From the Guidelines
Fanconi anemia is a genetically and phenotypically diverse syndrome, characterized by DNA damage repair defects, bone marrow failure, and cancer predisposition, caused by biallelic mutations in one of at least 19 genes involved in DNA damage repair. This condition is associated with congenital anomalies, such as short stature, abnormal thumbs, and café au lait spots, although some patients may not exhibit physical manifestations and are only diagnosed when presenting with cytopenias 1. The key features of Fanconi anemia include:
- Bone marrow failure, which presents in childhood in most patients
- A high relative risk of solid tumors and leukemia, with head and neck squamous cell cancer being the most common solid tumor
- AML being the most common hematologic malignancy, accounting for more than 80% of leukemias
- Patients with biallelic mutations in FANCD1/BRCA2 having a distinctive phenotype with severe congenital anomalies and a high cumulative incidence of leukemia and malignancy 1. The management of patients with Fanconi anemia involves proactive monitoring of the peripheral blood and bone marrow for progressive bone marrow failure, myelodysplastic syndrome, and/or clonal evolution, as well as regular cancer screening due to the significantly higher risk of developing malignancies 1.
From the Research
Definition and Characteristics of Fanconi Anemia
- Fanconi anemia (FA) is a rare genetic syndrome characterized by increased chromosomal breakage, congenital anomalies, bone marrow failure, and an increased tendency to develop malignancies 2.
- It is an inherited disease with congenital and developmental abnormalities, cross-linker hypersensitivity, and extreme cancer predisposition 3.
- FA is a rare inherited DNA disorder clinically characterized by congenital malformations, progressive bone marrow failure, and cancer susceptibility 4.
- It is an autosomal recessive chromosomal instability disorder, characterized by congenital anomalies, defective hematopoiesis, and a high risk of developing acute myeloid leukemia and certain solid tumors 5.
Clinical Features and Management
- The gold-standard screening test for FA is based on the characteristic hypersensitivity of FA cells to the crosslinking agents, such as mitomicin C or diepoxybutane 5.
- Stem cell transplantation (SCT) is the only option for establishing normal hematopoiesis, and nonmyeloablative conditioning for transplants has been advocated to reduce undue toxicities due to inherent hypersensitivity 5.
- Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure and the hematologic malignancies that FA patients develop 2.
- Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair enzymes 6.
Treatment and Prognosis
- The use of lentiviral vectors (LVs) has shown promise in recent clinical trials for the treatment of patients suffering from other genetic disorders, and LV trials for FA defects have been initiated 6.
- Optimized protocols for FA HSC culture and transduction, and the engineering of new gene transfer tools for FA HSCs, have been developed to overcome the obstacles unique to FA gene therapy 6.
- With better understanding of the genetic and molecular basis of the disease, and improved clinical management, FA has been transformed from a life-limiting pediatric disease to an uncommon chronic condition that needs lifelong multidisciplinary management 3.