Synonyms: Fanconi anaemia (FA), inherited bone marrow failure syndrome
This condition was first described by Fanconi in 1927. It is the commonest of a group of relatively rare diseases known as the Inherited Bone Marrow Failure Syndromes (IBMFS). It is usually inherited in an autosomal recessive fashion and is due to a disorder of chromosomal stability. 13 affected genes have been identified to date and sufferers are homozygous for one, or heterozygous for two separate loci. The exact pathophysiology is not understood, as the role of the proteins produced by the defective genes are multifunctional and not fully elucidated. However, the proteins are believed to be integral to mechanisms that repair damage to DNA, by removing faulty interstrand crosslinks.
The condition tends to cause:
A rare condition with approximately 3 per million population with heterozygote frequency estimated at 1 in 300 in Europe and USA. It affects many ethnic groups and appears to have a higher carrier frequency (~ 1 in 80) amongst Ashkenazi Jews and Afrikaners.
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Most are diagnosed before 7 years old but 9% are diagnosed as adults. Consider the diagnosis in adult patients presenting with:
- Aplastic anaemia.
- Myelodysplastic syndrome.
- Acute myeloid leukaemia (AML).
- Head and neck squamous cell carcinoma (HNSCC).
- Gynaecological cancers in women less than 50 years old.
There appears to be a correlation between the presence of significant birth defects and the age of onset of anaemia.
About 75% will have detectable physical abnormalities that can be relatively subtle:
- The skin may be hyperpigmented with café-au-lait spots.
- Often low birthweight and small for age.
- The face may be triangular in shape.
- The thumbs and radii can show structural abnormalities (usually aplasia or hypoplasia), as can the fingers and toes. There are a range of associated skeletal abnormalities.
- Microcephaly, microphthalmia and deafness occur.
- Cardiac and renal malformations are encountered.
- The gonads in older patients tend to be atrophic or dysmorphic with a range of associated genitourinary abnormalities, causing reduced fertility.
Usually presents in childhood as:
- Bleeding tendency
- Susceptibility to infection
It may present as leukaemia in about 10% and myelodysplastic syndrome in about 5% (usually teenagers/young adults) who have not had an antecedent history of anaemia.
The cumulative incidence of solid tumours by age 45 is about 30%, which continues to rise with the patient's age.
- Liver adenoma/hepatomas predominantly affect those who have had anaemia treated by androgens.
- Head and neck, oesophageal and gynaecological/genital tumours may occur.
- The risk of oral cancers appears to be increased by bone marrow transplantation.
- There does not appear to be an overall increased incidence of cancer in relatives but an increased risk of breast cancer has been found in carrier grandmothers, so a heterozygote allele may confer susceptibility to breast cancer.
- FBC may show macrocytosis with mild anaemia through to pancytopenia. Initial presentation may be with isolated thrombocytopenia or leukopenia.
- Bone marrow biopsy/aspiration reveals progressively hypocellular marrow with loss of myeloid and erythroid precursors and megakaryocytes, eventually becoming typical of aplastic anaemia with fatty marrow.
- Cytogenetics can provide definitive diagnosis. The metaphase appearance of multiple chromosomal breaks in lymphocytes stimulated by a clastogen, such as mitomycin C, is diagnostic in most cases. Direct testing for the known genetic abnormalities is usually only conducted for research purposes currently.
- Skeletal X-ray survey and echocardiography/liver and renal ultrasound are used to detect other abnormalities.
- Acquired aplastic anaemia.
- Thrombocytopenia absent radii (TAR) syndrome.
- VATER association: vertebral defects (V), anal atresia (A), tracheoesophageal fistula with (o)esophageal atresia (TE), and radial or renal dysplasia (R).
- Diamond-Blackfan anaemia.
- Nijmegen breakage syndrome (NBS) - extremely rare syndrome of immune deficiency, microcephaly, ionising radiation sensitivity and haematopoietic abnormality with a Slavic preponderance.
- Immune pancytopenia.
- Myelodysplastic syndrome.
- Families should be offered genetic counselling and cytogenetic testing. Apparently unaffected siblings should be tested for Fanconi's anaemia homozygosity. The potential for phenotypic variability within a family should be explained.
- Further investigations to find associated abnormalities may be conducted.
- Androgens may be used to boost haematopoiesis but there are many complications, including liver tumours, inappropriate masculinisation and epiphyseal fusion.
- Colony stimulating factors can be used in conjunction with androgens or in place of them if they have failed.
- Blood transfusions are used to maintain counts and treat symptomatic problems.
- Bone marrow/haematopoietic stem cell transplantation using related donors (where possible) is the only curative treatment. Timing is controversial. Less toxic 'conditioning' regimens are now being used with low-dose alkylating agents and less or no radiation (due to increased susceptibility) and have achieved medium-term survival rates of around 70%. After transplantation, careful monitoring for evidence of leukaemia/solid tumours is necessary.
Cumulative incidences (to 48 years old):
- Leukaemia - 10%.
- Death from bone marrow failure - 11%.
- Solid tumour - 29%.
- Bone marrow transplantation - 43%.
As individuals survive longer with bone marrow transplants, there is likely to be increased risk of solid tumour as the deaths from aplastic anaemia decrease.
Median survival is around 30 years but is improving with advances in therapy and screening for tumours.
Genetic counselling for affected families to enable carriers/potential carriers to make reproductive choices. Prenatal diagnosis is possible - radial ray abnormalities raise suspicion on antenatal ultrasound and flow cytometry/genetic testing on fetal cells (extracted via amniocentesis, chorionic villis sampling or cord blood) can provide diagnosis. Preimplantation genetic diagnosis is also possible using assisted reproductive techniques. These can similarly be used to produce an HLA-matched, unaffected sibling for future bone marrow transplantation needs.
Further reading & references
- Fanconi Anemia, Online Mendelian Inheritance in Man (OMIM)
- Contact a Family; Fanconi's anaemia
- Children's cancer web; Children's cancer web: Fanconi anaemia; Links to organisations worldwide
- Lobitz S, Velleuer E; Guido Fanconi (1892-1979): a jack of all trades. Nat Rev Cancer. 2006 Nov;6(11):893-8. Epub 2006 Oct 12.
- Knipscheer P, Raschle M, Smogorzewska A, et al; The Fanconi anemia pathway promotes replication-dependent DNA interstrand Science. 2009 Dec 18;326(5960):1698-701. Epub 2009 Nov 12.
- Tischkowitz MD, Hodgson SV; Fanconi anaemia. J Med Genet. 2003 Jan;40(1):1-10.
- Weinstein LB; Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health. 2007 Jan-Mar;30(1):50-62.
- Alter BP; Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program. 2007;2007:29-39.
- Alter BP; Bone marrow failure: a child is not just a small adult (but an adult can have a childhood disease). Hematology Am Soc Hematol Educ Program. 2005;:96-103.
- Alter BP, Lipton JM; Fanconi anemia, eMedicine, Sept 2009
- Tischkowitz M, Easton DF, Ball J, et al; Cancer incidence in relatives of British Fanconi Anaemia patients. BMC Cancer. 2008 Sep 11;8:257.
- Berwick M, Satagopan JM, Ben-Porat L, et al; Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007 Oct 1;67(19):9591-6.
- MacMillan ML, Wagner JE; Haematopoeitic cell transplantation for Fanconi anaemia - when and how? Br J Haematol. 2010 Apr;149(1):14-21. Epub 2010 Feb 5.
- Torjemane L, Ladeb S, Ben Othman T, et al; Bone marrow transplantation from matched related donors for patients with Fanconi anemia using low-dose busulfan and cyclophosphamide as conditioning. Pediatr Blood Cancer. 2006 Apr;46(4):496-500.
- Locatelli F, Zecca M, Pession A, et al; The outcome of children with Fanconi anemia given hematopoietic stem cell transplantation and the influence of fludarabine in the conditioning regimen: a report from the Italian pediatric group. Haematologica. 2007 Oct;92(10):1381-8.
- Rosenberg PS, Greene MH, Alter BP; Cancer incidence in persons with Fanconi anemia. Blood. 2003 Feb 1;101(3):822-6. Epub 2002 Sep 5.
- Kennelly MM, Moran P; A clinical algorithm of prenatal diagnosis of Radial Ray Defects with two and three dimensional ultrasound. Prenat Diagn. 2007 Aug;27(8):730-7.
- Bechtold A, Friedl R, Kalb R, et al; Prenatal exclusion/confirmation of Fanconi anemia via flow cytometry: a pilot study. Fetal Diagn Ther. 2006;21(1):118-24.
- Verlinsky Y, Rechitsky S, Schoolcraft W, et al; Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA. 2001 Jun 27;285(24):3130-3.
|Original Author: Dr Sean Kavanagh||Current Version: Dr Chloe Borton|
|Last Checked: 16/07/2010||Document ID: 2136 Version: 21||© EMIS|
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