Date of publication: 2009-03-30
Version: 1.0
Fanconi anaemia is an inherited disorder. Though primarily considered a blood disease, it may affect all systems and organs of the body. The condition is named after Swiss paediatrician Guido Fanconi, who published the first case description in 1927.
Haematological (blood) abnormalities in Fanconi anaemia include low counts of platelets (thrombocytes), red blood cells and white blood cells. Children with the condition are often born with skeletal anomalies, for example thumb and hip malformations or missing radius (one of the forearm bones), often in association with kidney, intestine and/or heart defects. Fanconi anaemia is also associated with an increased risk of bone marrow failure (aplastic anaemia).
Fanconia anaemia is associated with an increased predisposition to malignancies. Of the several types of cancer which may occur, pre-leukaemic conditions known as myelodysplastic syndromes (MDS) are most common. MDS can progress to blood cancer (acute myeloid leukaemia, AML). There is also a high risk of developing malignant solid tumours, primarily in the liver and head and neck region.
Large-scale patient studies show that Fanconi anaemia is a genetic disease, meaning that it is caused by a gene mutation. Fanconi anaemia is currently subdivided into 13 groups (complementation groups), depending on which gene is mutated. The most prevalent complementation group is known as FANCA.
The incidence of Fanconi anaemia is 1-5 individuals per million population. The disorder is equally distributed between the sexes and exists in all ethnic groups. In Sweden, approximately one child is diagnosed per year. The worldwide incidence of carriers, i.e. unaffected individuals carrying one copy of the gene mutation causing the disease, is approximately 1 per 200. As the disease may be asymptomatic or very mild it is likely that the disorder is under-diagnosed.
Fanconi anaemia is caused by a mutation in one of several genes coding for the production of proteins that contribute to protecting and repairing damaged DNA. The identification of the underlying mutation is an important part of diagnostics.
Mutations in 13 different genes have hitherto been associated with Fanconi anaemia. They are known as FANCA, FANCB, FANC, FANCC, FANCD1 (also known as BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL, FANCM och FANCN. In approximately 75 per cent of all cases, the underlying mutation is FANCA or FANCC. It is important to identify the specific gene mutation in each case, as the severity of the disease and the risk of developing aplastic anaemia or malignancies depends on the complementation group.
With one exception, all the complementation groups of Fanconi anaemia have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means that two mutated genes are needed in order to develop the disease. If both parents are healthy carriers of the mutated gene, their children will have a 25 per cent risk of inheriting two mutated genes (one from each parent) and developing the disease. In 25 per cent of the cases the child will inherit two normal genes and will neither develop the disease nor pass it down. In 50 per cent of the cases the child will inherit only one copy of the mutated gene (from one parent) and become a healthy carrier.
If one parent is not a carrier, but the other has an inherited autosomal recessive disorder (and thus has two mutated genes), the children will all be carriers of the defective gene but the condition will not affect them. If an individual with an inherited autosomal recessive disorder has a child with someone who has one copy of the defective gene, there is a 50 per cent risk that the child will develop the condition, while in 50 per cent of the cases the child will be a healthy carrier.
The inheritance pattern of a very rare complementation group, FANCB, is X-linked recessive. This means that the condition is passed down via female carriers of the mutation, who are normally healthy, while only males develop the disease.
The disease onset is usually insidious, but Fanconi anaemia should be suspected in newborns with characteristic forearm radius bone and hand abnormalities. Hand anomalies include an extra thumb, a missing thumb or misshapen thumbs. Children with Fanconi anaemia often have short stature and may have a characteristic appearance with a small head circumference and small eyes. They may also have minor skeletal defects, such as congenital hip abnormalities, spinal malformations and rib abnormalities. Some children have depigmented skin areas or café-au-lait spots (brownish skin discolorations), which are in themselves harmless. Some children may have a congenital heart defect in which the wall that separates the upper chambers (the atria) or the lower chambers of the heart (the ventricles) does not close completely (ASD, atrium septal defect or VSD, ventricular septum defect). Kidney malformations sometimes occur or one kidney may be absent. These abnormalities are often asymptomatic, and may therefore be discovered coincidentally in connection with other medical examinations.
Small children with Fanconi anaemia may fail to thrive owing to feeding difficulties, and are susceptible to infection. Motor development may be delayed, and some children have learning disorders or intellectual disabilities. Squinting and hearing loss are common symptoms. Some children with Fanconi anaemia fail to enter normal puberty, or its onset may be delayed. The disease may also affect the liver.
All Fanconi anaemia patients run a high risk of bone marrow failure (aplastic anaemia). Bone marrow is the soft tissue within the bone that is responsible for the production of blood cells. The first signs of a decrease in bone marrow activity include bleedings, infections, and episodes of fever and fatigue. The lowered production of blood cells is first detectable as a drop in platelet (thrombocyte) count, giving rise to symptoms such as bleedings in the skin (bruises), gums, nose or urinary tract. About a year later the white blood cell count also decreases, leading to recurrent throat, ear or lung infections. Finally, when the red blood cell count decreases, manifesting as fatigue, the diagnosis of aplastic anaemia can be confirmed.
Aside from the risk of aplastic anaemia, Fanconi anaemia is associated with an elevated risk of developing malignant tumours. The underlying cause is inability to repair DNA damages. The most common malignancies associated with Fanconi anaemia are myelodysplastic syndrome and acute myeloid leukaemia, liver cancer and tumours in the head and neck area.
The diagnosis is suspected on the basis of clinical expression, and can be confirmed in laboratory tests. The family should be offered genetic counselling as soon as the diagnosis is established.
Chromosomal breakage analysis
Fanconi anaemia belongs to a group of disorders associated with chromosome instability, known as chromosomal breakage syndromes. Abnormal findings of chromosome breaks in the cells therefore contribute significantly to the diagnosis. The analysis is usually carried out on lymphocytes, a type of white blood cell. In most individuals with the disease, the number of cells with spontaneous chromosome breaks is clearly elevated, but in some cases the number remains within the normal range. For this reason the test is now supplemented with an analysis of lymphocytes exposed to DNA-damaging agents, usually mitomycin C or diepoxybutane. In Fanconi anaemia, this test will detect a high frequency of chromosome breaks.
Cell cycle analysis
Cell cycle analysis (flow cytometry) is used to count the number of cells that have remained in a specific phase of cell development as a result of exposure to mitomycin C or diepoxybutane. In Fanconi anaemia, the number of cells arrested in this cycle phase is significantly increased.
Molecular genetic diagnostics
If any of the above tests suggest Fanconi anaemia, DNA diagnostics is available, for example at the European Fanconi Anaemia Center in Amsterdam, the Netherlands.
Prenatal diagnostics
Prenatal diagnosis is available if the specific mutation in the family is identified. The test is carried out through chorionic villius sampling (placental biopsy), performed from around the 12th week of gestation, or amniocentesis (sample of amniotic fluid from the uterus), from week 15.
Treatment teams
As Fanconi anaemia affects several internal organs and body systems, a number of different specialists are involved in treatment. Owing to the high incidence of haematological complications it is advisable for a paediatric haematologist/oncologist (a physician with advanced training in diagnosing and treating diseases of the blood and childhood cancers) to serve as coordinator for the treatment team.
Congenital malformations
A paediatric cardiologist should be consulted at an early stage for diagnosis and treatment of any cardiac anomaly. Surgical intervention is rarely required.
Corrective surgery, performed by a hand surgeon, is sometimes required in children with congenital thumb deformities.
Vision and hearing
Vision and hearing should also be checked early. Squinting can be treated by patching the normal eye. In some cases, surgery may be required. Nearsightedness (myopia) can be corrected by eyeglasses. An audiologist assesses the child’s hearing level. In cases of hearing loss, the auditory services provide assistance in selecting and fitting hearing aids.
Hormonal imbalances
Hormonal imbalances, manifesting for example as delayed puberty or failure to enter puberty, are assessed by an endocrinologist (a physician who specialises in hormonal conditions), or in some cases by a gynaecologist or urologist (a physician specialising in conditions affecting the urinary tract and the male reproductive organs).
Blood and bone marrow
Blood counts and bone marrow evaluations should be carried out on a regular basis. The serum AFP level (the level of alpha-fetoprotein, a substance excreted by liver tumours) should also be measured on these occasions. Check-up frequency is determined by the symptoms and the severity of the disease.
Bone marrow evaluations should be performed approximately once a year. If blood counts drop, the evaluation should be carried out without delay. The bone marrow assessment should be supplemented with cytogenetic analysis for early detection of chromosomal aberrations associated with myelodysplastic syndromes and acute myeloid leukaemia. Examples of these chromosome aberrations include monosomy 7, trisomy 1, and additional chromosomal material in the region 3q26q29.
Precautions should be taken to prevent infections. All infections should be taken seriously and treated promptly. Bacterial infections should always be treated with antibiotics.
It is also important to avoid injuries that cause bleeding. Caution is advised in general, for example by avoiding high-risk sports. Platelet transfusions are administered in cases of bleeding.
Hematopoietic stem cell transplantation (commonly referred to as bone marrow transplantation) may cure aplastic anaemia. Transplantation should always be considered in a patient requiring recurrent platelet and/or red blood-cell transfusions. In this procedure, blood stem cells from a healthy donor are used to replace the stem cells of the person with the disease. Stem cells can be harvested from bone marrow, peripheral blood or umbilical cord blood. As soon as blood counts drop and there is a risk of developing aplastic anaemia, the transplantation procedure should be planned. Parents and siblings are examined for tissue type (HLA antigens) to match the recipient. HLA is a cell-surface protein that is used by the immune system. If the immune system encounters cells with an HLA type that is not recognised, a rejection reaction is initiated. The HLA type is inherited from both parents, and there is a 25% chance of two siblings having the same type. If there is no HLA match within the family, an unrelated HLA-identical donor may be located in a bone marrow donor registry. It is also possible to use umbilical cord blood, which is rich in stem cells. The advantage of using stem cells from umbilical cord blood is that the HLA type only needs to be partially matched, which increases the chance of locating a suitable donor. There are international as well as national biobanks for donated umbilical cord blood.
The preparative regimen includes chemotherapy and antibody treatment. This procedure is required in order to allow the haematopoietic stem cells to engraft. However, as Fanconi anaemia patients have unstable chromosomes and cells with impaired ability to repair DNA damages they are more sensitive to chemotherapy and do not tolerate the doses usually prescribed for stem cell transplantation. The preparative regimen (in this case referred to as reduced-intensity conditioning) therefore diverges significantly from the standard treatment.
Hematopoietic stem cell transplantation fully restores bone marrow function, and individuals who have undergone a transplant can usually return to regular activities within six months to one year. The procedure, however, has no effect on other manifestations of Fanconi anaemia.
Patients who have not undergone hematopoietic stem cell transplantation require regular blood transfusions. A side-effect of this treatment is gradual iron accumulation, eventually leading to organ damage. Iron overload is treated with chelation therapy, which increases iron excretion in the urine. Unfortunately, this treatment is very demanding, as the chelating agent must be infused very slowly, either subcutaneously (under the skin) or intravenously. Although treatment for iron overload has recently become available in oral form, infusions are still required.
All Fanconi anaemia patients, irrespective of whether transplantation has been performed or not, require lifelong monitoring for early detection of subsequent malignancies.
Psychological and social support, habilitation
The affected child and family should be offered social and psychological support. Contact with other families in a similar situation, who are willing to share their knowledge and experience, may also be valuable. All regional paediatric centres offer support from a contact nurse with special responsibility for children with haematological and tumour diseases.
Some children and families will benefit from contact with a paediatric habilitation centre, offering the expertise of professionals such as occupational therapists, habilitation physicians, habilitation counselors, speech therapists, psychologists, physiotherapists and special education teachers. All interventions should be adapted to the capacities and limitations of the individual. Each school term should be preceded by careful planning to meet the child’s special requirements. Children with learning disorders and/or intellectual disabilities need special education.
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Resources for diagnostics:
The special cell-cycle analysis, in which cells are exposed to mytomycin C or diepoxybutane, is at present only carried out at the division of Clinical Genetics at Lund University Hospital.
DNA-based diagnostics is carried out at the European Fanconi Anaemia Centre, Amsterdam, the Netherlands.
Paediatric resources:
The paediatric departments of Swedish regional hospitals all cooperate with specialized haematological-oncological teams.
Resources for adults:
Regional hospital haematology clinics.
For children:
Dr Albert N. Békássy, Department of Paediatrics, Lund University Hospital, SE-221 85 Lund, Sweden. Tel +46 46 17 82 72, email: albert_n.bekassy@med.lu.se. Dr. Békássy is the Swedish coordinator for the European Registry for Fanconi Anaemia. He coordinates and provides information on genetic diagnostics and current research.
Professor Göran Elinder, Department of Paediatrics, The Sachsska Children’s Hospital, SE-118 95 Stockholm, Sweden. Tel +46 8 616 41 33, email: goran.elinder@sos.sll.se.
Professor Anders Fasth, The Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden. Tel +46 31 343 52 20, email: anders.fasth@gu.se.
Per Frisk, MD, PhD, paediatric oncology and haematology, University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 58 87, email: per.frisk@akademiska.se.
Professor Bertil Johansson, Clinical Genetics Clinic, Lund University Hospital, SE-221 85 Lund, Sweden. Tel +46 46 17 33 62, email: bertil.johansson@klingen.lu.se.
Professor Rolf Ljung, Paediatric Centre, Malmö University Hospital (UMAS), SE-205 02 Malmö, Sweden. Tel +46 40 33 12 86, email: rolf.ljung@skane.se.
Professor Jacek Winiarski, Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel +46 8 585 800 00, email: jacek.winiarski@klinvet.ki.se.
For adults:
Professor Gunnar Juliusson, Division of Haematology, Lund University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 13 15, email: gunnar.juliusson@med.lu.se.
Professor Per Ljungman, Division of Haematology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden. Tel +46 8 585 82 50, email: per.ljungman@karolinska.se.
Professor Johan Wennerberg, ENT Clinic, Lund University Hospital, SE-221 85 Lund, Sweden. Tel +46 46 17 28 10, email: johan.wennerberg@med.lu.se.
For children:
Information can be obtained from the Swedish Childhood Cancer Foundation and regional childhood cancer associations, Box 5408, SE-114 84, Stockholm, Sweden. Tel +46 8 584 209 00, Internet: www.barncancerfonden.se.
For adults:
Information can be obtained from the Swedish Blood Cancer Association, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel +46 8 546 40 40, Internet: www.blodcancerforbundet.nu.
Seven childhood cancer associations are members of the Swedish Childhood Cancer Foundation. Mailing address: Box 1386, SE-114 84 Stockholm, Sweden. Street address: Grevgatan 39, Stockholm. Tel +46 8 584 209 00, fax +46 8 584 109 00, email: Info@barncancerfonden.se. Further information is available at: www.barncancerfonden.se.
Fifteen regional blood cancer associations are members of the Swedish Blood Cancer Association. Mailing address: Box 1386, SE-172 27 Sundbyberg, Sweden. Street address: Sturegatan 4, Sundbyberg. Tel +46 8 546 40 540, fax +46 8 584 109 00, email: info@blodcancerforbundet.se. Further information is available at www.blodcancerforbundet.se.
There are also a number of associations in other countries:
United States: Fanconi Anemia Research Fund, Inc, 1801 Willamette Street, Suite 200, Eugene, OR 97401, USA. Email: info@fanconi.org, Internet: www.fanconi.org.
France: Association Francaise de la maladie de Fanconi (AFMF), Internet: www.fanconi.com.
Italy: Associazone Italiana per la Rierca sull’Anemia di Fanconi (AIRFA), Internet: www.airfa.it.
Canada: Fanconi Canada (information in English and French), Internet: www.fanconicanada.org.
United Kingdom: Fanconi Anemia Breakthrough United Kingdom (FABUK), Internet: www.fanconi-anaemia.co.uk.
Germany: Deutsche Fanconi-Anämie-Hilfe e.V., Internet: www.fanconi.de.
For physicians:
The Swedish Paediatric Haematology Working Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), belongs to the Swedish Paediatric Association’s section for haematology and oncology. Internet: www.orebroll.se/vph/gruppen.htm.
Nordic Society of Paediatric Haematology and Oncology, Working Group for Paediatric Aplastic Anaemia, Niels Clausen, Department of Paediatrics, Skejby Hospital, DK-8200 Århus N, Denmark. Email: nclausen@bas.dk, Internet: www.nopho.org.
In Sweden, all patients with Fanconi anaemia are invited to volunteer in ongoing research projects run by the European Registry for Fanconi anaemia (EUFAR).
The research laboratory of the European Fanconi Anaemia Centre in Amsterdam carries out clinical and experimental research and offers diagnostic services.
Functional genome analysis, VU University Medical Center Amsterdam, Internet: www.vumc.nl/klgen/onderzoek.
The European Group for Blood and Marrow Transplantation (EBMT) has working parties for paediatric diseases and aplastic anaemia that cooperate in cytokine studies and intervention trials. More information is available at: http://www.ebmt.org/5WorkingParties/wparties1.html.
The EWOG-MDS Clinical Trial Protocol 2006, Internet:
www.ewog-mds.org/public/index.html.
There is one international (US-based) and one European registry for Fanconi anaemia. Sweden contributes to the European registry and Dr Albert N. Békássy at Lund University Hospital is in charge as national coordinator (the address is listed under “Resource personnel”).
An information folder on Fanconi anaemia, which summarises the information in this database text, is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2005-12-188). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.
The American patient association Fanconi Anemia Research Fund, Inc, offers information about the disease in English, French and Spanish at: www.fanconi.org.
Fanconi Anemia: A Handbook for Families and their Physicians (2000), available at www.fanconi.org/pubs/books/FAHandbook3.pdf.
Fanconi Anemia Standards for Care (2003), available at: www.fanconi.org/pubs/books/FAStandards.pdf.
Family newsletter
Science letter
FA Courier
Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR et al. Identification of FAAP24, a novel Fanconi Anemia core complex protein that interacts with FANCM. Mol Cell 2007; 25: 331-344.
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Popp H, Kalb R, Fischer , Lobitz S, Kokemohr I, Hanenberg H et al. Screening Fanconi anemia lymphoid cell lines of non-A, C, D2, E, F, G subtypes for defects in BRCA2/FANCD1. Cytogenet Genome Res 2003; 103: 54-57.
Rosenberg PS, Greene M, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003; 101: 822-826.
Tamary H, Dgany O, Toledano H, Shalev Z, Krasnov T, Shalmon L et al. Molecular characterization of three novel Fanconi anemia mutations in Israeli Arabs. Eur J Haematol 2004; 72: 330-336.
Tonnies H, Huber S, Kuhl JS, Gerlach A, Ebell W, Neitzel H. Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. Blood 2003; 101: 3872-3874.
Van der Heijden MS, Brody JR, Gallmeier E, Cunningham SC, Dezentje DA, Shen D et al. Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. Am J Pathol 2004; 165: 651-657.
Venkitaraman AR. Tracing the network connecting BRCA and Fanconi Anemia proteins. Nat Rev Cancer 2004; 4: 266-276.
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The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical expert who wrote the draft of this information material is Dr Albert Békássy, Lund University Hospital, Sweden.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Date of publication: 2009-03-30
Version: 1.0
Publication date of the original Swedish version:
2007-11-19
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.