Genetics and causes
- Fanconi anemia is an autosomal recessive disease in more than 99% of patients.
- Spontaneous chromosomal breakage is a feature of this disease along with predisposition to leukemia.
- It is assumed that the basic defect is related to the repair of DNA damage, in particular that of so-called DNA crosslinks.
- Fanconi cells may be susceptible to damage by oxygen free radicals.
- Fanconi cells have a defect in cell cycle regulation.
- The hematopoietic stem cell is defective in Fanconi anemia.
- A defect in the DNA-damage response pathway is present in Fanconi anemia.
- Fanconi anemia is a premalignant disorder.
Patients with biallelic mutations in FANCD1/BRCA2 and FANCJ/PALB2 have a very severe phenotype, including features of the vertebral, anal, cardiac, tracheal, esophageal, and limb (VACTERL) association.
- Skin - Generalized hyperpigmentation on trunk, neck, and intertriginous areas; café au lait spots; hypopigmented areas
- Body - Short stature, delicate features
- Thumbs - Absent or hypoplastic, supernumerary, bifid, rudimentary, short, low set, attached by a thread, triphalangeal, tubular, stiff, hyperextensible
- Radii - Absent or hypoplastic (only with abnormal thumbs [ie, terminal defects]), absent or weak pulse
- Hands - Clinodactyly, hypoplastic thenar eminence, 6 fingers, absent first metacarpal, enlarged abnormal fingers, short fingers
- Ulnae – Dysplastic
- Males - Hypogenitalia, undescended testes, hypospadias, abnormal or absent testis, atrophic testes, azoospermia, phimosis, abnormal urethra, micropenis, delayed development
- Females - Hypogenitalia; bicornuate uterus; aplasia of uterus and vagina; atresia of uterus, vagina, or ovary/ovaries
Other skeletal anomalies
- Head and face - Microcephaly, hydrocephalus, micrognathia, peculiar face, bird face, flat head, frontal bossing, scaphocephaly, sloped forehead, choanal atresia
- Neck - Sprengel abnormality, short, low hairline, webbed
- Spine - Spina bifida (thoracic, lumbar, cervical, occult sacral), scoliosis, abnormal ribs, sacrococcygeal sinus, Klippel-Feil syndrome, vertebral anomalies, extra vertebrae
- Toe syndactyly, abnormal toes, flat feet, short toes, clubfoot, 6 toes
- Congenital hip dislocation, Perthes disease, coxa vara, abnormal femur, thigh osteoma, abnormal legs
- Small, strabismus, epicanthal folds, hypertelorism, ptosis, slanted, cataracts, astigmatism, blindness, epiphora, nystagmus, proptosis, small iris
- Deaf (usually conductive), abnormal shape, atresia, dysplasia, low-set, large, small, infections, abnormal middle ear, absent drum, dimples, rotated, canal stenosis
Ectopic or pelvic, horseshoe, hypoplastic or dysplastic, absent, hydronephrosis or hydroureter, infections, duplicated, rotated, reflux, hyperplasia, no function, abnormal artery
High-arch palate, atresia (eg, esophagus, duodenum, jejunum), imperforate anus, tracheoesophageal fistula, Meckel diverticulum, umbilical hernia, hypoplastic uvula, abnormal biliary ducts, megacolon, abdominal diastasis, Budd-Chiari syndrome
Patent ductus arteriosus, ventricular septal defect, peripheral pulmonic stenosis, aortic stenosis, coarctation, absent lung lobes, vascular malformation, aortic atheromas, atrial septal defect, tetralogy of Fallot, pseudotruncus, hypoplastic aorta, abnormal pulmonary drainage, double aortic arch, cardiomyopathy
Developmental delay, hyperreflexia, Bell palsy, CNS arterial malformation, stenosis of the internal carotid, small pituitary gland
Test and diagnosis
- CBC count may reveal trilineage pancytopenia or may only show RBCs that are macrocytic for age. Thrombocytopenia or leukopenia may precede full-blown aplasia.
- Chromosome breakage is usually examined in short-term cultures of peripheral blood T-cell mitogen–stimulated lymphocytes in the presence of DNA cross-linkers, such as DEB or MMC.
- Flow cytometry of FA cells cultured with nitrogen mustard and other clastogens demonstrates an arrest in G2/M.
- Fetal hemoglobin (HbF) may be increased for age as a manifestation of stress erythropoiesis.
- Red cell adenosine deaminase (ADA) is increased in most patients with Diamond-Blackfan anemia (DBA) but appears to be normal in FA.
- Serum erythropoietin levels are markedly increased and higher than expected for the degree of anemia
- Perform a skeletal survey to identify all developmental defects involving bone.
- Perform initial abdomen ultrasonography to document size and location of kidneys and perform follow-up ultrasonography annually to monitor for liver tumors or peliosis hepatis.
- Perform cardiac ultrasonography to evaluate for congenital anomalies.
- Bone marrow aspiration and biopsy
Treatment is recommended for significant cytopenias, such as hemoglobin less than 8 g/dL, platelets fewer than 30,000/µL, or neutrophils fewer than 500/µL.
Although the first line of therapy is stem cell transplantation, androgens, to which approximately 50-75% of patients respond, are used for those in whom transplantation is not an option
Anabolic and androgenic steroids
These enhance the production and urinary excretion of erythropoietin in anemias caused by bone marrow failure and often stimulates erythropoiesis in anemias caused by deficient red cell production.
Although oral androgens have a risk of liver toxicity, they are easier to use in children than parenteral androgens. The lowest effective dose should be used.
Aminocaproic acid- These agents may decrease bleeding, particularly oral mucosal bleeding, in patients with thrombocytopenia by stabilization of thrombi.
Hematopoietic growth factors
Filgastrim/G-CSF- G-CSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils
Epoetin alpha- Stimulates division and differentiation of committed erythroid progenitor cells; induces release of reticulocytes from bone marrow into blood stream.
Corticosteroids are used on alternate days and may delay the growth acceleration caused by androgens. They may also stabilize endothelial cells, leading to reduced bleeding at a given degree of thrombocytopenia.
- Transfusions of packed RBCs in case of symptomatic anemia
- Symptomatic thrombocytopenia can be treated with similarly treated platelets; single-donor platelets are preferred to reduce the frequency of antibody formation
- Symptomatic neutropenia usually responds to granulocyte colony-stimulating factor (G-CSF)
Stem cell transplantation
Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia. It should be considered for those who have an HLA-matched sibling donor (survival rate is >80%).
- Hand surgery and splinting may be indicated for thumb and radial anomalies. Hand surgery should be performed early in life to ensure maximal function.
- Congenital heart defects may require surgery
- GI anomalies, such as tracheoesophageal fistulas and imperforate anus, are also treated surgically.
- The major cause of death in Fanconi anemia is bone marrow failure, followed in frequency by leukemia and solid tumors.
- Many patients eventually develop
- Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers.
- Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer.