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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Fanconi anaemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: June 2002 Online updated version: http://AtlasGeneticsOncology.org/Kprones/FA10001.html DOI: 10.4267/2042/37911 This article is an update of: Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 1998;2(2):68-69 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. Identity Alias Fanconi pancytopenia 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. Treatment Androgens and steroids to improve haematopoietic functions; bone marrow transplantation prevents from terminal pancytopenia, and from ANLL as well. Prognosis Clinics 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 FAF. FA group G patients patients and patients homozygous for null mutations in FANCA are highrisk groups with a poor hematologic outcome and should be considered as candidates both for 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 Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4) 308 Fanconi anaemia Huret JL A: gaps; B: breaks; C: deletion; D: triradials; E: quadriradials; F: complex figures; G: dicentric. Giemsa staining - Editor. Cytogenetics 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 (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 FANCF in 11p15.The genes FANCB and FANCD1 have yet to be uncovered. Inborn conditions To be noted 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. 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. Note 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. 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 Note Slowing of the cell cycle (G2/M transition, with accumulating of cells in G2). Impaired oxygen metabolism. Defective P53 induction. References Glanz A, Fraser FC. Spectrum of anomalies in Fanconi anaemia. J Med Genet. 1982 Dec;19(6):412-6 Genes involved and proteins Huret JL, Tanzer J, Guilhot F, Frocrain-Herchkovitch C, Savage JR. Karyotype evolution in the bone marrow of a patient with Fanconi anemia: breakpoints in clonal anomalies of this disease. Cytogenet Cell Genet. 1988;48(4):224-7 Note There are 7 complementation groups (A to G). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4) 309 Fanconi anaemia Huret JL Auerbach AD, Allen RG. Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi Anemia Registry. Cancer Genet Cytogenet. 1991 Jan;51(1):1-12 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. Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood. 2000 Dec 15;96(13):4064-70 Strathdee CA, Duncan AM, Buchwald M. Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet. 1992 Jun;1(3):196-8 Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992 Apr 30;356(6372):763-7 Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001 Feb;7(2):249-62 Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD. Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study. Blood. 1994 Sep 1;84(5):1650-5 Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum Mol Genet. 2001 Oct 1;10(20):2253-9 Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum Mol Genet. 2001 Feb 15;10(4):423-9 Diatloff-Zito C, Duchaud E, Viegas-Pequignot E, Fraser D, Moustacchi E. Identification and chromosomal localization of a DNA fragment implicated in the partial correction of the Fanconi anemia group D cellular defect. Mutat Res. 1994 May 1;307(1):33-42 Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner. J Biol Chem. 2001 Jun 29;276(26):23391-6 . Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996 Nov;14(3):324-8 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. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet. 1996 Nov;14(3):320-3 Yamashita T, Nakahata T. Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes. Int J Hematol. 2001 Jul;74(1):33-41 Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44 D'Andrea AD, Grompe M. Molecular biology of Fanconi anemia: implications for diagnosis and therapy. Blood. 1997 Sep 1;90(5):1725-36 This article should be referenced as such: Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD. Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex. Mol Cell Biol. 1999 Jul;19(7):4866-73 Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4) Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):308-310. 310