AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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• Miscellaneous
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Background

Fanconi anemia (FA) is the most frequently reported of the rare inherited bone marrow failure syndromes, with more than 1800 cases reported in the medical literature. In 1927, Guido Fanconi first reported 3 brothers with pancytopenia and physical abnormalities. Subsequent cases were clinically diagnosed because of the combination of aplastic anemia and various characteristic physical anomalies (see Physical).

In the early 1960s, several groups observed that cultured cells from patients with FA had increased numbers of chromosome breaks; later, the breakage rate was found to be specifically increased by the addition of DNA cross-linkers, such as diepoxybutane (DEB) or mitomycin C (MMC). This led to the identification of patients with FA and aplastic anemia without birth defects and the diagnosis of FA in patients without aplastic anemia but with abnormal physical findings. Furthermore, in cultured FA cells, cell cycle arrest in gap 2/mitosis (G2/M) occurs at lower concentrations of clastogens than in normal cells. This observation has led to flow cytometry–based screening tests used at some centers.

Most recently, the advent of molecular diagnostics has further improved the specificity of FA diagnosis (see Other Tests). FA comprises approximately 25% of the cases of aplastic anemia seen at large referral centers. Approximately 25% of known patients with FA do not have major birth defects.

Pathophysiology

FA is an autosomal recessive disease in more than 99% of patients; each patient with FA is homozygous or doubly heterozygous for mutations in one of the 13 genes known to be responsible for FA. The cloned genes are FANCA, B, C, D1, D2, E, F, G, I, J, L, M, and N. Although most are unique genes, several were previously known, including FANCD1 (BRCA2), GANCG (XRCC9), FANCI(KIAA1794), FANCJ (BRPI1/BACH1), FANCL (PHF9/POG), FANCM (Hef), and FANCN (PALB2). Heterozygotes for BRCA2 and possibly BACH1 and PALB2 are at increased risk of breast and other cancers.

The FA proteins A, B, C, E, F, G, L and M appear to form a nuclear complex, which leads to ubiquitination of the I and D2 proteins; the latter is involved in DNA damage response mechanisms in cooperation with FANCD1, FANCJ, and FANCN, as well as BRCA1, RAD51, Mre11, and other proteins. The widely variant FA phenotype may depend on whether the mutation is null or leads to a partially functional gene product rather than the specific gene that is involved. The specific role of mutations in the FA genes in the pathogenesis of birth defects, bone marrow failure, or oncogenesis is not yet clear.

Frequency

United States

In general, the carrier frequency is estimated to be approximately 1 per 300 people, leading to an expected birth rate of approximately 1 per 360,000 people. Among Ashkenazi Jews, the carrier frequency is approximately 1 per 90 people, with a projected birth rate of 1 per 30,000 people.

International

The general carrier frequencies are similar to those in the United States, depending on the population. Due to founder effects, the heterozygote frequency is less than 1 per 100 in South African Afrikaaners,¹ sub-Saharan Blacks, and Spanish Gypsies,² leading to expected birth rates in these populations of around 1 per 40,000.

Mortality/Morbidity

• The major cause of death in FA is bone marrow failure, followed in frequency by leukemia and solid tumors. The projected median survival from all causes for more than 1800 cases reported in the literature is age 20 years, although this has improved to older than 30 years in the cases reported in the most recent decade.
• Bone marrow failure usually presents in childhood, with petechiae, bruising, and hemorrhages due to thrombocytopenia; pallor and fatigue from anemia; and infections due to neutropenia. More than 90% of patients with FA develop pancytopenia caused by aplastic anemia, which is often fatal.
• Leukemia has been reported in approximately 10% of patients, and myelodysplastic syndrome has been reported in about 6% of patients, primarily in teens and young adults, some of whom may not have had a preceding phase of aplastic anemia.
• Solid tumors have been reported in close to 10% of patients, often in young adults who may never have had aplastic anemia. The most common tumors are liver adenomas and hepatomas, primarily in patients who had aplastic anemia that was treated with oral androgens. Other types of solid tumors occur in young adults and primarily involve the head and neck, esophagus, and gynecologic areas. Oral cancers have been reported in patients with FA who have received bone marrow transplantation; transplantation (especially if graft versus host disease occurs) appears to further increase the risk of these cancers.
• The risk of liver tumors is increased 400-fold, the risk of leukemia and head and neck cancers is increased 700-fold, the risk of esophageal cancer is increased 2000-fold, and the risk of vulvar cancer is increased 4000-fold. In competing risk analyses, the cumulative incidence of solid tumors reaches 30% by age 45 years and does not level off. Although bone marrow failure and leukemia, which may be treated or prevented by hematopoietic stem cell transplant or gene therapy, are the concerns in treating children and adolescents, solid tumors remain the major threat to older patients with FA.
• In a retrospective analysis of 145 patients with Fanconi anemia, 9 patients evolved to leukemia, and 14 developed 18 solid tumors.³ Although this is a relatively small cohort, it does allow for a more statistically valid analysis than do the previous literature reviews. Thus, the ratio of observed-to-expected cancers for all cancer diagnoses or for solid tumors was 50, and the ratio was 700 for leukemia. The cumulative incidence of leukemia, death from marrow failure, death from a solid tumor, and having a stem cell transplant (not necessarily a favorable outcome) was 10%, 11%, 29%, and 43%, respectively. Note that the risk of solid tumors posttransplant likely increases.

Race

FA has been reported in all races, although "founder" effects are recognized, which result in higher carrier frequencies in Ashkenazi Jews,⁴ South African Afrikaaners,¹ sub-Saharan Blacks, and Spanish Gypsies² (see Frequency).

Sex

The male-to-female ratio in the literature cases is 1.2:1, although equal numbers are expected in autosomal recessive disease.

Age

FA has been diagnosed in patients from birth to age 49 years, with a median age of 7 years. Individuals with birth defects (see Physical) are diagnosed at younger ages than persons without birth defects.

CLINICAL

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History

Patients with Fanconi anemia (FA) with characteristic birth defects (eg, radial ray anomalies, poor growth, genitourinary problems) are often treated by various medical specialists during infancy. The diagnosis of FA must first be considered and can only be established if specific tests are ordered. During childhood, short stature and skin pigmentation, including café au lait spots, may become apparent. The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pallor, fatigue, and infections. Because macrocytosis usually precedes thrombocytopenia, patients with typical congenital anomalies associated with FA should at least be evaluated for an elevated erythrocyte mean corpuscular volume. In approximately 25% of patients with FA who have cancer, the diagnosis of leukemia or a tumor preceded the diagnosis of FA.

Physical

About 75% of patients with FA have birth defects, such as altered skin pigmentation and/or café au lait spots (>50%), short stature (50%), thumb or thumb and radial anomalies (40%), abnormal male gonads (30%), microcephaly (25%), eye anomalies (20%), structural renal defects (20%), low birth weight (10%), developmental delay (10%), and abnormal ears or hearing (10%).

Literature reports may, however, be biased toward this association because the clinical diagnosis initially depended on the combination of aplastic anemia and physical anomalies; thus, the frequencies may be overestimated. Patients with biallelic mutations in FANCD1/BRCA2 and FANCJ/PALB2 have a very severe phenotype, including features of the vertebral, anal, cardiac, tracheal, esophageal, and limb (VACTERL) association.

• Skin - Generalized hyperpigmentation on trunk, neck, and intertriginous areas; café au lait spots; hypopigmented areas
• Body - Short stature, delicate features
• Upper limbs
• • Thumbs - Absent or hypoplastic, supernumerary, bifid, rudimentary, short, low set, attached by a thread, triphalangeal, tubular, stiff, hyperextensible
  • Radii - Absent or hypoplastic (only with abnormal thumbs [ie, terminal defects]), absent or weak pulse
  • Hands - Clinodactyly, hypoplastic thenar eminence, 6 fingers, absent first metacarpal, enlarged abnormal fingers, short fingers
  • Ulnae - Dysplastic
• Gonads
• • Males - Hypogenitalia, undescended testes, hypospadias, abnormal or absent testis, atrophic testes, azoospermia, phimosis, abnormal urethra, micropenis, delayed development
  • Females - Hypogenitalia; bicornuate uterus; aplasia of uterus and vagina; atresia of uterus, vagina, or ovary/ovaries
• Other skeletal anomalies
• • Head and face - Microcephaly, hydrocephalus, micrognathia, peculiar face, bird face, flat head, frontal bossing, scaphocephaly, sloped forehead, choanal atresia
  • Neck - Sprengel abnormality, short, low hairline, webbed
  • Spine - Spina bifida (thoracic, lumbar, cervical, occult sacral), scoliosis, abnormal ribs, sacrococcygeal sinus, Klippel-Feil syndrome, vertebral anomalies, extra vertebrae
  • Feet - Toe syndactyly, abnormal toes, flat feet, short toes, clubfoot, 6 toes
  • Legs - Congenital hip dislocation, Perthes disease, coxa vara, abnormal femur, thigh osteoma, abnormal legs
• Eyes - Small, strabismus, epicanthal folds, hypertelorism, ptosis, slanted, cataracts, astigmatism, blindness, epiphora, nystagmus, proptosis, small iris
• Ears - Deaf (usually conductive), abnormal shape, atresia, dysplasia, low-set, large, small, infections, abnormal middle ear, absent drum, dimples, rotated, canal stenosis
• Kidneys - Ectopic or pelvic, horseshoe, hypoplastic or dysplastic, absent, hydronephrosis or hydroureter, infections, duplicated, rotated, reflux, hyperplasia, no function, abnormal artery
• Gastrointestinal system - High-arch palate, atresia (eg, esophagus, duodenum, jejunum), imperforate anus, tracheoesophageal fistula, Meckel diverticulum, umbilical hernia, hypoplastic uvula, abnormal biliary ducts, megacolon, abdominal diastasis, Budd-Chiari syndrome
• Cardiopulmonary system - Patent ductus arteriosus, ventricular septal defect, peripheral pulmonic stenosis, aortic stenosis, coarctation, absent lung lobes, vascular malformation, aortic atheromas, atrial septal defect, tetralogy of Fallot, pseudotruncus, hypoplastic aorta, abnormal pulmonary drainage, double aortic arch, cardiomyopathy
• Other anomalies - Developmental delay, hyperreflexia, Bell palsy, CNS arterial malformation, stenosis of the internal carotid, small pituitary gland

Causes

As described in Pathophysiology, at least 13 genes are involved in the FA pathway. The exact link between mutations and phenotype is not clear, although patients who are homozygous for null mutations appear to have more severe FA than those with altered proteins. Various aspects of pathophysiologic research include the following:

• FA cells may be susceptible to damage by oxygen free radicals.
• FA cells have a defect in cell cycle regulation.
• The hematopoietic stem cell is defective in FA.
• A defect in the DNA-damage response pathway is present in FA.
• FA is a premalignant disorder.

DIFFERENTIALS

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Other Problems to be Considered

Acquired aplastic anemia
Acute myeloid leukemia
Bloom syndrome
Diamond-Blackfan anemia
Dubowitz syndrome
Rothmund-Thomson syndrome
Seckel syndrome
VACTERL association
Werner syndrome
Immune pancytopenias
In utero viral infections
Teratogens

WORKUP

Section 5 of 11  

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Lab Studies

• CBC count may reveal trilineage pancytopenia or may only show RBCs that are macrocytic for age. Thrombocytopenia or leukopenia may precede full-blown aplasia.
• Chromosome breakage is usually examined in short-term cultures of peripheral blood T-cell mitogen–stimulated lymphocytes in the presence of DNA cross-linkers, such as DEB or MMC. These agents lead to increased numbers of breaks, gaps, rearrangements, and quadriradii in Fanconi anemia (FA) homozygote cells. Some patients may have hematopoietic somatic mosaicism, with correction of the FA defect in the blood. In these cases, skin fibroblasts may be needed for the chromosome breakage test.
• Flow cytometry of FA cells cultured with nitrogen mustard and other clastogens demonstrates an arrest in G2/M.
• Fetal hemoglobin (HbF) may be increased for age as a manifestation of stress erythropoiesis.
• Red cell adenosine deaminase (ADA) is increased in most patients with Diamond-Blackfan anemia (DBA) but appears to be normal in FA.
• Serum erythropoietin (Ep) levels are markedly increased and higher than expected for the degree of anemia, similar to that observed in DBA. However, levels may be low in patients with impaired renal function.

Imaging Studies

• Perform a skeletal survey to identify all developmental defects involving bone.
• Perform initial abdomen ultrasonography to document size and location of kidneys and perform follow-up ultrasonography annually to monitor for liver tumors or peliosis hepatis.
• Perform cardiac ultrasonography to evaluate for congenital anomalies.
• CNS MRI is indicated to identify any structural defects, such as absence of the corpus callosum, small pituitary, or cerebellar hypoplasia.

Other Tests

• Mutations in specific FA genes can often be identified. These tests are generally performed only in research laboratories, with the exception of the relatively common FA mutation found in Ashkenazi Jews (IVS4 +4 A to T). FA lymphocytes are treated with vectors containing normal clones of the known FA genes; correction of chromosome breakage or of impaired growth by a specific vector indicates that the cells have a mutation in that gene. The specific mutation can then be determined by various molecular diagnostic approaches.

Procedures

• Bone marrow aspirate and biopsy may reveal hypocellularity, loss of myeloid and erythroid precursors and megakaryocytes (with relative lymphocytosis), or full-blown aplasia with a fatty marrow. Signs of myelodysplastic syndrome include dyserythropoiesis (multinuclearity, ringed sideroblasts), dysmyelopoiesis (hyposegmentation, hypogranularity, hypergranularity), and hypolobulated or hyperlobulated megakaryocytes. Presence of a cytogenetic clone in a high and increasing proportion over time may suggest an evolution to leukemia, but this is currently unproven.
• Prenatal FA diagnosis can be accomplished by demonstration of chromosome breaks in cells obtained in utero from chorionic villus biopsy, amniocentesis, or cord blood (by cordocentesis) or by identification of FA gene mutations in DNA extracted from fetal cells.
• Preimplantation genetic diagnosis can be established using molecular methods, resulting in implantation of an embryo without FA mutations and, if so desired, who is human leukocyte antigen (HLA)–matched with an affected child with FA; cord blood from the delivery can be used for a hematopoietic stem cell transplantation, resulting in the cure of the sibling's aplastic anemia or leukemia.

TREATMENT

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Medical Care

Treatment is recommended for significant cytopenias, such as hemoglobin less than 8 g/dL, platelets fewer than 30,000/µL, or neutrophils fewer than 500/µL. Although the first line of therapy is stem cell transplantation, androgens, to which approximately 50-75% of patients respond, are used for those in whom transplantation is not an option (see Medication).

Supportive care for patients with symptomatic anemia includes transfusions of packed RBCs that have been leukodepleted (and are not from family members, to avoid sensitization in case of a future transplantation). Symptomatic thrombocytopenia can be treated with similarly treated platelets; single-donor platelets are preferred to reduce the frequency of antibody formation. Symptomatic neutropenia usually responds to granulocyte colony-stimulating factor (G-CSF). See Medication. In the past, some clinicians advocated corticosteroids, to delay growth plate closure in patients treated with androgens and to improve vascular integrity and reduce bleeding.

Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia. It should be considered for those who have an HLA-matched sibling donor (survival rate is >80%). The survival rate after transplantation from alternative donors is improving, depending on the completeness of the HLA-matching. This procedure has been reserved for patients who have leukemia or myelodysplasia and do not have HLA-matched related donors and for patients either unable to tolerate or refractory to standard medical treatment; this practice is changing. In any case transplants should take place at institutions with experience in the treatment of patients with Fanconi anemia (FA).

Surgical Care

Hand surgery and splinting may be indicated for thumb and radial anomalies. Hand surgery should be performed early in life to ensure maximal function. Congenital heart defects may require surgery. GI anomalies, such as tracheoesophageal fistulas and imperforate anus, are also treated surgically. Cancer surgery should be performed by experienced surgeons in consultation with hematologists and oncologists with experience in the management of FA.

Consultations

Patients with specific birth defects or medical problems should be referred to the appropriate consultants (eg, hand surgeon, cardiologist, dermatologist, endocrinologist, gastroenterologist, geneticist).

Activity

Patients with thrombocytopenia should avoid trauma, such as that resulting from contact sports, and should use helmets and padding. Those with anemia should participate in strenuous activities only under supervision and only as tolerated. Those with severe neutropenia need to avoid exposure to people with active infections.

MEDICATION

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Drug Category: Androgenic agents

These enhance the production and urinary excretion of erythropoietin in anemias caused by bone marrow failure and often stimulate erythropoiesis in anemias caused by deficient red cell production. They appear to make hematopoietic stem cells more responsive to differentiation, but the exact mechanism is not clear. The usual agent in the United States is oral oxymetholone, a 17-beta-hydroxylated androgen. Although oral androgens have a risk of liver toxicity, they are easier to use in children than parenteral androgens. The lowest effective dose should be used.

Drug Name	Nandrolone decanoate (Deca-Durabolin)
Description	A parenteral androgen is sometimes selected because of the lower risk of hepatic tumors. As with oxymetholone, the lowest effective dose should be used. This drug is no longer manufactured in the United States.
Adult Dose	1-2 mg/kg/wk IM
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; male breast or prostate cancer; metastatic female breast cancer with hypercalcemia; nephrosis or nephrotic phase of nephritis; known or suspected pregnancy; severe liver disease
Interactions	May increase sensitivity to anticoagulants (dosage of an anticoagulant may have to be decreased to maintain PT at desired therapeutic level); may increase insulin effects
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Virilization (deepening of the voice, hirsutism, acne, enlargement of genitalia) common and may be irreversible, even after prompt discontinuance of therapy; menstrual irregularities, including amenorrhea, also possible; insulin or PO hypoglycemic dosage may need adjustment; may cause suppression of clotting factors II, V, VII and X and increase in PT

Drug Category: Antifibrinolytic agents

These agents may decrease bleeding, particularly oral mucosal bleeding, in patients with thrombocytopenia by stabilization of thrombi.

Drug Category: Hematopoietic growth factors

These factors are glycoproteins that act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation, commitment, and some end cell functional activation.

Drug Name	Epoetin alfa (Epogen, Procrit)
Description	Stimulates division and differentiation of committed erythroid progenitor cells; induces release of reticulocytes from bone marrow into blood stream.
Adult Dose	100-250 U/kg SC 3 times/wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity (including hypersensitivity to human albumin, hypersensitivity to mammalian cell-derived products); uncontrolled hypertension
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hypertension, history of seizures, thrombocytosis, chronic hepatic impairment, ischemic vascular disease, or malignant tumors; blood pressure must be monitored

Drug Category: Glucocorticoids

Corticosteroids are used on alternate days and may delay the growth acceleration caused by androgens. They may also stabilize endothelial cells, leading to reduced bleeding at a given degree of thrombocytopenia. Some clinicians accept the use of corticosteroids.

FOLLOW-UP

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Further Inpatient Care

• Inpatient care may be needed for complications of bone marrow failure (eg, bleeding, infection). Transfusions may be given as inpatient or outpatient treatment. Hematopoietic stem cell transplantation is currently an inpatient procedure. Hospitalization may be needed for treatment of other complications (eg, leukemia, tumors).

Further Outpatient Care

• Blood counts are recommended at 3-month intervals or more often as needed. Transfusions of red cells or platelets can be given to outpatients. Annual or more frequent bone marrow examinations can be outpatient procedures.

Deterrence/Prevention

• Carrier screening can be offered as part of reproductive counseling for groups in which a founder effect and a carrier rate of more than 1 per 100 population are recognized. In utero prenatal diagnosis is available, and preimplantation genetic diagnosis may be possible.
• In families in which the mutation has been identified in a proband or through carrier screening, in vitro fertilization and preimplantation genetic diagnosis may be offered.
• In families with an affected proband, cord blood may be saved for future use as a source of hematopoietic stem cells at the birth of a sibling. In vitro fertilization and preimplantation genetic diagnosis can be used to identify a fetus that is an HLA-match and does not have Fanconi anemia (FA).

Complications

• Possible complications include hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors, and other cancers.
• Leukemia was reported in more than 150 patients with FA (out of more than 1800 reported in the literature), of which 95% were acute myeloid leukemias (usually rare in children).
• Myelodysplastic syndrome was reported in more than 100 patients; many of these patients did not develop leukemia but died from complications of impaired marrow function.
• Liver tumors occurred in more than 40 patients, often in the context of aplastic anemia or other tumors, and were not usually malignant (although two thirds were histologically hepatomas and the rest were adenomas).
• More than 175 solid tumors were reported in more than 160 patients. In order of frequency, these tumors were tumors of the oropharynx, esophagus, vulva, brain, skin (nonmelanoma), cervix, breast, kidney, lung, lymph nodes (lymphoma), stomach, and colon, followed by osteogenic sarcoma and retinoblastoma. At least 18 oral cancers have been reported in patients with FA following bone marrow transplantation.
• FA patients in the D1/BRCA2 and N/PALB2 groups have inordinately high rates of acute myeloid leukemias, brain tumors, and Wilms tumors, with a cumulative incidence of at least one of these cancers of 95% by age 5 years.

Prognosis

• Treatment of aplastic anemia with medications, supportive use of blood products, and stem cell transplantation increases the life expectancy beyond the projected median of approximately age 30 years.
• Cancer prevention and screening to identify early malignancies may reduce the mortality rate from cancer.
• Although many patients with FA are short and have skeletal anomalies, intelligence is usually normal, and education and career planning should be encouraged.

Patient Education

• Educate patients and their families regarding behaviors with risk of bleeding as well as maintenance of hygiene to reduce infections. Emphasize the need to comply with medications and transfusions. Educate patients and their families about cancer prevention (eg, smoking, drinking, diet, lifestyle) and cancer screening (eg, bone marrow, oropharyngeal, and gynecological examinations).
• The genetic basis of FA needs to be explained, and apparently unaffected siblings should be tested for FA homozygosity. Provide genetic counseling to parents, caregivers, and other carriers or potential carriers with regard to the risk of recurrence. Discuss phenotypic variability within a family.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to diagnose aplastic anemia or leukemia may lead to delays in treatment. The diagnosis of Fanconi anemia (FA) must be made to avoid the inappropriate use of immunosuppressive therapy for aplastic anemia, the use of toxic levels of chemotherapy or radiotherapy in leukemia or solid tumors, or toxic types of preparation for stem cell transplantation. FA is one of the few forms of aplastic anemia in which the response to androgens is more than 50%.
• Related transplant donors must be proven not to have FA in order for a transplantation to succeed.
• Patients who have tumors that are characteristic of FA but who present without the usual risk factors for those tumors need to be screened for FA (eg, head and neck cancer in a 20-year-old woman who does not smoke or drink).

Special Concerns

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

MULTIMEDIA

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• Multimedia
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Media file 1:  A 3-year-old patient with Fanconi anemia. Note the multiple birth defects, including short stature, microcephaly, microphthalmia, epicanthal folds, dangling thumbs, site of ureteral reimplantation, congenital dislocated hips, and rocker bottom feet. (Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: WB Saunders, Inc, 1993: 216-316.)
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Media type:  Photo

Media file 2:  The 3-year-old patient with Fanconi anemia seen in Media file 1. (Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: WB Saunders, Inc, 1993: 216-316.)
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Media type:  Photo

Media file 3:  Café au lait spot and hypopigmented area in a 3-year-old patient with Fanconi anemia (same patient as in Media files 1-2). (Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: WB Saunders, Inc, 1993: 216-316.)
	View Full Size Image
Media type:  Photo

Media file 4:  Thumbs attached by threads on a 3-year-old patient with Fanconi anemia (same patient as in Media files 1-3). (Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA: WB Saunders, Inc, 1993: 216-316.)
	View Full Size Image
Media type:  Photo

REFERENCES

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1. Tipping AJ, Pearson T, Morgan NV, et al. Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci U S A. May 8 2001;98(10):5734-9. [Medline].
2. Callen E, Casado JA, Tischkowitz MD, et al. A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood. Mar 1 2005;105(5):1946-9. [Medline].
3. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. Feb 1 2003;101(3):822-6. [Medline].
4. Verlander PC, Kaporis A, Liu Q, et al. Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Blood. Dec 1 1995;86(11):4034-8. [Medline].
5. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer. Jan 15 2003;97(2):425-40. [Medline].
6. Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look T, eds. Hematology of Infancy and Childhood. 6^th ed. Philadelphia, Pa: Harcourt Health Sciences; 2003:280-365.
7. Alter BP, Caruso JP, Drachtman RA, et al. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet. Mar 2000;117(2):125-31. [Medline].
8. Bagby GC, Alter BP. Fanconi anemia. Semin Hematol. Jul 2006;43(3):147-56. [Medline].
9. Faivre L, Guardiola P, Lewis C, et al. Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood. Dec 15 2000;96(13):4064-70. [Medline].
10. Garcia-Higuera I, Taniguchi T, Ganesan S, et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. Feb 2001;7(2):249-62. [Medline].
11. Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet. Jun 2001;2(6):446-57. [Medline].
12. Rosenberg PS, Huang Y, Alter BP. Individualized risks of first adverse events in patients with Fanconi anemia. Blood. Jul 15 2004;104(2):350-5. [Medline].
13. Rosenberg PS, Socie G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood. Jan 1 2005;105(1):67-73. [Medline].
14. Taniguchi T, D'Andrea, AD. The molecular pathogenesis of fanconi anemia: recent progress. Blood. Jun 1 2006;107:4223-33. [Medline].
15. Verlinsky Y, Rechitsky S, Schoolcraft W, et al. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA. Jun 27 2001;285(24):3130-3. [Medline].
16. Young NS, Alter BP. Aplastic Anemia: Acquired and Inherited. Philadelphia, PA: WB Saunders Co; 1994:410.

Article Last Updated: Dec 21, 2007