Fanconi anemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Fanconi anaemia; Fanconi hypoplastic anemia; Fanconi panmyelopathy; Fanconi pancytopenia; FA

Overview

Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.

Historical Perspective

The discovery of fanconi anemia is largely the work of Swiss pediatrician Guido Fanconi who observed various finding of fanconi anemia to be different then pernicious anemia and led to its discovery.

Pathophysiology

Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 90s, nothing was known about the proteins encoded by FA genes.

• However, more recently, studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M assemble to form a core protein complex in the nucleus.
• This complex has also been suggested to exist in cytoplasm and its translocation into the nucleus is dependent on the nuclear localization signals on FANCA and FANCE.
• Assembly is thought to be activated by DNA damage due to cross-linking agents or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage.

Causes

There are at least 13 genes of which mutations are known to cause FA.

Common Genes

•  FANCA, FANCB, FANCC, FANCD1 (BRCA2).
• FANCD2, FANCE, FANCF FANCG.

Differentiating Fanconi anemia from other Diseases

Fanconi Anemia must be differentiated from Aplastic Anemia, Paraoxysomal Nocturnal Hemoglobinuria, and Chromosomal breakage syndrome and Hereditary Bone marrow failure syndrome (Dyskeratosis congenita and other short telomere syndromes).

• Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, Congenital anomalies, and associated with malignancy such as Aplastic Anemia, Rare chromosomal breakage syndrome and inherited bone marrow failure.

• As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia.
• Must be differentiated on basis on congenital anomalies and chromosomal breakage test.

Epidemiology and Demographics

FA is rare overall, but it is one of the most common inherited bone marrow failure syndromes.

• The incidence of FA is approximately 1 in 100,000 to 250,000 births.
• Approximately 10 to 20 children are born with FA each year in the United States.
• The probability of FA in the US population, FA, was estimated to be 1 in 129,600 births
• Most children are diagnosed between six and nine years of age, concurrent with the onset of bone marrow failure . Rarely, marrow failure from FA can present in infants and small children

Diagnosis

Diagnostic Study of Choice

History and Symptoms

The majority of patients with fanconi anemia present with congenital anomalies. Sometimes, FA may be suspected at birth by one or more of these physical traits:

• Skin discolorations, Hand, arm and other skeletal anomalies, Kidney problems, Small head or eyes.
• Low birth weight, Gastrointestinal problems (bowel), Small reproductive organs in males, Heart defects.

Since these physical characteristics can be indicative of other conditions, and since some patients may have no obvious physical traits of FA, the condition may not be diagnosed at birth. They may exhibit symptoms such as:

• Unexplained fatigue, Recurrent colds or viral infections, Recurrent nosebleeds.
• Easy bruising, Blood in the stool or urine, Shortness of breath, Poor growth / short stature.

In rare cases, symptoms do not occur until early adulthood.

Physical Examination

CLINICAL FEATURES:

The most common presenting features of FA are congenital malformations. Cytopenias are also common, and many patients eventually develop bone marrow failure. Common malignancies include myelodysplastic syndrome (MDS), leukemia, and solid tumors, especially squamous cell cancers (SCC)

Physical Examination[edit | edit source]

• Congenital malformations are the most common presenting features of FA.

• Patients with FA usually present with hypo/hyperpigmentation, café-au-lait spots, short staure and thumb or other radial abnormalities.

• Vital Signs Usually normal sometime patients present with fever due to superimposed infection.

• Skin abnormalities in Fanconi anemia can include generalized hyperpigmentation on the trunk, neck, and intertriginous areas, the aforementioned café au lait spots, and hypopigmented areas. Delicate features can also be characteristic of patients.

Laboratory Findings

The diagnosis of Fanconi anemia is not based on routine laboratory tests; it must be considered and tested for using chromosome breakage in blood or fibroblasts, or germline mutation analysis. Siblings who do not apparently have Fanconi anemia need to be screened for occult Fanconi anemia.

Any patient with single-lineage or multi-lineage cytopenias without known cause who also has one or more congenital malformations strongly associated with FA.

Laboratory findings consistent with the diagnosis of Fanconi Anemia include Pancytopenia, Chromosomal breakage test positive, and Flow cytometry shows arrest in G2/M phase.

Electrocardiogram

X Ray

Although non-specific, these are one of the best described features and include:

• radial ray anomalies: including absent thumb.
• triphalangeal thumb.

Perform a skeletal survey to identify all developmental defects involving bone. Keep in mind that radiation doses should be limited in patients with Fanconi anemia. Care should be taken to avoid unnecessary radiation in patients with a cancer predisposition.

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Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1

Related Chapters

• Absent radius

References

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• Tischkowitz M, Dokal I. Fanconi anaemia and leukaemia - clinical and molecular aspects. Br.J.Haematol. 2004;126:176-191.
• Lensch MW, Rathbun RK, Olson SB, Jones GR, Bagby GC, Jr. Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia. Leukemia 1999;13:1784-1789.
• Kutler DI, Auerbach AD. Fanconi anemia in Ashkenazi Jews. Fam.Cancer 2004;3:241-248.
• Rosendorff J, Bernstein R, Macdougall L, Jenkins T. Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa. Am.J.Med.Genet. 1987;27:793-797.
• Howlett NG, Taniguchi T, Olson S et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002;297:606-609.
• Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat.Rev.Genet. 2001;2:446-457.
• Auerbach AD, Rogatko A, Schroeder-Kurth TM. International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood 1989;73:391-396.
• Dokal I. The genetics of Fanconi's anaemia. Baillieres Best.Pract.Res.Clin.Haematol. 2000;13:407-425.
• Kutler DI, Singh B, Satagopan J et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003;101:1249-1256.
• Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003;97:425-440.
• Butturini A, Gale RP, Verlander PC et al. Hematologic abnormalities in Fanconi anemia: an

International Fanconi Anemia Registry study. Blood 1994;84:1650-1655.

• Alter BP, Caruso JP, Drachtman RA et al. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet.Cytogenet. 2000;117:125-131.
• 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;51:1-12.
• Tonnies H, Huber S, Kuhl JS et al. 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.
• Gluckman E, Auerbach AD, Horowitz MM et al. Bone marrow transplantation for Fanconi anemia. Blood 1995;86:2856-2862.
• Gluckman E. Radiosensitivity in Fanconi anemia: application to the conditioning for bone marrow transplantation. Radiother.Oncol. 1990;18 Suppl 1:88-93.
• Cipolleschi MG, Dello SP, Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 1993;82:2031-2037.
• Zhang X, Li J, Sejas DP, Pang Q. Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. Blood 2005
• Naf D, Kupfer GM, Suliman A, Lambert K, D'Andrea AD. Functional activity of the fanconi anemia protein FAA requires FAC binding and nuclear localization. Mol.Cell Biol. 1998;18:5952-5960.
• de Winter JP, Leveille F, van Berkel CG et al. Isolation of a cDNA representing the Fanconi anemia complementation group E gene. Am.J.Hum.Genet. 2000;67:1306-1308.
• Pagano G, Youssoufian H. Fanconi anaemia proteins: major roles in cell protection against oxidative damage. Bioessays 2003;25:589-595.
• Park SJ, Ciccone SL, Beck BD et al. Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins. J.Biol.Chem. 2004;279:30053-30059.
• Connor F, Bertwistle D, Mee PJ et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat.Genet. 1997;17:423-430.
• Meetei AR, de Winter JP, Medhurst AL et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat.Genet. 2003;35:165-170.
• Vandenberg CJ, Gergely F, Ong CY et al. BRCA1-independent ubiquitination of FANCD2. Mol.Cell 2003;12:247-254.
• D'Andrea AD, Dahl N, Guinan EC, Shimamura A. Marrow failure. Hematology.(Am.Soc.Hematol.Educ.Program.) 200258-72.
• Garcia-Higuera I, Taniguchi T, Ganesan S et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol.Cell 2001;7:249-262.
• Wang Y, Cortez D, Yazdi P et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000;14:927-939.
• Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999;286:1162-1166.
• Taniguchi T, Garcia-Higuera I, Xu B et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 2002;109:459-472.
• Kruyt FA, Hoshino T, Liu JM et al. Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood 1998;92:3050-3056.
• Cumming RC, Lightfoot J, Beard K et al. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat.Med. 2001;7:814-820.
• Hadjur S, Ung K, Wadsworth L et al. Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase. Blood 2001;98:1003-1011.
• Pang Q, Fagerlie S, Christianson TA et al. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Mol.Cell Biol. 2000;20:4724-4735.
• Futaki M, Igarashi T, Watanabe S et al. The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage. Carcinogenesis 2002;23:67-72.
• de Winter JP, Waisfisz Q, Rooimans MA et al. The Fanconi anaemia group G gene FANCG is identical with XRCC9. Nat.Genet. 1998;20:281-283.
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Suspected clinical FA

Chromosome breakage test on peripheral film

Ambiguous

Repeat Chromosome breakage test

Abnormal

Normal

Highly suspected FA

Not highly suspected FA

Chromosome breakage test on skin fibroblast

Abnormal

Normal

Consider other IBMFS

Diagnosis of FA

Genetic testing for Korean mutations FANCAexon 27 & 37 FANCGintron 3 & exon 8

Other FA associated genes