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Fanconi Anemia.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2002 Feb 14 [updated 2013 Feb 7].



Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include one or more of the following: short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ears (and decreased hearing), heart, gastrointestinal system, central nervous system; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 50 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.


The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 15 genes, which are responsible for the known FA complementation groups (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1], L, M, N [PALB2], O [RAD51C], and P [SLX4]). The latter two genes are still thought of as tentative as they do not fall within a very easily characterized compartment biologically and have very few representative individuals. If the relevant complementation group is identified, molecular genetic testing can be directed to the appropriate gene.


Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell, white cell, and platelets) in approximately 50% of individuals with FA; subcutaneous administration of G-CSF improves the neutrophil count in some; hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, but the high risk of solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity. Surveillance: Monitoring of growth and pubertal development; monitoring for evidence of bone marrow failure (regular blood counts; at least annual bone marrow aspirate/biopsy to evaluate morphology, cellularity, and cytogenetics); for those receiving androgen therapy, monitoring liver chemistry profile and regular ultrasound examination of the liver; monitoring for solid tumors (oropharyngeal and gynecologic examinations). Agents/circumstances to avoid: Transfusions of red cells or platelets for persons who are candidates for HSCT; family members as blood donors if HSCT is being considered; blood products that are not filtered (leukodepleted) or irradiated; toxic agents that have been implicated in tumorigenesis; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications). Evaluation of relatives at risk: DEB/MMC testing of all sibs of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers.


Abnormalities of Fanconi anemia (FA) genes are inherited in an autosomal recessive manner except for pathogenic variants in FANCB, which are inherited in an X-linked manner. Autosomal recessive FA: Each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting both normal genes and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic. X-linked FA: For carrier females the chance of transmitting the pathogenic variant in each pregnancy is 50%; males who inherit the variant will be affected; females who inherit the variant will be carriers and will usually not be affected. For both autosomal recessive and X-linked FA: Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

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