Fanconi anemia

Fanconi anemia (FA), also known as Fanconi cancer, is a rare, autosomal recessive genetic disease characterized by aplastic anemia, congenital defects, endocrinological abnormalities, and an increased incidence of developing cancer. The study of Fanconi anemia has improved scientific understanding of the mechanisms of normal bone marrow function and the development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and liver cancer. 90% develop aplastic anemia (the inability to produce blood cells) by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has a later onset of bone marrow failure.

FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair via homologous recombination. The well-known cancer susceptibility genes BRCA1 and BRCA2 are also examples of FA genes (FANCS and FANCD1 respectively), and biallelic mutation of any of the two genes usually results in an embryonically lethal outcome, and should the proband come to term, experience a severe form of Fanconi anemia.

Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available. Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C. The typical age of death was 30 years in 2000.

FA occurs in about one per 130,000 live births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. Some forms of Fanconi anemia, such as those of complementation group D1, N, and S, are embryonically lethal in most cases, which might account for the rare observation of these complementation groups. It should not be confused with Fanconi syndrome, a kidney disorder also named after Dr. Fanconi.

FA is characterized by bone marrow failure, AML, solid tumors, and developmental abnormalities. Classic features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, including café au lait spots, abnormal facial features (triangular face, microcephaly), abnormal kidneys, and decreased fertility. Many FA patients (about 30%) do not have any of the classic physical findings, but diepoxybutane chromosome fragility assay, showing increased chromosomal breaks, can make the diagnosis. About 80% of FA will develop bone marrow failure by age 20.^{[citation needed]}

The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pale appearance, feeling tired, and infections. Because macrocytosis usually precedes a low platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevated red blood cell mean corpuscular volume.

FA is primarily an autosomal recessive genetic disorder. This means that two mutated alleles (one from each parent) are required to cause the disease. The risk is 25% that each subsequent child will have FA. About 2% of FA cases are X-linked recessive, which means that if the mother carries one mutated Fanconi anemia allele on one X chromosome, a 50% chance exists that male offspring will present with Fanconi anemia.^{[citation needed]}

Scientists have identified 21 FA or FA-like genes: FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCO (RAD51C), FANCP (SLX4), FANCQ (XPF), FANCS (BRCA1), FANCT (UBE2T), FANCU (XRCC2), FANCV (REV7), and FANCW (RFWD3). FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. These genes are involved in DNA repair.^{[citation needed]}