Fanconi anemia is a rare genetic disorder part of bone marrow failure syndromes Hereditary (Inherited Bone Marrow Failure Syndromes in English). It affects both sexes and its diagnosis is often made at the stage of appearance of bone marrow failure, hematologic changes are made to a severe aplastic anemia or leukemia. The only treatment is based on the marrow. It is named after the Swiss pediatrician Guido Fanconi, who described this disease in children from the Alpine valleys where geographic isolation favored inbreeding.
The clinical picture combines small size, birth defects, skin lesions, the appearance of secondary bone marrow failure and an increased risk of leukemia and cancer.
Genetic disease of autosomal recessive (except for very few patients in group B), associated with chromosomal instability, Fanconi anemia (FA) is characterized by great phenotypic heterogeneity. In this clinical heterogeneity, is also genetic heterogeneity. The number of Fanconi genes is steadily increasing and so far we know 13 genes whose mutations are responsible for the disease.
These genes are called FANCA FANCB, FANCC, FANCD1 (also known as BRCA2 gene is involved in familial breast cancer), FANCD2, FANCE, FANCF, FANCG, FANCA, FANCJ, FANCL, and FANCN FANCM. They are worn by all autosomes except FANCB gene that is carried on the X chromosome, explaining why patients in this group are all boys and is the only group for which the transmission is related to sex. For a given patient, only one gene is involved and 2 copies of each gene must carry a mutation, one of these copies from the father and one mother.
The gene most frequently involved is the FANCA gene involved in two-thirds of patients. Mutations in FANCA, FANCC, FANCG and FANCD2 are found in more than 90% of patients. Other genes are rarely involved with some of them less than 5 known patients.
The hypothesis that these genes were involved in a common pathway could be confirmed with the identification of the FANCD2 gene is the gene most conserved during evolution, most of the proteins encoded by genes FA (Fance , FancB, FANCC, FANCA, and FANCG FancF) indeed belong to a protein complex, known as "FA core complex," whose function is mono-ubiquitin, thus activating the protein FANCD2, the latter occurs in process of DNA repair (repair of double strand breaks) that allow the maintenance of genome integrity.
Incidence and prevalence
Fanconi anemia was found in all ethnic groups, its incidence is estimated at 1/350.000 births.
As with all recessive disease its frequency is increased in case of inbreeding. A founder effect can be found for sub-populations. For example, Ashkenazi Jews from New York, the gene in question is most often FANCC and certain mutations in this gene are in this population, found with great frequency. Similarly, a very specific mutation of the gene FANCA is found in almost all patients of Boer in South Africa.
There is a vast phenotypic heterogeneity: the clinical picture is highly variable from one patient to another and this is true in the same family.
The main symptoms are:
- Small size: it starts during the uterine life (growth retardation intrauterine) and children born small. In the vast majority of cases, short stature is moderate (2 standard deviations) but it may be more pronounced in some patients.
- Birth defects: they are highly variable. The most frequent sit on the face (especially microcephaly and appearance of the face) and the radial column: abnormal or inch radius. They can also affect the kidneys and urinary tract, genitals, gastrointestinal tract, heart, eyes, hearing aid, the central nervous system, endocrine glands, bones ...
- There is no general delay in psychomotor development and intellectual
- Signs skin spots combine cafe-au-lait spots and achromic melanodermia. They are increasing over time.
Hematological signs appear at a median age of 7-8 years. The first signs of cytopenia (low rate of blood cells) anemia, neutropenia or thrombocytopenia. Gradually settles a severe aplastic pancytopenia responsible for causing repeated infections and transfusion requirements. Over 90% of patients progressed to aplastic anemia before the age of 20. Acute leukemia, mostly myeloid type, can complicate this process.
Cancers, siege varied, are in three circumstances:
- Toddlers aged under 5 years on transfer of genes FANCD1/BRCA2, and FANCJ/BRIP1 FANCN/PALB2. Mutations in these three genes also involved in all prédispostions family to breast cancer, affecting less than 5% of patients.
- Patients over 20 years, who were able to survive beyond adolescence through a bone marrow transplant.
- Rarely, in adult patients experiencing genetic mosaicism, in whom the diagnosis of Fanconi anemia had not been raised most often far.
The diagnosis is often suggested clinically but unfortunately for many patients, it is at the stage of bone marrow failure.
Faced with an array of children's bone marrow, elevation of alpha-fetoprotein blood and fetal hemoglobin are arguments for AF.
The cellular hypersensitivity to DNA cross-linking agents is the basis of laboratory diagnosis and testing of chromosomal breaks is essential to confirm a diagnosis of AF. It looks for the existence of spontaneous chromosome breaks and, especially, the increase in the number of breaks after exposure to an agent known as "brittle": caryolysine, cyclophosphamide Some figures ... chromosome, whose appearance is secondary to the breaks: Sorting Figures -tetra-radial and radial, are also characteristic for cytogeneticist.
So rare, fracture test may be normal in the blood due to a genetic reversion (somatic mosaicism).
More recently a new diagnostic test, whose development has been possible thanks to the understanding of the way Fanconi showed his interest: the test FANCD2. He is on blood lymphocytes but also on fibroblasts obtained from skin biopsy, the latter approach allows the diagnosis of genetic forms with reversion.
Treatment & management
- The allogeneic hematopoietic stem cell (HSC) remains to date the only treatment for Fanconi anemia. CSH may be obtained from a related donor marrow (or sibling) or unrelated (donor marrow voluntary written on a file) and may also come from a cord blood which can be familial or not related (cord blood bank). Transplantation corrects the bone marrow failure and allows the survival of patients. It does not fix well on other events. It does also not immune to cancer development. The results of these grafts, especially for grafts made with unrelated donors, currently improved through the use of new packaging, made with fludarabine and cyclophosphamide or without irradiation.
- In case of impossibility of realization of a transplant, treatment with androgens can partly correct the bone marrow failure. Its effect is often limited in time, also the toxicity of androgens is important virilization and induction of liver tumors.
- The management of patients is also involved many organ specialists who will deal with the consequences of existing defects and to ensure systematic monitoring, particularly for screening in situ cancers.
It is an autosomal recessive except for exceptional patients in group B for which transmission is related to sex (see above). In a family where a patient has already reached the 2 parents are heterozygous and the risk of birth of another child with regard to pregnancy 4.
The severity of this disease justifies prenatal diagnosis for families who wish, implying that they are asylum-termination of pregnancy if the child is reached. Several approaches are possible:
- The search for chromosome breakage in the fetal blood was historically the first possibility. It assumes a fetal blood sampling at the umbilical vein. This can be done late in pregnancy and is not without risk to pregnancy.
- In families where the disease has been studied, the gene involved known and the causative mutations identified accurately, a molecular diagnosis is possible. This is feasible on biopsy trophoblast (placenta) from the 16th week of gestation.
- Accurate identification of mutations may also allow preimplantation genetic diagnosis in an IVF procedure.
See also Anemia