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^{[check spelling]}, 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.