Definition
Fanconi anemia (FA) is usually a recessive chromosome instability syndrome that is characterized by congenital malformations, progressive bone marrow failure, an increased risk of cancer, and endocrinological anomalies. 23 FA genes have been identified to date (FANCA-Y). The corresponding gene products interact in a complex signaling pathway, which functions to repair DNA interstrand crosslinks (ICLs).
Key Data
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Synonym | FA |
Genes | 23 known FA genes; FANCA (60-70%), FANCC, and FANCG (each around 10%) |
Gene products | Repair proteins |
Function | Repair of pathological DNA bridges between complementary DNA stands (interstrand crosslinks, ICLs) |
Heredity | FANCB – X-linked FANCR – autosomal dominant All other subtypes – autosomal recessive |
Prevalence | 1:200.000-400.000 (homozygous; 10x more frequent in Ashkenazi Jews and Africans; 1:300 (heterozygous) |
Genotype-phenotype correlation | Patients with a mutation in the signaling pathway of “late” FA genes (e.g. FANCD1 and FANCB) have a higher cancer risk. Patients with mutations in “early” FA genes have a milder phenotype. |
Penetrance | High, median age at diagnosis, 6.5 years; 90% of FA patients have cytopenia by the age of 40. |
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Diagnosis
Approach when there is clinical suspicion and for all cases of congenital bone marrow failure:
Differential Diagnoses
Clinical Presentation
Clinical Abnormalities
60-70% of FA patients exhibit obvious clinical anomalies:
Predisposition to Tumors
Hematology:
MDS/AML (cumulative incidence of 30-40% at 40 years of age, AML is generally preceded by MDS); evaluation based on the morphology (proliferation of blasts or increase in cellularity despite persistent pancytopenia), cytogenetics, and molecular genetics (-7, EVI1 changes, RUNX1 mutations)
Oncology:
Solid tumors (cumulative incidence of 28% at 40 years of age):
Therapeutic Considerations
Surveillance Recommendations
Surveillance Recommendations
Examination Recommendations from AACR 2016
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Hematology |
Regular monitoring of blood count, annual bone marrow evaluation (bone marrow puncture and biopsy) based on a clinical assessment, early referral to a transplant center |
Oncology |
Six-monthly ENT surveillance examination from early adolescence, annual gynecological screening from menarche, HPV vaccination for boys and girls recommended starting from adolescence |
Immunology |
Immunologists recommend monitoring immunoglobulin levels |
Dermatology |
Annual skin examination |
Pulmonology |
Basic function testing with follow-up as needed |
Gastroenterology |
Annual liver function tests, frequently during androgen therapy |
Endocrinology |
Annual diabetes test, growth curve |
Orthopedics |
Testing for bone apposition disorder of the forearm and possibly management |
Urology |
Basic examination for renal malformations |
Cardiology |
Basic examination for cardiac malformations |
ENT-region |
Annual hearing test, six-monthly tumor screening as of the second decade of life |
Dental |
Six-monthly checkups (clinical, no X-rays) |