Handbook of Genetic Counseling/Fanconi Anemia

Fanconi Anemia Overview Inherited anemia leading to bone marrow failure (aplastic anemia) and myelodysplasia (5%) or acute myelogenous leukemia (10%) and physical abnormalities (60-75%), and increased risk for other solid cancers Associated Cancers Acute myelogenous leukemia Older patients risk of head and neck, esophageal, gastrointestinal, and genital tract cancers Usually develop after 13 years of age (average age is 23) Difficult to treat due to sensitivity to DNA-damaging agents such a chemo and radiation Patients who receive androgen treatment are at increased risk of liver tumors Physical Characteristics/symptoms (25-40% have no physical abnormalities) Short stature (60%) Extreme fatigue Frequent infections Nosebleeds or easy bruising Low white cell, red cell, or platelet count (age of onset highly variable) Myelodysplasia Upper limb malformations: misshapen, missing or extra thumbs or an incompletely developed or missing radius (50%) Other skeletal anomalies (30%) - short low hairline, spina bifida, scoliosis, sacrococcygeal sinus, vertebral anomalies Renal malformations (25%) pelvic, horseshoe, hypoplastic, dysplastic kidney or abnormal artery or abnormal collecting system Abnormal skin pigmentation (café-au-lait spots, hyperpigmentation, hypopigmentation (65%) Microcephaly Eyes (25%) - micropthalmia, strabismus, epicanthal folds, hypertelorism/hypotelorism, ptosis, slanting, cataracts, epiphora, nystagmus Genitalia (40%) - males: hypogenitalia, undescended, absent or atrophic testes, azospermiasimilar to azoospermia August 2022, delayed puberty. Few males have fathered children females: hypogenitalia, bicornuate uterus, absence of uterus or vagina, ovarian atresia, delayed menarche, irregular menses, early menopause. Successful pregnancies have been reported Ears (10%) - deafness usually conductive due to middle ear anomalies, abnormal pinna, stenosis or atreasia of external auditory meatus, lowest, large or small ears Heart structural defects, cardiomyopathy Lower limbs-toe syndactyly, pes planus, abnormal toes, congenital hip dislocation Mental retardation or learning disabilities Low birth weight Gastrointestinal problems/malformations Genetic Basis Mutations in any one the eleven known genes cause FA Autosomal recessive inheritance FANCA 66% (16q24.3), FANCC 9.5% (9q22.3), FANCD1/BRCA2 3.3% (13q12.3), FANCD2 3.3% (3p25.3), FANCE 2.5% (6p21.3), FANCF 2.0% (11p15), FANCG 8.7% (9p13), FANCJ/BRIP1 1.6% (17q22-q24), FANCL 0.4% (2p16.1) and FANCM 0.4% (14q21.3) X-linked inheritance FANCB 0.8% (Xp22.3) FANCA and FANCC mutations account for 76% of patients FA pathway regulates DNA repair Incidence Found equally in males and females All ethnic groups 1 in 100,000 live births Carrier frequency Estimated between 1 in 600 and 1 in 100 gene clinics states 1 in 300 for general population in US, Europe and Japan AJ frequency is 1 in 89 Diagnosis and testing Chromosomal breakage studies in presence of diepoxybutane (DEB) or mitomycin C (MMC) Only FA cells exhibit increased chromosomal breakage in response to DEB Chromosomal breakage can be performed prenatally with cells from CVS or amnio If mutations known, mutation analysis can be performed prenatally Chromosome breakage tests don't detect carriers Siblings should be tested since 25-40% of individuals with FA may have no physical abnormalities Complementation studies and mutation analysis available for 6 of the genes on research basis Fanconi Anemia mutation database found at www.rockefeller.edu/fanconi/mutate/ FA cell repository in Oregon (will do complementation analysis) Carrier testing available once mutations identified Mosaicism Some cells revert to normal phenotype Attributed to recombination or gene conversion May cause false negative DEB test Geneotype-Phenotype Appear to be some correlations Differential Diagnosis Bloom syndrome, ataxia telangiectasia, and other chromosomal breakage syndromes are all ruled out by DEB chromosomal breakage test NF1 shares café au lait spots Thrombocytopenia with absent radii VACTERL syndrome Above are ruled out by DEB or MMC test Leukemia Malignancy where bone marrow produces excess quantities of immature white cells called blasts These suppress the development of healthy blood cells Results in infections and bleeding AML is a particularly aggressive type usually found in older people Management of FA (focuses on surveillance of and treatment for physical abnormalities, bone marrow failure, and related cancers) Baseline tests Ultrasound of kidneys and urinary tract Formal hearing test Baseline developmental assessment Referral to ophthalmologist, endocrinologist, and geneticist for initial screening and counseling Follow by hematologist HLA typing of patient, sibs, and parents: full blood typing and blood chemistries Regular blood counts Many recommend annual bone marrow aspirate or biopsy to evaluate morphology, cellularity, and cytogenetics Androgens Improve blood counts in ~50% of patients stimulate production of RBC's, often platelets, sometimes WBC's patients often eventually fail to respond to this treatment Hematopoetic growth factors G-CSF or GM-CSF stimulate production of WBC's in some patients Improved platelet and red cell count in a few patients Generally not recommended for patients with a clonal cytogenetic abnormality Blood transfusions Should be avoided or minimized if patient is a candidate for bone marrow transplantation Family members should be avoided as blood donors to minimize chance of sensitization if considering bone marrow transplant Bone marrow transplant Only long-term cure for blood problems Many associated risks Gene therapy Clinical trials for patients with mutations in A or C gene Potentially correct the hematopoietic defect, but not reduce the risk of developing solid tumors in other tissues Not done if considering bone marrow transplant Resources Fanconi Anemia Cell Repository Department of Medical and Molecular Genetics Oregon Health & Science University 3181 SW Sam Jackson Park Rd, L103 Portland, OR 97201 Phone: 503-494-6888 Fanconi Anemia Research Fund, Inc (FARF) 1801 Willamette Street, Suite 200 Eugene, OR 97401 Phone: 800-828-4891; 541-687-4658 Fax: 541-687-0548 Email: info@fanconi.org www.fanconi.org Fanconi Anemia Mutation Registry www.rockefeller.edu/fanconi/mutate Fanconi Anemia Comprehensive Care Program University of Minnesota Medical Center, Fairview 500 Harvard St., Minneapolis, MN 55455 612-273-2800 (local),888-601-0787 (toll-free) specifically for genetic counseling information call Heather Zierhut, MS 612-626-6743 http://www.fairviewbmt.org/index.asp Cancer Fund of America 2901 Breezewood Lane, Knoxville, TN 37921-1009 (423) 938-5281 Supplies and financial aid for low income cancer patients Fanconi Anemia Comprehensive Care Center 3333 Burnet Avenue, MLC 2022, Cincinnati, Ohio 45229 513-636-3218, Toll-free: 1-800-344-2462, extension 3218 http://www.cincinnatichildrens.org/svc/alpha/b/blood/programs/fanconi-anemia/default.htm Fanconi Anemia: Signs, Symptoms, Long-Term Outlook http://www.cincinnatichildrens.org/health/info/blood/diagnose/fanconi-anemia.htm For more resources see Fanconi Anemia: A Handbook for Families and Their Physicians, 2000 References Gene Reviews www.geneclinics.com Fanconi anemia Handout from presentation by Dr. Alan D'Andrea Lynn and Dave Frohnmayer. Fanconi Anemia: A Handbook for Families and Their Physicians Third Edition, 2000 "Biallelic Inactivation of BRCA2 in Fanconi Anemia" was published in the June 13, 2002 edition of Sciencexpress, one of the on-line versions of the journal Science. Fanconi Anemia Research Fund www.fanconi.org Notes The information in this outline was last updated on December 6, 2006.