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 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, azospermia, delayed puberty. Few males have fathered children
 * females: hypogenitalia, bicornauate 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

 * AR inheritance
 * At least 8 FA genes A (16q24.3) 66%, B(?) 4%, C(9q22.3) 12%, D1 rare, D2(3p25.3) rare, E(6p21-22) 12%, F(11p15) rare, G(9p13) rare, (BRCA2 is thought to be B or D1)
 * FA-A and FA-C 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


 * Cancer Fund of America
 * 2901 Breezewood Lane, Knoxville, TN 37921-1009
 * (423) 938-5281
 * Supplies and financial aid for low income
 * cancer patients


 * For more resources see Fanconi Anemia: A Handbook for Families and Their Physicians, 2000