Home > D. Systemic pathology > Genetic and developmental anomalies > Fanconi disease

Fanconi disease


Monday 29 September 2003

Definition: Fanconi anaemia (FA) is a rare autosomal recessive disease characterized by increased spontaneous and DNA crosslinker-induced chromosome instability, progressive pancytopenia and cancer susceptibility.

Fanconi anemia (FA) is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents.

Identification of 11 genes for FA has led to progress in the molecular understanding of this disease. FA proteins, including a ubiquitin ligase (FANCL), a monoubiquitinated protein (FANCD2), a helicase (FANCJ/BACH1/BRIP1), and a breast/ovarian cancer susceptibility protein (FANCD1/BRCA2), appear to cooperate in a pathway leading to the recognition and repair of damaged DNA.

Molecular interactions among FA proteins and responsible proteins for other chromosome instability syndromes (BLM, NBS1, MRE11, ATM, and ATR) have also been found.

Furthermore, inactivation of FA genes has been observed in a wide variety of human cancers in the general population. These findings have broad implications for predicting the sensitivity and resistance of tumors to widely used anticancer DNA crosslinking agents (cisplatin, mitomycin C, and melphalan).

Fanconi anaemia (FA) is therefore an attractive model to study breast cancer susceptibility (BRCA) genes, as three FA genes, FANCD1, FANCN and FANCJ, are identical to the BRCA genes BRCA2, PALB2 and BRIP1.

Increasing evidence shows that FA proteins (FANCs) function as signal transducers and DNA-processing molecules in a DNA-damage response network, consisting of many proteins that maintain genome integrity, including ataxia telangiectasia and Rad3 related protein (ATR), Bloom syndrome protein (BLM), and BRCA1.


- fetal systemic anomalies

  • low birth weight
  • small stature - craniofacial anomalies
  • microcephaly
  • strabismus
  • microphthalmia

- fetal skeletal anomalies

  • radial aplasia (radial agenesis)
  • thumb deformity
  • thumb aplasia
  • thumb hypoplasia
  • duplicated thumb

- hematological anomalies

  • anemia
  • neutropenia
  • thrombocytopenia
  • reticulocytopenia
  • pancytopenia
  • bleeding
  • leukemia

- cutaneous anomalies (#20973772# )

  • anemic pallor
  • bruisability
  • pigmentary changes
  • hyperpigmentation
  • cafe-au-lait spots

- VACTERL association (#16410081#)
- cardiac malformations

- renal malformations

  • absent kidney (renal agenesis)
  • duplicated kidney (renal duplication)
  • duplicated collecting system
  • horseshoe kidney
  • Renal ectopia

- genital anomalies

  • hypergonadotropic hypogonadism
  • cryptorchidism

- tumoral predisposition

  • Fanconi-associated leukemias
    • Fanconi-associated acute lymphoblastic leukemia
  • Fanconi-associated lymphomas
  • Fanconi-associated Wilms tumor (#14670928#, #16410081#)
  • Fanconi-associated medulloblastoma (#14670928#)
  • hepatoblastoma (#21138478#)
  • Fanconi-associated neuroblastoma (#16410081#)
  • Fanconi-associated carcinomas
    • Fanconi-associated squamous cell carcinomas
      • Fanconi-associated tonsillar squamous cell carcinomas (#21925890#)
      • metachronous squamous cell carcinoma (#21701297#)


- chromosomal instability
- multiple chromosomal breaks
- chromosomal breakage induced by diepoxybutane (DEB), and mitomycin C
- deficient excision of UV-induced pyrimidine dimers in DNA
- prolonged G2 phase of cell cycle


12 Fanconi anemia complementation group genes (FANCs)

Locus Gene MIM Loc.
FANCA FANCA MIM.607139 16q24.3
FANCB FAAP95 MIM.300514 Xp22.31
FANCC FANCC MIM.227645 9p22.3
FANCD1 BRCA2 MIM.605724 13q12.3
FANCD2 FANCD2 MIM.227646 3p25.3
FANCE FANCE MIM.600901 6p22-p21
FANCF FANCF MIM.603467 11p15
FANCG XRCC9 MIM.602956 9p13
FANCJ BRIP1 MIM.605882 17q22
FANCL PHF9 MIM.608111 2p16.1

5 known proteins (2003)


- Fanconi anemia patients have decreased number of all cellular elements of the blood (i.e., erythrocytes, leukocytes and platelets), hyperpigmentation and short stature.

- Cultured cells from some FA patients are sensitive to chemical agents, such as mitomycin C (MMC) or photoactivated psoralen derivatives, that induce the formation of interstrand crosslinks on DNA. Thus, FA cells seem to have a defect on the specific repair for this kind of lesions. However, this is not true for all FA patients, indicating certain genetic heterogeneity for the disease.

- In fact, at least five genetic complementation groups (groups A to E) have been found associated with FA. Only two of the genes have been cloned, FAA (Lo Ten Foe et al., 1996) and FAC (Strathdee et al., 1992), but no specific functions have been attributed to the FAA and FAC proteins until now.

- The cDNA clone for the FAA gene encodes a polypeptide predicted to contain 2 overlapping bipartite nuclear localization signals and a partial leucine zipper consensus sequence, suggesting that the protein is localized in the nucleus.

- However, the FAC protein is normally found in the cytoplasm (Yamashita et al., 1994), which is not expected for a DNA repair enzyme. Recent data reveal that cells from FA patients also have elevated recombination activity (Thyagarajan and Campbell, 1997) and deregulated apoptosis (Ridet et al., 1997).

- These findings implicate that the FA genes may play major roles in the control of DNA metabolism and of apoptosis.

- An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a proteic complex called "FA complex" that is required for FANCD2 activation in response to DNA crosslinks.

- Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation.

- crosstalk with ATM, BRCA1 and BRCA2, involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability

- Fanconi anemia proteins (FANCs) function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2.

- A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1. The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs.

- Fanconi anemia is an autosomal recessive disorder characterised by progressive bone marrow failure and an increased risk of cancer, most commonly acute myeloid leukaemia. Patients with this disease have chronologically accelerated telomere shortening. Cells from patients with Fanconi anemia have increased sensitivity to DNA crosslinking agents.

- Fanconi anemia can arise from mutations in different genes, including the breast cancer susceptibility gene BRCA2. These and other findings firmly establish a direct role for Fanconi anaemia group proteins in the response to DNA damage.

- In view of the raised oxidative stress sensitivity of Fanconi anemia cells, an increased rate of cell turnover could chronologically accelerate telomere shortening.

- Alternatively, a faster rate of telomere shortening with each cell division could result from increased telomere damage. Cells of patients with ataxia telangiectasia show increased telomere damage, but immortal ataxia telangiectasia cell lines do not differ from controls in any measured variable of telomere length maintenance. Therefore, rates of telomere shortening will have to be measured directly in different cell types from individuals with Fanconi anemia and from healthy people, to establish a direct effect of disease on rate of telomere loss.

- Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination.


- diepoxybutane-induced chromosomal breakage test in fetal blood cells


The first line of therapy is androgens and hematopoietic growth factors, but only 50-75% of patients respond. A more permanent cure is hematopoietic stem cell transplantation.

If no potential donor exist, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to match the recipients HLA type.

If there is no matching donor, some parents have conceived a second child by in vitro fertilization, screening the zygotes by preimplantation genetic diagnosis for a sibling that will be a genetic match (for human leucocyte antigen) and will be free from Fanconi anemia itself.

See also

- Fanconi anemia protein complex (FA complex)
- PHF9 (ubiquitin ligase activity)


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