# 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, 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.