Fanconi anemia (FA) it is a chromosome fragility syndrome characterized by progressive bone marrow failure (BMF), malformations and cancer predisposition, especially acute mieloid leukaemia (AML) and head and neck carcinoma. There are several subtypes with variable clinical phenotype, age of onset of cancer and BMF and cancer spectrum.
FA is a genetic disease with several modes of inheritance: it is autosomal recessive in most cases with mutations in one of the FA genes (FANCA, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCS and FANCT); few male patients are due to mutations in the X chromosome-linked gene FANCB and due to de novo dominant mutations in FANCR. There are discussions in the field whether FANCM biallelic mutations do cause FA and whether FANCO, FANCS and FANCR should be better called FA-like genes as the corresponding patients have chromosome fragility but normal blood counts. All the proteins coded by the above genes participate in a DNA repair pathway whose role is critical to maintain chromosome stability. FA is a very rare disease with an incidence of 1 to 5 new cases per 1,000.000 newborns.
Most infant patients have low blood counts (platelets, red blood cells, neutrophils) progressing to BMF. Anemia, excessive bleeding or bruises are commonly seen, usually preceded by an unusual big volume of red blood cells (macrocytosis). Newborn patients usually show malformations especially in hands (thumbs), forearms and in some internal organs such us kidneys. Small eyes, head and body are also common. Some patients suffer endocrine problems. During the second and third decade, blood (AML) and solid cancers, respectively, are also commonly observed. FANCD1 patients can suffer brain and Wilms tumours and AML in early infancy. Parents and other carrier relatives are healthy with the exception of few cases that are linked to mutations in breast cancer susceptibility genes (FANCD1/BRCA2, FANCS/BRCA1, FANCJ/BRIP1, FANCN/PALB2 or FANCO/RAD51C).
Many patients are first treated with androgens and hematopoietic growth factors. However, they are not curative and not all of them respond. Blood transfusions can also be required. The only cure of the blood disease is hematopoietic stem cell transplantation ideally with an HLA matched donor sibling. The outcome of transplanting patients with FA using HLA-matched unrelated donors has greatly improved. Some families opt to concieve saviour babies by preimplantational genetic diagnosis to match the patient HLA. However, this procedure has low success rate.
Two people who carry each one copy of one of the mutated gene have a 25 percent risk of having a child affected at each pregnancy. The risk of having a child who is a healthy carrier of the disorder is 50 percent at each pregnancy, and the risk that a child will not have the disorder and will not be a carrier is 25 percent. In the case of FANCB, only mothers are healthy carriers and have a risk of 50 percent of having an affected son and a healthy carrier daughter. Ask for genetic counselling to get a complete explanation.