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, 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

• 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.