Clinical characteristics: Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Diagnosis/testing: The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC). The diagnosis is confirmed by identification of one of the following:
Management: Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA; 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 for solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity. Early detection and surgical removal remains the mainstay of therapy for solid tumors. Prevention of primary manifestations: Human papilloma virus (HPV) vaccination to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals. Prevention of secondary complications: T-cell depletion of the donor graft to minimize the risk of graft vs host disease; conditioning regimen without radiation prior to HSCT to reduce the risk of subsequent solid tumors. Surveillance: Annual evaluation with a multidisciplinary team including an endocrinologist; 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 function tests 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; unsafe sex practices, which increase the risk of HPV-associated malignancy; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications). Evaluation of relatives at risk: DEB/MMC testing or molecular genetic testing (if the family-specific pathogenic variants are known) of all sibs of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers.
Genetic counseling: Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA). 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 alleles and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic. Autosomal dominant FA: Given that all affected individuals with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low. X-linked FA: For carrier females the chance of transmitting the pathogenic variant in each pregnancy is 50%; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.
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