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What is Fanconi anemia and whom does it affect?
In spite of its name, this is a syndrome characterised by the presence of many other manifestations, as well as anemia. The most significant being:
- Progressive bone marrow failure (anemia, leukopenia and thrombocytopenia)
- Constitutional and somatic anomalies
- Predisposition to developing acute myeloblastic leukaemia (AML), myelodysplastic syndromes (MDS) and solid tumours.
The carrier frequency (heterozygote) of the mutation responsible for this disease is 1 in 300 and that of those afflicted by FA (homozygote) is 1 in 100,000 of all born. Inheritance is autosomal recessive, except in a few cases in which it is associated with the X chromosome.
In the case of 80% of patients the alterations are detected between the ages of 4 and 14 (the average is 7 years of age), although they can be detected between the ages of 0 and 35.
Types of Fanconi anemia
To date, mutations in up to 13 genes have been identified as causing FA, as well as 8 proteins that are dependent upon them (FANC A, FANC B, FANC C, FANC E, FANC F, FANC G, FANC L and FANC I), some correlations existing between FA subtypes, genetic mutations and the disease's behaviour.
Patients with anomalies in the radii, and additionally, other anomalies (in development, cardiopulmonary, renal, auditive and microcephalia) present early and intense pancytopenia.
For patients with FANC C mutation the aplasia is earlier and survival shorter than that for carriers of FANC A and FANC G mutations.
Patients with FANC G have a greater risk of developing leukaemias and solid tumours than those with FANC A.
Subtypes FANC D1 and FANC N carry the risk of developing medulloblastoma or Wilms tumour. Heterozygotic mutations FANC D1, FANC J and FANC N carry an increased risk of breast cancer.
- Bone marrow failure. Pancytopenia (a deficit in red and white blood cells and platelets) is observed in more than half of the patients, but it is not infrequent (40%) that the only finding be for an isolated thrombocytopenia.
- Somatic and constitutional anomalies. 25% of patients do not present anomalies, or they are minimal. For the others they may be many, and severe enough to be diagnosed shortly after birth, often requiring immediate intervention. Early diagnosis of minor anomalies such as facial or cutaneous anomalies, short stature and hypoplasia of the thenar eminence, assist with diagnosis.
Notable amongst the possible manifestations are:
- Facial characteristics: wide nose base, epicanthus, micrognathia.
- Skin: café au lait spots , hyperpigmentation, hypopigmented areas.
- Growth: retarded, short stature.
- Hands: Thenar hypoplasia, absence or hypoplasia of the thumb, clinodactyly, polydactyly, syndactyly, absent or hypoplastic radii.
- Eyes: Microphthalmia, strabismus, epicanthus, hypertelorism.
- Kidneys: ectopia or horseshoe kidney, hypoplastic or absent, dysplasia, urethral duplication, hydronephrosis, megaureter, reflux.
- Skeleton: Microcephalia, Seckel syndrome (bird-headed dwarfism), frontal bulge, spina bifida, scoliosis, anomalies of the ribs and vertebrae.
- Genitals: In men, hypogonadism, hypospadias, cryptorchidism (undescended testes), testicular atrophy, micropenis. In women, vaginal hypoplasia, uterine hypoplasia, atresia.
- Heart: Ductus arteriosus, interventricular septum defects, coarctation of the aorta, tetralogy of Fallot.
- Digestive tract: Oesophageal, duodenal or anal atresia, tracheoesophageal fistula, narrow palate.
- Ears: Deafness or hearing loss, atresia, dysplasia.
- Nervous system: Hyperreflexia, hydrocephalus, Bell palsy, arteriovenous malformations.
- Development of neoplasms: 30% of patients develop clonal cytogenetic anomalies that mainly affect chromosomes 7 and 8. These alterations favour the progression to MDS or AML. The probability of transformation to AML at the age of 40 is 30%.
The incidence of solid tumours at the age of 40 is 28%, the average age of presentation being 23. The most frequent solid tumours are squamous-cell cancers of the head and neck (tongue, gums, pharynx, esophagus), vulva, cervix, and anus. Most of these tumours have a poor prognosis if they are not diagnosed very early. Hepatic tumours may also be presented (adenomas and carcinomas), especially amongst patients treated with androgens, as may Wilms tumour, medulloblastomas and breast carcinomas. Some patients develop two or more cancers.
The clinical manifestations taken as a whole, and the hematological alterations are, in most cases, what guides the diagnosis. In the absence of clear somatic or constitutional alterations (25% of patients) the diagnosis for bone marrow hypoplasia is much more complex.
The fundamental diagnostic test is based on a chromosome fragility test that analyses chromosome damage induced by clastogenic agents, mitomycin C (MMC), or dexproxibutene (DEB). It is a standard, specific and sensitive test. The results are expressed as the number of ruptures by cell. If the results are doubtful, the test needs to be repeated and, in the case of continued doubt, the test should be performed with skin fibroblasts.
Chromosome fragility tests should be performed for all children and young people with bone marrow aplasia, patients who present somatic anomalies that suggest FA, patients with MDS, AML and some tumours with some trace of an associated phenotype, and tests should be performed on members of the patients' families.
The diagnosis must be completed with an analysis of the gene mutation, which is useful for confirming the diagnosis, detecting carriers, pre-natal diagnosis and pre-implantation genetic diagnosis.
When the anemia and thrombocytopenia are intense and symptomatic, the transfusion of red blood cells and platelets is necessary.
Androgenic derivatives (oxymetholone in doses of 2–4 mg/kg/day) may reduce the degree of anemia and avoid the need for transfusions, but the appearance of side effects must be monitored (virilisation, accelerated growth, liver malfunction, liver cancers). Their use must be transitory as a bone marrow transplant is awaited.
A transplant of hematopoietic progenitors is the only treatment that can restore normal hematopoiesis, but it can not revert the somatic lesions or prevent the development of solid tumours.
The use of classic myeloablative protocols with cyclophosphamide and irradiation produce poor results due to the hypersensitivity of FA cells to the genotoxic agents that produce severe lesions in the tissues. It is because of this that reduced intensity conditioning protocols adapted to patients should be employed and radiotherapy always avoided.
Patients with FA who have received a hematopoietic progenitor transplant (HPT) require close monitoring due to the risk of developing neoplasms. Such monitoring includes monitoring growth, endocrinology and bone marrow cytogenetic tests, and regular oral examinations given any suspicious lesion.
The probability of transformation to AML is 30% and the incidence of solid tumours at the age of 40 is 28%.
Without HPT the average age to which patients can expect to live is 24. The incidence of bone marrow failure reaches 90% at the age of 40. Death, in 90% of cases, is due to hematological alterations (bone marrow aplasia, MDS, AML) or to complications deriving from treatment.
Transplants from healthy compatible siblings provide the possibility of survival free from hematological disease of up to 90%. The use of other sources does not provide such good results, non-related 50%, umbilical cord blood 40%, but this is improving constantly.
Links of interest concerning medical issues relating to Fanconi anemia
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