Fanconi Anemia

Definition and History

Fanconi anemia is the most common form of constitutional aplastic anemia and was initially described in three brothers by Fanconi in 1927.219 It is inherited as an autosomal recessive condition that results from defects in genes that modulate the stability of DNA.

Epidemiology or cause

Fanconi Anemia is an uncommon disorder and is estimated to be present in 1 in 1 million individuals. It is far more frequent in Afrikaners of European descent.220 This unusually high frequency has been attributed to a founder effect.

Etiology and Pathogenesis

Thirteen complementation groups, defined by somatic cell hybridization, are associated with the development of Fanconi anemia.221 A complementation group is a genetic subgroup. Identifying a complementation group requires adding a gene to the genome of a cell to correct (complement) the genetic defect. This procedure can be done by cell fusion studies. After fusing two cells together, thereby joining their genetic material, one can test the cells for the genetic defect. In the case of Fanconi anemia, this would be with the diepoxybutane test. Hybrids in which the hypersensitivity to diepoxybutane is corrected (complemented) can be assumed to result from the fusion of cells from different genetic subgroups (complementation groups), whereas hybrids that still show the sensitivity are the result of fusion of cells from the same subgroup. Because one can determine the complementation group without knowing the gene involved, this approach is the first step in understanding the genetic basis of a disease. Once the genes are known, one does not need to use cell fusion studies; rather, retroviral vectors can be used to insert corrected genes into the cells.

Table 34–7. Gene Mutations Found in Fanconi Anemia
Gene Chromosome Location % of Patients Inheritance Protein Function
FANCA 16q24.3 ~65* AR FA Core Complex
FANCB Xp22.31 rare XLR FA Core Complex
FANCC 9q22.3 ~10 AR FA Core Complex
FANCDI (BRCA2) 13q12.3 rare AR RAD51 Recruitment
FANCD2 3p25.3 rare AR Monoubiquitinated protein
FANCE 6p21.3 ~10 AR FA Core Complex
FANCF 11p15 rare AR FA Core Complex
FANCG (XRCC9) 9p13 ~10 AR FA Core Complex
FANCI (KIAA1794) 15q25–26 rare AR Monoubiquitination of FANCD2
FANCJ (BACH1/BRIP1) 17q22.3 rare AR 5′ to 3′ DNA helicase/ATPase
FANCL (PHF9/ POG) 2q16.1 rare AR FA Core Complex, E3 Ubiquitin ligase
FANCM (Hef) 14q21.3 rare AR FA Core Complex, ATPase/translocase, DNA helicase motifs
FANCN (PALB2) 16q12.1 rare AR Regulation of BRCA2 localization
To be identified ~5

Clinical Features- Symptoms & Signs

Growth retardation results in short stature, and skeletal anomalies are common. Absent, misshapen, or supernumerary thumbs and dysplastic radii occur in half the patients. Hip and vertebral abnormalities also may occur. Septal heart defects, eye abnormalities, and absent, misshapen, or fused kidneys may be present. Learning disability is frequent, and microcephaly and mental retardation may be a feature. Hypogonadism also may be evident. The skin may be generally hyperpigmented or may have areas of abnormal skin pigmentation referred to as café-au-lait spots, which are flat, light brown, and from 1 to 12 centimeters in diameter. Hepatosplenomegaly is not a feature of the disease. Some patients have no or minor phenotypic abnormalities and may be diagnosed as a result of the onset of marrow failure or a cancer involving any of many sites as late as the fifth decade of life.

The onset of marrow failure is gradual and usually is evident during the last half of the first decade of life. The manifestations of anemia, including weakness, fatigue, and dyspnea on exertion, and of thrombocytopenia with epistaxis, purpura, or other unexpected bleeding, are the principal findings. Hematologic and visceral manifestations are combined eventually in more than a third of patients, but some may have cytopenias and inconspicuous somatic changes, whereas others may have somatic anomalies with no or a nominal disorder of blood cell formation for months or years. Some who carry the gene may be virtually unaffected.225–227 In a review of the more than 1300 patients in the literature, 100 patients or fewer than 7 percent without anomalies were identified by chromosome breakage studies (see “Laboratory Features” below) because of affected siblings.227 In the past, children in Fanconi families with an onset of aplastic anemia without congenital somatic abnormalities were thought to have a different disorder termed Estren-Dameshek syndrome.228 However, these children, whose lymphocytes show sensitivity to diepoxybutane, are considered to have Fanconi anemia without skeletal abnormalities.

Laboratory Features

Blood counts and marrow cellularity are often normal until 5 to 10 years of age, when pancytopenia develops over an extended interval. Macrocytosis with anisocytosis and poikilocytosis may be present before any cytopenia occurs. Thrombocytopenia may precede the development of granulocytopenia and anemia. The marrow becomes hypocellular, and in vitro colony assays reveal a decrease in CFU-GM and BFU–E.227

Random chromatid breaks are present in myeloid cells, lymphocytes, and chorionic villus biopsy samples. This chromosome damage is intensified after exposure to DNA cross-linking agents such as mitomycin C or diepoxybutane. The hypersensitivity of the chromosomes of marrow cells or lymphocytes to the latter agent is used as a diagnostic test for this condition. Cell-cycle progression is prolonged at the G2 to M transition, and the cells are more susceptible to oxygen toxicity when cultured in vitro. It is important to test the lymphocytes from pediatric patients with aplastic anemia for sensitivity to diepoxybutane, because therapy for Fanconi anemia differs from that used for acquired aplastic anemia.

In the near future, clinical laboratories will be able to genotype suspected patients. Determining the specific gene mutation responsible in a patient (see Table 34–7) is important because it confirms the diagnosis, identifies the genotype linked to BRCA2 that may predispose to a cancer (e.g. breast, ovary), and permits carrier detection.229

Differential Diagnosis

The differential diagnosis of Fanconi anemia includes other causes of aplastic anemia, particularly those familial syndromes associated with skeletal anomalies and other dysmorphic features. Other familial types of aplastic anemia have been reported with or without associated anomalies. In those instances in which no sensitivity to DNA damaging agents is observed, the syndrome does not represent Fanconi anemia. Several uncommon syndromes of this type are described below and are tabulated in Table 34–8

Table 34–8. Other Rare Syndromes Associated with Aplastic Anemia
Disorder Findings Inheritance Mutated Gene References
Ataxia-pancytopenia (myelocerebellar disorder) Cerebellar atrophy and ataxia; aplastic pancytopenia; ± monosomy 7; increased risk of AML AD Unknown 256–258
Congenital amegakaryocytic thrombocytopenia Thrombocytopenia; absent or markedly decreased marrow megakaryocytes; hemorrhagic propensity; elevated thrombopoietin; propensity to progress to aplastic pancytopenia; propensity to evolve to clonal myeloid disease AR (compound heterozygotes) MPL 259, 260
DNA ligase IV deficiency Pre- and postnatal growth delay; dysmorphic facies; aplastic pancytopenia AR (compound heterozygotes) LIG4 261–263
Dubowitz syndrome Intrauterine and post-partum growth failure; short stature; microcephaly; mental retardation; distinct dysmorphic facies; aplastic pancytopenia; increased risk of AML and ALL AR Unknown 264, 265
Nijmegen breakage syndrome Microcephaly; dystrophic facies; short stature; immunodeficiency; radiation sensitivity; aplastic pancytopenia; predisposition to lymphoid malignancy AR NBS1 266, 267
Reticular dysgenesis (type of severe immunodeficiency syndrome) Lymphopenia; anemia and neutropenia; corrected by hematopoietic stem cell transplantation XLR Unknown 268, 269
Seckel syndrome Intrauterine and post- partum growth failure; microcephaly; characteristic dysmorphic facies (bird-headed profile); aplastic pancytopenia; ? increased risk of AML AR ATR (and RAD3-related gene); PCNT 270–273
WT syndrome Radial/ulnar abnormalities; aplastic pancytopenia; increased risk of AML AD Unknown 274
AD, autosomal dominant; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; AR, autosomal recessive; XLR, X-linked recessive.

NOTE: The listed clinical findings in each syndrome are not comprehensive. The designated clinical findings may not be present in all cases of the syndrome. Isolated cases of familial aplastic anemia with or without associated anomalies that are not consistent with Fanconi anemia or other defined syndromes have been reported.227

Treatment ,Therapy and Course

Most patients with Fanconi anemia do not respond to ATG or cyclosporine but do improve with androgen preparations, often for as long as several years. Cytokines may provide some improvement in blood counts, but their effect may wane. Studies in a mouse model also suggest that cytokine effects may not be sustained.230 The cumulative median survival is about 20 years from progressive marrow failure, conversion to myelodysplastic syndrome, acute myelogenous leukemia (approximately 10 percent of patients), or the development of a variety of other cancers such as genitourinary system, digestive system (especially liver), head and neck.231 Multiple cancers in an individual patient also occur. Cancers may occur as late as the fifth decade of life and precede the diagnosis of Fanconi anemia in 25 percent of patients.231 The presence of a clonal cytogenetic abnormality or marrow morphology consistent with myelodysplasia markedly reduces the 5-year survival.232 Allogeneic hematopoietic stem cell transplantation is curative for the marrow manifestations of Fanconi anemia.232–235 A marked reduction in dosage of the marrow-conditioning regimen of cyclophosphamide and radiation is necessary owing to the undue sensitivity of the tissues to DNA-damaging exposures. The risk of cancer is so high that, where practical, surveillance should be used, for example, frequent pelvic exams in females, hepatic ultrasonography to detect adenomas, and careful oropharyngeal examinations. Therapy of cancer in patients with Fanconi anemia needs to consider the marked sensitivity of their cells to DNA cross-linking agents and radiotherapy.

Normal cDNA has been transferred into cells from patients with restoration of resistance to DNA damaging agents.236,237 Difficulties in this approach include the paucity of stem cells in these patients, as well as the potential toxicity of the gene transfer methodology.


1. The International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: The relevant diagnostic criteria. Blood 70:1718, 1987.
2. Ehrlich P: Über einen Fall von Anamie mit Bemerkungen über regenerative Veranderungen des Knochenmarks. Charite Ann 13:300, 1888.
3. Chauffard M: Un cas d’anémie pernicieuse aplastique. Bull Soc Med Hop Paris 21:313, 1904.
4. Scott JL, Cartwright GE, Wintrobe MM: Acquired aplastic anemia: an analysis of thirty-nine cases and review of the pertinent literature. Medicine (Baltimore) 38:119, 1959. [PMID: 13656164]
5. Thomas ED, Storb R, Fefer A, et al: Aplastic anemia treated by bone marrow transplantation. Lancet 1: 284, 1972. [PMID: 4109931]
6. Thomas ED, Storb R, Giblett B et al: Recovery from aplastic anemia following attempted marrow transplantation. Exp Hematol 4:97, 1976. [PMID: 770181]
7. Champlin RE, Feig SA, Sparkes RS, Gale RP: Bone marrow transplantation from identical twins in the treatment of aplastic anaemia: Implication for the pathogenesis of the disease. Br J Haematol 56:455, 1984. [PMID: 6365155]
8. Speck B, Gluckman E: Treatment of aplastic anemia by antilymphocyte globulin with and without allogeneic bone marrow infusions. Lancet II:1145–1148, 1977.
9. Mary JY, Baumelou E, Guiguet M: Epidemiology of aplastic anemia in France: A prospective multicenter study. Blood 75:1646, 1990. [PMID: 2183887]
10. Montané E, Ibáñez L, Vidal X, et al: Epidemiology of aplastic anemia: A prospective multicenter study. Haematologica 93:518, 2008. [PMID: 19781462]