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Fanconi anaemia


Other namesFanconi pancytopenia
Atlas_Id 10001
Note Fanconi anaemia is a chromosome instability syndrome with progressive bone marrow failure and an increased risk of cancers
Inheritance autosomal recessive; frequency is about 2.5/105 newborns


Phenotype and clinics
  • growth retardation (70% of cases)
  • skin abnormalities: hyperpigmentation and/or café au lait spots in 80%
  • squeletal malformations (60%), particularly radius axis defects (absent or hypoplastic thumb or radius...)
  • no immune deficiency (in contrast with most other chromosome instability syndromes)
  • progressive bone marrow failure; mean age of onset of anemia: 8 yrs; diagnosis made before onset of haematologic manifestations in only 30%
  • other: renal anomalies, hypogonadism, mental impairment, heart defects, and perhaps diabetes mellitus, also occur in 10 to 30% of cases
  • Neoplastic risk
  • myelodysplasia (MDS) and acute non lyphocytic leukaemia (ANLL): 15% of cases; i.e. a 15000 fold increased risk of MDS and ANLL has been evaluated in FA, and it has been assumed that 'it is reasonable to regard the Fanconi anemia genotype as "preleukemia"'; mean age at diagnosis: 13-15 yrs
  • hepatocarcinoma (androgen-therapy induced) in 10%; mean age at diagnosis: 16 yrs
  • other cancers in 2-5%: in particular squamous cell carcinoma
  • Treatment androgens and steroids to improve haematopoietic functions; bone marrow transplantation prevents from terminal pancytopenia, and from ANLL as well
  • mean age at death: 16 years; most patients die from marrow aplasia (haemorrhage, sepsis), and others from malignancies; MDS and ANLL in FA bear a very poor prognosis (median survival of about 6 mths); survival is also poor in the case of a squamous cell carcinoma.
  • It has recently been shown that significant phenotypic differences were found between the various complementation groups (see below). In FA group A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. FA group G patients had more severe cytopenia and a higher incidence of leukemia. FA group C patients had less somatic abnormalities, which, in reverse, were more frequent in the rare groups FA-D, FA-E, and FA-F. FA group G patients patients and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention.
  • There may also be a certain degree of clinical heterogeneity.according to the degree of mosaicism. Therefore, clinical manifestations may be variable within a given family, according to the stage of embryonic development at which the somatic reverse mutation occurred.
  • Cytogenetics

    Inborn conditions
  • spontaneous chromatid/chromosome breaks, triradials, quadriradials
  • hypersensitivity to the clastogenic effect of DNA cross-linking agents (increased rate of breaks and radial figures); diepoxybutane, mitomycin C, or mechlorethamine hydrochlorid are used for diagnosis
      A: gaps; B: breaks; C: deletion; D: triradials; E: quadriradials; F: complex figures; G: dicentric. Giemsa staining - Editor
    Cytogenetics of cancer various clonal anomalies are found in MDS or ANLL in Fanconi anaemia patients, such as the classical -5/del(5q), and -7/del(7q), found in 10 % of cases; telomeres appear to be non randomly involved in FA's clonal anomalies.

    Other findings

  • slowing of the cell cycle (G2/M transition, with accumulating of cells in G2)
  • impaired oxygen metabolism
  • defective P53 induction
  • Genes involved and Proteins

  • There are 7 complementation groups (A to G).
    The most prevalent complementation groups are: group A (65-70% of cases), groups C and G (10-15% each)
    Rare complementation groups are groups B, D, E, and F (<1 to 3 % each).

  • Six genes have been discovered, corresponding to the frequent phenotypes:
    FANCA in 16q24,
    FANCC in 9q22,
    and FANCG in 9p13,
    and to the rarer phenotypes:
    FANCD2 in 3p25.
    FANCE in 6p21,
    and in 11p15,
    NOTE The genes FANCB and FANCD1 have yet to be uncovered.

  • To be noted

  • Clinical diagnosis may, in certain cases, be very difficult; cytogenetic ascertainment is then particularly useful; however, cytogenetic diagnosis may also, at times, be very uncertain; this is a great problem when bone marrow engraftment has been decided in a pancytopenic patient: if this patient has FA, bone marrow conditioning must be very mild, as FA cells are very clastogen sensitive. The recent discover of genes involved in the disease should improve diagnostic ascertainment.
  • FA patients (i.e. patients with defective alleles) may have, in a percentage of cells, a somatic reversion (by revert mutation towards wild-type gene); such a phenomenon is also known in Bloom syndrome, another chromosome instability syndrome
  • External links

    OrphanetFanconi anemia
    AssociationFanconi's Anemia International Registry
    AssociationAssociation Francaise de la Maladie de Fanconi
    RegistryInternational Fanconi Anemia Registry (IFAR)


    Spectrum of anomalies in Fanconi anaemia.
    Glanz A, Fraser FC
    Journal of medical genetics. 1982 ; 19 (6) : 412-416.
    PMID 7154038
    Karyotype evolution in the bone marrow of a patient with Fanconi anemia: breakpoints in clonal anomalies of this disease.
    Huret JL, Tanzer J, Guilhot F, Frocrain-Herchkovitch C, Savage JR
    Cytogenetics and cell genetics. 1988 ; 48 (4) : 224-227.
    PMID 3248378
    Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi Anemia Registry.
    Auerbach AD, Allen RG
    Cancer genetics and cytogenetics. 1991 ; 51 (1) : 1-12.
    PMID 1984836
    Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9.
    Strathdee CA, Duncan AM, Buchwald M
    Nature genetics. 1992 ; 1 (3) : 196-198.
    PMID 1303234
    Cloning of cDNAs for Fanconi's anaemia by functional complementation.
    Strathdee CA, Gavish H, Shannon WR, Buchwald M
    Nature. 1992 ; 356 (6372) : 763-767.
    PMID 1574115
    Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study.
    Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD
    Blood. 1994 ; 84 (5) : 1650-1655.
    PMID 8068955
    Identification and chromosomal localization of a DNA fragment implicated in the partial correction of the Fanconi anemia group D cellular defect.
    Diatloff-Zito C, Duchaud E, Viegas-Pequignot E, Fraser D, Moustacchi E
    Mutation research. 1994 ; 307 (1) : 33-42.
    PMID 7513813
    Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.
    Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H
    Nature genetics. 1996 ; 14 (3) : 320-323.
    PMID 8896563
    Positional cloning of the Fanconi anaemia group A gene. The Fanconi anaemia/breast cancer consortium.
    Nature genetics. 1996 ; 14 (3) : 324-328.
    PMID 8896564
    Molecular biology of Fanconi anemia: implications for diagnosis and therapy.
    D'Andrea AD, Grompe M
    Blood. 1997 ; 90 (5) : 1725-1736.
    PMID 9292505
    Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.
    Garcia-Higuera I, Kuang Y, Nˆ§f D, Wasik J, D'Andrea AD
    Molecular and cellular biology. 1999 ; 19 (7) : 4866-4873.
    PMID 10373536
    Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
    Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M, Havenga C, Morgan N, de Winter J, Digweed M, Savoia A, Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E, Mathew CG
    Blood. 2000 ; 96 (13) : 4064-4070.
    PMID 11110674
    Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.
    Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD
    Molecular cell. 2001 ; 7 (2) : 249-262.
    PMID 11239454
    Fanconi anemia and DNA repair.
    Grompe M, D'Andrea A
    Human molecular genetics. 2001 ; 10 (20) : 2253-2259.
    PMID 11673408
    Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway.
    Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG
    Human molecular genetics. 2001 ; 10 (4) : 423-429.
    PMID 11157805
    Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner.
    Qiao F, Moss A, Kupfer GM
    The Journal of biological chemistry. 2001 ; 276 (26) : 23391-23396.
    PMID 11297559
    Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes.
    Yamashita T, Nakahata T
    International journal of hematology. 2001 ; 74 (1) : 33-41.
    PMID 11530803
    Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.
    Callˆ©n E, Samper E, Ramˆ‚rez MJ, Creus A, Marcos R, Ortega JJ, Olivˆ© T, Badell I, Blasco MA, Surrallˆ©s J
    Human molecular genetics. 2002 ; 11 (4) : 439-444.
    PMID 11854176
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    Written02-1998Jean-Loup Huret
    Updated06-2002Jean-Loup Huret


    This paper should be referenced as such :
    Huret JL
    Fanconi anaemia;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version :
    History of this paper:
    Atlas Genet Cytogenet Oncol Haematol. June 2002

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Jun 17 15:19:50 CEST 2015

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