorder and is caused by germline mutations in factors involved in DNA repair. These disorders have an autosomal recessive inheritance pattern except for FANCB, which is X-linked. To date, more than 20 genes have been identified as a part of the FANC gene family, and together their protein products are responsible for identifying DNA damage and targeting these sites for repair. The cumulative risk of AML or MDS among FA patients is approximately 10% to 15%, with peak incidence during the teenage years.
Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by inherited mutations in the telomere maintenance pathway. DKC can be inherited in an autosomal dominant (Online Mendelian Inheritance in Man [OMIM] 127550), autosomal recessive (OMIM 224230), or X-linked recessive pattern (OMIM 305000). Mutations in TERT, DKC1, TERC, or TINF2 account for most cases. These patients will typically develop bone marrow failure by 20 to 30 years of age, although variable penetrance of short telomere syndromes may result in later onset of leukemia—particularly in those with a telomere mutation but without the DKC “triad” phenotype of skin hyperpigmentation, nail dystrophy, and oral leukoplakia. Transformation to AML occurs in approximately 10% of patients and is thought to occur via genomic instability related to shortened telomeres and associated DNA damage, resulting in dysplasia and an increased risk of hematopoietic malignancy.
Shwachman-Diamond syndrome (OMIM 260400) is an autosomal recessive disorder caused by mutations in SBDS. AML or MDS occurs in up to a third of patients by 30 years of age and is thought to relate to chromosomal instability and accelerated rates of apoptosis, which may be due to the role of SBDS in stabilizing the mitotic spindle during mitosis.
Severe congenital neutropenia or Kostmann syndrome is associated with neutropenia at birth and has been associated with a variety of genetic mutations. The pattern of inheritance can be autosomal dominant (ELANE or GFI1), autosomal recessive (HAX1, G6PC3, VPS45, or JAGN1), or X-linked (WAS). Nearly a third of patients develop AML or MDS during adolescence. Transformation into AML is frequently characterized by the acquisition of somatic mutations in CSF3R, which encodes the granulocyte colony-stimulating factor (G-CSF) receptor. The causal relationship to chronic G-CSF therapy remains controversial.
Diamond-Blackfan anemia (DBA) (OMIM 105650) is characterized by red cell aplasia and typically spares the leukocyte and platelet lineages. DBA is typically inherited in an autosomal dominant fashion and is associated with mutations in a number of ribosomal proteins. AML can occur in up to 20% of patients and typically occurs after 40 years of age.
Congenital amegakaryocytic thrombocytopenia (CAMT) (OMIM 604498) and thrombocytopenia with absent radii (TAR) (OMIM 274000) syndrome are both characterized by hypoplastic thrombocytopenia. CAMT is inherited in an autosomal recessive manner via mutations in the MPL gene, which encodes the receptor for thrombopoietin (TPO). CAMT is associated with an increased incidence of AML, typically in the second decade of life. TAR syndrome has been associated with mutations in RBM8A, which is involved in messenger RNA (mRNA) splicing. The thrombocytopenia in TAR syndrome often improves over time; both acute lymphoblastic leukemia and AML have been reported among patients with this rare disorder.
Down syndrome, caused by trisomy 21, is associated with an approximately 10- to 20-fold elevated relative risk of AML and MDS compared with the general population and in particular an increased risk for acute megakaryocytic leukemia, FAB M7. Infants with Down syndrome may experience transient abnormal myelopoiesis (TAM), where circulating peripheral blood blasts are seen and may be accompanied by hepatic dysfunction, effusions, and rash; this occurs in approximately 10% of these patients. The majority of TAM cases harbor somatic mutations in GATA1, resulting in altered function of this transcription factor that plays an important role in hematopoietic cell maturation, particularly in the megakaryocyte lineage. Indeed, up to 30% of persons with TAM will progress to AML, commonly acute megakaryocytic leukemia. The development of AML in patients with Down syndrome likely relates both to acquired somatic mutations, such as GATA1, and also the presence of additional copies of genes on chromosome 21 that facilitate leukemogenesis, such as the oncogenes RUNX1, ERG, and ETS2.
