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:

  • Testing of cultured lymphocytes or fibroblasts (specifically in cases with somatic mosaicism) for increased rates of spontaneous chromosome breakage. The addition of DNA-intercalating agents (diepoxybutane (DEB) or mitomycin C (MCC), allows the evaluation of an increased chromosome breakage rate.

  • Flow cytometry: more cells arrest in G2

  • Molecular genetics (next generation sequencing -> gene panel analysis)

  • Determining the FA subclass is decisive for assessing the tumor risk in homozygous or heterozygous mutation carriers with consecutive recommendations for early detection, e.g. FANCD1 -> BRCA2 mutation; with heterozygosity, there is already an increased risk of malignant mammary and ovarian carcinomas; with homozygous -> Fanconi anemia

Differential Diagnoses

  • SAA, MDS, congenital syndromes with bone marrow failure

  • DNA repair defects such as Nijmegen breakage syndrome and Bloom syndrome

Clinical Presentation

Clinical Abnormalities

60-70% of FA patients exhibit obvious clinical anomalies:

  • Skeletal malformations of the upper extremities (typically radius line and thumb)

  • Main pigment changes (hyperpigmentation, hypopigmentation, vitiligo)

  • Dwarfism

  • Microcephaly, small eyes, broad nasal root, micrognathia, and epicanthus -> characteristic facial expression in FA patients

  • Malformations of the internal organs, primarily the kidneys and heart

  • Endocrinological disorders (80% of patients):

    • Dwarfism
    • Hypothyroidism
    • Reduced glucose tolerance
    • Diabetes mellitus
    • Hyperinsulinism

  • Progressive bone marrow failure, starting in the first decade of life (often the first clinical sign of the disease, leading to further diagnostics)
    Bicytopenia or tricytopenia in > 80% of FA patients at the age of 10 and in 90% by the age of 40 (thrombocytes < 100,000/µl, Hb < 10 g/dl, absolute number of neutrophils < 1000/µl)

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):

  • Squamous epithelial carcinomas of the head and neck region (risk increased 500-700 times, 65% oral cavity, very aggressive, 2-year survival rate < 50%, extensive surgical excision if possible)

  • Squamous epithelial carcinomas in the anogenital region (particularly vulvar carcinoma, risk increased 2000-4000 times)

  • Liver tumors: usually only benign liver adenomas during androgen therapy, with spontaneous regression after the treatment is discontinued; hepatocellular carcinomas rare

  • Medulloblastoma

  • Nephroblastoma

Therapeutic Considerations

  • Blood transfusions / G-CSF with cytopenia requiring treatment (thrombopenia without active signs of bleeding does not require a transfusion)

  • Synthetic androgens with progressive bone marrow failure

  • Bone marrow transplant with advanced bone marrow failure or signs of transformation

  • Growth hormones to correct dwarfism

  • If avoidable, no exposure to radiation due to hypersensitivity to ionizing radiation

  • Hypersensitivity to alkylating agents (cyclophosphamide, ifosfamide, melphalan, mechlorethamine, busulfan, nitrosourea, procarbazine, dacarbazine, temozolomide, thiotepa, and also platinum derivatives)

  • Patient education with respect to oral hygiene and monthly oral self-monitoring for changes in the mucous membranes (or with parental help)

  • Avoiding alcohol and tobacco consumption

  • No medications given that would impair thrombocyte function, such as non-steroidal antiphlogistic drugs (e.g. ibuprofen).

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)
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