From the Guidelines
Fanconi anemia is a rare inherited genetic disorder characterized by bone marrow failure, physical abnormalities, and an increased risk of developing certain cancers, caused by mutations in one of several genes involved in DNA repair, particularly the FANC group of genes, as reported in the most recent study 1.
Definition and Characteristics
Fanconi anemia (FA) is a genetically and phenotypically diverse syndrome, characterized by DNA damage repair defects, bone marrow failure (BMF), and cancer predisposition, with most patients having congenital anomalies, including short stature, abnormal thumbs, and café au lait spots, although some patients have no physical manifestations and are only diagnosed when presenting with cytopenias 1.
Clinical Features and Diagnosis
The diagnosis of FA is confirmed by chromosomal breakage studies measuring DNA breaks after exposure to diepoxybutane or mitomycin C and germline sequencing, with 21 FA genes identified that operate in distinct functional complexes, and the inheritance pattern for FA is AR, except for complementation groups FA-B (X-linked) and FA-R (AD) 1.
Treatment and Management
Treatment focuses on managing symptoms and may include blood transfusions, antibiotics for infections, and hematopoietic growth factors to stimulate blood cell production, with hematopoietic stem cell transplantation (HSCT) being the only curative option for severe cases, ideally from a matched sibling donor, and regular cancer screening is essential due to the high risk of developing leukemia, head and neck cancers, and gynecological cancers 1.
Cancer Risk and Screening
Patients with FA are at increased risk of developing MDS/AML and various solid tumors, particularly HNSCC, which develop much earlier than in the general population, with the cumulative incidence of MDS, leukemia, and solid tumors by the age of 50 years being approximately 50%, 10%, and 20%–30%, respectively, and cancer screening protocols include monthly oral self-examinations, biannual dental examination, and annual HNSCC evaluation by an otolaryngologist beginning in early adolescence 1.
Genetic Counseling
Genetic counseling is recommended for families with a history of Fanconi anemia, as it follows an autosomal recessive inheritance pattern in most cases, and parents of children with the more common FA subtypes do not appear to have an increased cancer risk, but heterozygous mutations in several of the more rare FA subtype genes are associated with moderate adult onset cancer risks, particularly for breast and ovarian cancer 1.
From the Research
Definition and Characteristics of Fanconi Anemia
- Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability, somatic abnormalities, marrow failure, and cancer predisposition 2.
- It is the most common of the inherited bone marrow failure syndromes with an incidence of approximately 1/100,000 to 1/200,000 live births 3.
- FA is a genetically complex and phenotypically heterogeneous condition involving birth defects, bone marrow failure, and cancer predisposition 3.
Clinical Manifestations
- The main cause of morbidity and mortality is bone marrow failure, which typically arises in the first decade of life and progresses to full-blown transfusion dependence and severe neutropenia in a variable number of years 2.
- Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) may arise on the background of marrow failure 2.
- FA causes decreased production of all types of blood cells 4.
Genetic Basis
- FA is caused by a defective repair of DNA interstrand crosslinks and to date, mutations in over 20 genes have been linked to the disease 4.
- The genetic defect fragilizes the hematopoietic stem cells (HSCs) 5.
- Mutations in the FANC genes, coding for DNA repair enzymes, are responsible for the disease 5.
Treatment and Management
- The current standard treatment for FA patients is hematopoietic stem cell transplantation, which is associated with exposure to radiation or chemotherapy, immunological complications, and increased risk of morbidity 4.
- New arising treatments include gene addition therapy, genome editing using CRISPR-Cas9 nuclease, and hematopoietic stem cell generation from induced pluripotent stem cells 4.
- Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure for the disease 5.