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Anemia, Fanconi
Updated: Dec 21, 2007
Introduction
Background
Fanconi anemia (FA) is the most frequently reported of the rare inherited bone marrow failure syndromes, with more than 1800 cases reported in the medical literature. In 1927, Guido Fanconi first reported 3 brothers with pancytopenia and physical abnormalities. Subsequent cases were clinically diagnosed because of the combination of aplastic anemia and various characteristic physical anomalies (see Physical).
In the early 1960s, several groups observed that cultured cells from patients with FA had increased numbers of chromosome breaks; later, the breakage rate was found to be specifically increased by the addition of DNA cross-linkers, such as diepoxybutane (DEB) or mitomycin C (MMC). This led to the identification of patients with FA and aplastic anemia without birth defects and the diagnosis of FA in patients without aplastic anemia but with abnormal physical findings. Furthermore, in cultured FA cells, cell cycle arrest in gap 2/mitosis (G2/M) occurs at lower concentrations of clastogens than in normal cells. This observation has led to flow cytometry–based screening tests used at some centers.
Most recently, the advent of molecular diagnostics has further improved the specificity of FA diagnosis (see Other Tests). FA comprises approximately 25% of the cases of aplastic anemia seen at large referral centers. Approximately 25% of known patients with FA do not have major birth defects.
Pathophysiology
FA is an autosomal recessive disease in more than 99% of patients; each patient with FA is homozygous or doubly heterozygous for mutations in one of the 13 genes known to be responsible for FA. The cloned genes are FANCA, B, C, D1, D2, E, F, G, I, J, L, M, and N. Although most are unique genes, several were previously known, including FANCD1 (BRCA2), GANCG (XRCC9), FANCI (KIAA1794), FANCJ (BRPI1/BACH1), FANCL (PHF9/POG), FANCM (Hef), and FANCN (PALB2). Heterozygotes for BRCA2 and possibly BACH1 and PALB2 are at increased risk of breast and other cancers.The FA proteins A, B, C, E, F, G, L and M appear to form a nuclear complex, which leads to ubiquitination of the I and D2 proteins; the latter is involved in DNA damage response mechanisms in cooperation with FANCD1, FANCJ, and FANCN, as well as BRCA1, RAD51, Mre11, and other proteins. The widely variant FA phenotype may depend on whether the mutation is null or leads to a partially functional gene product rather than the specific gene that is involved. The specific role of mutations in the FA genes in the pathogenesis of birth defects, bone marrow failure, or oncogenesis is not yet clear.
Frequency
United States
In general, the carrier frequency is estimated to be approximately 1 per 300 people, leading to an expected birth rate of approximately 1 per 360,000 people. Among Ashkenazi Jews, the carrier frequency is approximately 1 per 90 people, with a projected birth rate of 1 per 30,000 people.
International
The general carrier frequencies are similar to those in the United States, depending on the population. Due to founder effects, the heterozygote frequency is less than 1 per 100 in South African Afrikaaners,1 sub-Saharan Blacks, and Spanish Gypsies,2 leading to expected birth rates in these populations of around 1 per 40,000.
Mortality/Morbidity
- The major cause of death in FA is bone marrow failure, followed in frequency by leukemia and solid tumors. The projected median survival from all causes for more than 1800 cases reported in the literature is age 20 years, although this has improved to older than 30 years in the cases reported in the most recent decade.
- Bone marrow failure usually presents in childhood, with petechiae, bruising, and hemorrhages due to thrombocytopenia; pallor and fatigue from anemia; and infections due to neutropenia. More than 90% of patients with FA develop pancytopenia caused by aplastic anemia, which is often fatal.
- Leukemia has been reported in approximately 10% of patients, and myelodysplastic syndrome has been reported in about 6% of patients, primarily in teens and young adults, some of whom may not have had a preceding phase of aplastic anemia.
- Solid tumors have been reported in close to 10% of patients, often in young adults who may never have had aplastic anemia. The most common tumors are liver adenomas and hepatomas, primarily in patients who had aplastic anemia that was treated with oral androgens. Other types of solid tumors occur in young adults and primarily involve the head and neck, esophagus, and gynecologic areas. Oral cancers have been reported in patients with FA who have received bone marrow transplantation; transplantation (especially if graft versus host disease occurs) appears to further increase the risk of these cancers.
- The risk of liver tumors is increased 400-fold, the risk of leukemia and head and neck cancers is increased 700-fold, the risk of esophageal cancer is increased 2000-fold, and the risk of vulvar cancer is increased 4000-fold. In competing risk analyses, the cumulative incidence of solid tumors reaches 30% by age 45 years and does not level off. Although bone marrow failure and leukemia, which may be treated or prevented by hematopoietic stem cell transplant or gene therapy, are the concerns in treating children and adolescents, solid tumors remain the major threat to older patients with FA.
- In a retrospective analysis of 145 patients with Fanconi anemia, 9 patients evolved to leukemia, and 14 developed 18 solid tumors.3 Although this is a relatively small cohort, it does allow for a more statistically valid analysis than do the previous literature reviews. Thus, the ratio of observed-to-expected cancers for all cancer diagnoses or for solid tumors was 50, and the ratio was 700 for leukemia. The cumulative incidence of leukemia, death from marrow failure, death from a solid tumor, and having a stem cell transplant (not necessarily a favorable outcome) was 10%, 11%, 29%, and 43%, respectively. Note that the risk of solid tumors posttransplant likely increases.
Race
FA has been reported in all races, although "founder" effects are recognized, which result in higher carrier frequencies in Ashkenazi Jews,4 South African Afrikaaners,1 sub-Saharan Blacks, and Spanish Gypsies2 (see Frequency).
Sex
The male-to-female ratio in the literature cases is 1.2:1, although equal numbers are expected in autosomal recessive disease.
Age
FA has been diagnosed in patients from birth to age 49 years, with a median age of 7 years. Individuals with birth defects (see Physical) are diagnosed at younger ages than persons without birth defects.
Clinical
History
Patients with Fanconi anemia (FA) with characteristic birth defects (eg, radial ray anomalies, poor growth, genitourinary problems) are often treated by various medical specialists during infancy. The diagnosis of FA must first be considered and can only be established if specific tests are ordered. During childhood, short stature and skin pigmentation, including café au lait spots, may become apparent. The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pallor, fatigue, and infections. Because macrocytosis usually precedes thrombocytopenia, patients with typical congenital anomalies associated with FA should at least be evaluated for an elevated erythrocyte mean corpuscular volume. In approximately 25% of patients with FA who have cancer, the diagnosis of leukemia or a tumor preceded the diagnosis of FA.
Physical
About 75% of patients with FA have birth defects, such as altered skin pigmentation and/or café au lait spots (>50%), short stature (50%), thumb or thumb and radial anomalies (40%), abnormal male gonads (30%), microcephaly (25%), eye anomalies (20%), structural renal defects (20%), low birth weight (10%), developmental delay (10%), and abnormal ears or hearing (10%).Literature reports may, however, be biased toward this association because the clinical diagnosis initially depended on the combination of aplastic anemia and physical anomalies; thus, the frequencies may be overestimated. 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
- Upper limbs
- 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
- Gonads
- 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
- Feet - Toe syndactyly, abnormal toes, flat feet, short toes, clubfoot, 6 toes
- Legs - Congenital hip dislocation, Perthes disease, coxa vara, abnormal femur, thigh osteoma, abnormal legs
- Eyes - Small, strabismus, epicanthal folds, hypertelorism, ptosis, slanted, cataracts, astigmatism, blindness, epiphora, nystagmus, proptosis, small iris
- Ears - Deaf (usually conductive), abnormal shape, atresia, dysplasia, low-set, large, small, infections, abnormal middle ear, absent drum, dimples, rotated, canal stenosis
- Kidneys - Ectopic or pelvic, horseshoe, hypoplastic or dysplastic, absent, hydronephrosis or hydroureter, infections, duplicated, rotated, reflux, hyperplasia, no function, abnormal artery
- Gastrointestinal system - 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
- Cardiopulmonary system - 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
- Other anomalies - Developmental delay, hyperreflexia, Bell palsy, CNS arterial malformation, stenosis of the internal carotid, small pituitary gland
Causes
As described in Pathophysiology, at least 13 genes are involved in the FA pathway. The exact link between mutations and phenotype is not clear, although patients who are homozygous for null mutations appear to have more severe FA than those with altered proteins. Various aspects of pathophysiologic research include the following:
- FA cells may be susceptible to damage by oxygen free radicals.
- FA cells have a defect in cell cycle regulation.
- The hematopoietic stem cell is defective in FA.
- A defect in the DNA-damage response pathway is present in FA.
- FA is a premalignant disorder.
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References
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Callen E, Casado JA, Tischkowitz MD, et al. A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood. Mar 1 2005;105(5):1946-9. [Medline].
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Further Reading
Keywords
Fanconi anemia, FA, constitutional aplastic anemia, bone marrow failure, inherited bone marrow failure syndrome, aplastic anemia, leukemia, myelodysplastic syndrome, liver adenoma, hepatoma, radial ray anomalies, poor growth, genitourinary problems, short stature, skin pigmentation, café au lait spots, petechiae, bruises, bruising, pallor, fatigue, infections, thumb anomalies, thumb and radial anomalies, abnormal male gonads, microcephaly, eye anomalies, structural renal defects, low birth weight, developmental delay, abnormal ears, abnormal hearing, Estren Dameshek Fanconi anemia, pancytopenia
