Fanconi Anemia – Definition
Fanconi anemia (FA) is predominantly a recessive chromosomal instability syndrome, characterized by congenital differences, progressive bone marrow failure, an elevated cancer risk, and endocrine variations. Currently, 22 FA genes (FANCA-W) have been identified. The corresponding gene products interact within a complex signaling pathway responsible for repairing “DNA interstrand cross-links” (ICLs).
Synonym:
FA
Gene:
22 known FA genes; FANCA (60-70%), FANCC and ANCG (about ~10% each)
Gene products:
Repair proteins
Function:
Repair of pathological DNA bridges between complementary DNA strands (inter-strand cross-links, ICL)
Inheritance:
FANCB – X-linked
FANCR – autosomal dominant
all other subtypes – autosomal-recessive
Prevalence:
1:200,000 – 400,000 (homozygous, 10x more common in individuals of Ashkenazi Jewish or African descent); 1: 300 (heterozygous)
Genotype-phenotype correlation:
Patients with mutations in the signaling pathway of “late” FA genes (e.g. FANCD1, FANCB) have a higher cancer risk. Patients with mutations in “early” FA genes have a milder phenotype.
Penetrance:
High, median age of diagnosis 6.5 years; 90% of FA patients are cytopenic at the age of 40 years
Fanconi Anemia – Diagnosestellung
Procedure for clinical suspicion and congenital bone marrow failures:
- Testing of lymphocytes or fibroblasts in culture, particularly in cases of somatic mosaicism, for increased spontaneous chromosome fragility. Chromosome fragility can be enhanced by adding DNA-intercalating substances such as diepoxybutane (DEB) or mitomycin C (MMC).
- Flow cytometry: Identification of increased cells with G2 arrest.
- Molecular genetics: Utilization of next-generation sequencing for gene panel analysis.
- Determination of the Fanconi Anemia (FA) subclass is crucial for estimating tumor risk in carriers of homozygous or heterozygous mutations. This information leads to recommendations for early detection. For instance, carriers of FANCD1/BRCA2 mutation already have a significantly increased risk for breast and ovarian carcinomas in heterozygosity, while in homozygosity, it indicates Fanconi anemia.
Differential Diagnoses
- SAA, MDS, congenital syndromes with bone marrow failure
- DNA repair defects such as Nijmegen Breakage Syndrome, Bloom Syndrome
Clinical Presentation
Clinical Abnormalities
60-70% of FA patients show obvious clinical abnormalities:
- Skeletal anomalies of the upper extremity (classically radius and thumb)
- Skin pigmentation changes (hyperpigmentation, hypopigmentation, vitiligo)
- Short stature
- Microcephaly, small eyes, broad nasal root, micrognathia and epicanthus characteristic facial expression in FA patients
- Malformations of the internal organs, primarily kidneys and heart
- Endocrinological disorders (80% of patients):
- Short stature
- Hypothyroidism
- Reduced glucose tolerance
- Diabetes mellitus
- Hyperinsulinism
Progressive bone marrow failure beginning in the first decade of life (often the first clinical sign of disease that leads to the need for further diagnostics) Bi- or tricytopenia at the age of 10 years in >80%, at 40 years 90% of FA patients (platelets <100,000/µl, Hb <10g/dl, absolute neutrophil count <1000/µl)
Tumor predisposition
Hematology:
- MDS/AML (cumulative incidence at 40 years 30-40%), as a rule AML is preceded by MDS
- Assessment based on morphology (blast proliferation or increase in cellularity despite persistent pancytopenia)
- Cytogenetics
- Molecular genetics (-7, EVI1 changes, RUNX1 mutations)
Oncology:
- Solid tumors (cumulative incidence at 40 years 28%):
- Squamous cell carcinomas of the head and neck region (risk 500-700 times higher, 65% oral cavity, very aggressive, 2-year survival <50%, wide surgical excision if possible)
- Squamous cell carcinoma in the anogenital region (especially vulvar carcinoma, risk increased 2000-4000 times)
- Liver tumors: usually only under androgen therapy benign liver adenomas with spontaneous regression after discontinuation of therapy, rarely hepatocellular carcinomas
- Medulloblastomas
- Nephroblastomas
Special Features of Treatment
- Blood transfusions/G-CSF for cytopenias requiring therapy
- Synthetic androgens for progressive bone marrow failure
- Bone marrow transplantation for advanced bone marrow failure or signs of transformation
- Growth hormones for correcting short stature
- Avoiding radiation exposure when unnecessary due to hypersensitivity to ionizing radiation
- Hypersensitivity to alkylating agents (cyclophosphamide, ifosfamide, melphalan, mechlorethamine, busulfan, treosulfan, nitrosoureas, procarbazine, dacarbazine, temozolomide, thiotepa, and platinum derivatives)
- Patient education regarding oral hygiene and monthly oral self-inspection for mucosal changes (with parental assistance if needed)
- Avoidance of alcohol and tobacco consumption
- No administration of medication that impairs platelet function, such as non-steroidal anti-inflammatory drugs (e.g., ibuprofen).
Diagnose Fanconi Anemia. Wie geht es weiter?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnose Fanconi Anemia. Wie geht es weiter?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Examination Recommendations According to AACR 2016 and FARF Guidelines
- Hematology
Regular blood count checks, annual bone marrow assessment (KMP and biopsy) based on clinical assessment, early referral to a transplant center - Oncology
Semi-annual ENT screening examinations from early adolescence, annual gynecological screening from menarche (see below) - Gynecology
Annual gynecological screening from menarche/13 years, PAP smear as soon as sexually active or from 18 years, HPV vaccination recommended for boys and girls - Immunology
Monitoring of immunoglobulin levels as recommended by the immunologist - Dermatology
Annual dermatological examination, from the age of 18 at the latest - Pulmonology
After HSCT: Basic function test with follow-up as required - Gastroenterology
Annual liver function tests, more frequently under androgen therapy - Endocrinology
Annual diabetes test, growth curve - Orthopaedics
Testing for bony abnormalities of the forearm and management if necessary - Urology
Basic examination for kidney malformations - Cardiology
Basic examination for heart malformations - ENT area
Basic hearing test and regular check-ups every 2-3 years, semi-annual tumor screening from the 2nd decade of life - Dentistry
Semi-annual check-ups (clinical, no x-rays)
In this context, please also note the supplementary recommendations of the Fanconi Anemia Registry (download PDF).
