Download Cancer Prone Disease Section Fanconi anaemia Atlas of Genetics and Cytogenetics

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