Fanconi Anemia 

Updated: Jun 20, 2018
Author: Jeffrey M Lipton, MD, PhD; Chief Editor: Jennifer Reikes Willert, MD 

Overview

Background

Fanconi anemia is the most frequently reported of the rare inherited bone marrow failure syndromes (IBMFSs), with approximately 2000 cases reported in the medical literature. In 1927, Guido Fanconi first reported 3 brothers with macrocytosis, pancytopenia, and physical abnormalities. Subsequent cases were clinically diagnosed because of the combination of aplastic anemia and various characteristic physical anomalies (see Physical Examination).

In the early 1960s, several groups observed that cultured cells from patients with Fanconi anemia had increased numbers of chromosome breaks; later, the breakage rate was found to be specifically increased by the addition of deoxyribonucleic acid (DNA) cross-linkers, such as diepoxybutane (DEB) or mitomycin C (MMC). This led to the identification of patients with Fanconi anemia and aplastic anemia without birth defects and the diagnosis of Fanconi anemia in patients without aplastic anemia but with abnormal physical findings. (See Etiology.)

Furthermore, in cultured Fanconi anemia 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. (See Workup.)

The advent of molecular diagnostics has further improved the specificity of Fanconi anemia diagnosis.

Fanconi anemia accounts for approximately 25% of the cases of aplastic anemia seen at large referral centers. Approximately 25% of known patients with Fanconi anemia do not have major birth defects. (See Physical Examination.)

Birth defects (present in up to 75% of Fanconi anemia patients, depending on the level of scrutiny) associated with Fanconi anemia are demonstrated in the images below.

A 3-year-old patient with Fanconi anemia. Note the 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.)
The 3-year-old patient with Fanconi anemia seen in The 3-year-old patient with Fanconi anemia seen in the previous image. (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.)
Café au lait spot and hypopigmented area in a 3-ye Café au lait spot and hypopigmented area in a 3-year-old patient with Fanconi anemia. Same patient as in the previous images. (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.)
Thumbs attached by threads on a 3-year-old patient Thumbs attached by threads on a 3-year-old patient with Fanconi anemia (same patient as in the previous images). (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.)

Go to Pediatric Chronic Anemia, Anemia of Prematurity, Donath-Landsteiner Hemolytic Anemia, Pediatric Acute Anemia, and Pediatric Megaloblastic Anemia for complete information on these topics. Additionally, readers interested in an in depth review of Fanconi anemia and other IBMFSs are referred to an article by Shimamura and Alter in the journal Blood Reviews: “Pathophysiology of inherited bone marrow failure syndromes.”[1]

Complications

Possible complications of Fanconi anemia include hemorrhages, infections, leukemia, myelodysplastic syndrome, and liver tumors and other cancers.[2, 3] (See Prognosis.)

Cancer risk[4, 5, 6]

From literature reviews, it is estimated that 9% of patients developed leukemia, of which 95% were acute myeloid leukemia (usually rare in children), with a relative risk for acute myeloid leukemia of approximately 500-fold. The majority of cases develop between ages 15 and 35 years, with a cumulative incidence of 13% by age 50 years.

Myelodysplastic syndrome was reported in 7% of patients (>100 patients); many of these patients did not develop leukemia but died from complications of impaired marrow function. The risk of myelodysplastic syndrome in Fanconi anemia is increased about 5000-fold.

Liver tumors occurred in more than 45 patients, 43 of which were associated with androgen use, 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).

There is a marked increase in solid tumors. In order of frequency, these tumors were tumors of the oropharynx, esophagus, vulva/vagina, brain, skin (nonmelanoma), cervix, breast, kidney, lung, lymph nodes (lymphoma), stomach, and colon, followed by osteogenic sarcoma and retinoblastoma. The relative risk of all cancers was approximately 40-fold with a cumulative incidence of 30% by age 50 years. The risk of head and neck squamous cell carcinoma is 600-fold and for vulvar/vaginal squamous cell carcinoma approximately 3000-fold. A large number of oral cancers have been reported in patients with Fanconi anemia following bone marrow transplantation.

Due to the high sensitivity to chemotherapeutic agents, which damage DNA, the outcome for patients with Fanconi anemia and cancer is quite poor.

Patients with Fanconi anemia in the FANCD1/BRCA2 (the highest cancer risk genotype) and N/PALB2 and J/BRIP1 groups (monoallelic breast cancer predisposition genes) have inordinately high rates of acute myeloid leukemia, brain tumors (medulloblastoma), and Wilms tumor, with a cumulative incidence of at least 1 of these cancers of 95% by age 5 years.

Congenital anomalies

The vast majority (75%) of individuals with Fanconi anemia have at least one physical anomaly. The most common are short stature and cutaneous, skeletal, craniofacial, and genitourinary anomalies. Additionally, approximately 5% of patients with Fanconi anemia have at least 3 of the defining features of VATER, or VACTERL, association (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, renal and/or radial anomalies, limb defects). Furthermore, individuals with an expanded phenotype VACTERC-H (the highest incidence in the FANCD1/BRCA2 genotype), regardless of hematologic status, must be evaluated for Fanconi anemia.[5]

Other anomalies include developmental delay, hearing loss, congenital heart disease, and CNS anomalies (arterial malformation, stenosis of the internal carotid, and small pituitary gland). (The clinical presentation of Fanconi anemia is discussed under Physical Examination.)

Etiology

Fanconi anemia is an autosomal recessive disease in more than 99% of patients (FANCB is X-linked recessive); each patient with Fanconi anemia is homozygous or doubly heterozygous for mutations in 1 of the 15 genes known to be responsible for Fanconi anemia. The cloned genes are FANCA, B, C, D1/BRCA2, D2, E, F, G/XRCC9, I, J/BRIP1, L, M, N/PALB2, O/RAD51C and P/SLX4. Although most are unique genes, as shown several were previously known, including FANCD1 (BRCA2), FANCG (XRCC9), FANCJ (BRPI1/BACH1), and FANCN (PALB2), FANCO (RED51C) and (SLX4). Heterozygotes for BRCA2 and possibly BACH1 and PALB2 are at increased risk of breast and other cancers.

The first 13 Fanconi anemia proteins have discrete functions, with A, B, C, E, F, G, L, and M appearing 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 Fanconi anemia phenotype may depend not on the specific gene involved but on whether the mutation is null or leads to a partially functional gene product. The specific role of mutations in the Fanconi anemia genes in the pathogenesis of birth defects, bone marrow failure, or oncogenesis is not yet clear. The designation of the extremely rare proteins O and P remains controversial.

Epidemiology

Fanconi anemia has been reported in persons of all races. However, owing to founder effects, the heterozygote frequency is greater in South African Afrikaners,[7] sub-Saharan blacks, and Spanish gypsies[8] than in the overall world population, leading to expected birthrates in these subpopulations of around 1 cases per 40,000 births. Among Ashkenazi Jews in the United States, the carrier frequency is approximately 1 case per 90 people, with a projected birthrate of 1 case per 30,000 people.[9]

The male-to-female ratio in the literature cases is 1.2:1, although equal numbers are expected in a disorder with over 99% autosomal recessive inheritance.

Fanconi anemia has been diagnosed in patients from birth to age 49 years, with a median age of 7 years. Individuals with birth defects are diagnosed at younger ages than are persons without birth defects.

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, in particular the avoidance of smoking, and screening to identify early malignancies may reduce the mortality rate from cancer. With regard to the first serious adverse event, patients with a large number of birth defects are at higher risk of early-onset severe aplastic anemia, while those with fewer anomalies are more likely to develop leukemia or a solid tumor as young adults.

Although many patients with Fanconi anemia are short and have skeletal anomalies, intelligence is usually normal, and education and career planning should be encouraged.

Mortality/morbidity

Regarding mortality and morbidity,[1] major adverse events for patients with Fanconi anemia are aplastic anemia (usually severe), leukemia, and solid tumors. The projected median survival from all causes for more than 2000 cases reported in the literature has improved in the past decade; from 1927-1999 and 2000-2009, median survivals are age 21 years and 29 years, respectively.

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. The annual hazard rate for severe aplastic anemia reached 5% per year by age 10 years and was less than 1% per year in adults, with a cumulative incidence of 50% by age 50 years.

Leukemia usually presents primarily in teens and young adults, reaching a hazard rate of 1% per year, with a cumulative incidence of 10% by age 50 years. About one third of the cases of Fanconi anemia and leukemia in the literature did not have a prior diagnosis of Fanconi anemia, as well as a preceding phase of aplastic anemia. More than 100 cases in the literature were reported to have myelodysplastic syndrome (MDS).

The hazard rate for solid tumors rises steadily to greater than 10% per year by age 45 years, with a cumulative incidence of 25% by age 50 years, often without prior hematologic disease. As for acute myelogenous leukemia (AML), about one third of reported cases presented with a tumor and were subsequently diagnosed as Fanconi anemia.

A positive correlation between absent or abnormal radii and other congenital anomalies and bone marrow failure has been noted. The relative hazard of bone marrow failure and leukemia is higher in FANCG, compared with FANCA, and in FANCC, compared with FANCA. Patients with homozygous null mutations in FANCA have a higher risk of leukemia than those with allelic mutations, leading to an abnormal protein. Patients with biallelic mutations in BRCA2/FANCD1 have an extraordinarily high risk of acute myeloid leukemia, brain tumors (medulloblastoma), and Wilms tumors, with an approximately 95% chance of developing one of these tumors by age 5 years. Genetic background (Japanese vs Ashkenazi Jewish) and specific allelic mutations in FANCC can modulate the phenotype.

The risk of liver tumors is increased 400-fold, the risk of leukemia is about 500-fold, and head and neck cancers are increased approximately 600-fold. The risk of esophageal cancer is increased 2000-fold, and the risk of vulvar/vaginal cancer is increased 3000-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 transplantation or gene therapy, are the concerns in treating children and adolescents, solid tumors remain the major threat to older patients with Fanconi anemia.

In a retrospective analysis of 145 patients with Fanconi anemia, 9 patients evolved to leukemia and 14 developed 18 solid tumors.[5] The ratio of observed-to-expected cancers for all cancer diagnoses or for solid tumors was 40, and the ratio was 600 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 head and neck squamous cell carcinomas appeared to be higher in patients who had received a bone marrow transplantation.[6, 10]

A study by Sauter et al suggested that the prevalence of oral human papillomavirus (HPV) is greater in persons with Fanconi anemia. The study found the oral HPV rate to be 11.1% in 126 patients with Fanconi anemia, versus 2.5% in 162 unaffected first-degree family members. More specifically, the oral HPV rate in sexually active persons with Fanconi anemia was 17.7%, versus 2.4% in family members, while in sexually inactive individuals with Fanconi anemia the prevalence of HPV was 8.7%, versus 2.9% in siblings.[11]

A study by Sathyanarayana et al suggested that in patients with Fanconi anemia, greater age is positively correlated with the incidence of chronic kidney disease.[12]

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 gynecologic examinations).

The genetic basis of Fanconi anemia needs to be explained, and apparently unaffected siblings should be tested for Fanconi anemia 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 patient education information, see Anemia.

 

Presentation

History

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 Fanconi anemia should at least be evaluated for an elevated erythrocyte mean corpuscular volume. In approximately 35% of patients with Fanconi anemia who were reported to have cancer, the diagnosis of leukemia or a tumor preceded the diagnosis of Fanconi anemia.

Physical Examination

About 75% of patients with Fanconi anemia 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%). (See the images below.)

A 3-year-old patient with Fanconi anemia. Note the 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.)
The 3-year-old patient with Fanconi anemia seen in The 3-year-old patient with Fanconi anemia seen in the previous image. (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.)
Café au lait spot and hypopigmented area in a 3-ye Café au lait spot and hypopigmented area in a 3-year-old patient with Fanconi anemia. Same patient as in the previous images. (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.)
Thumbs attached by threads on a 3-year-old patient Thumbs attached by threads on a 3-year-old patient with Fanconi anemia (same patient as in the previous images). (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.)

However, literature reports may 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 have a very severe phenotype, including features of the vertebral, anal, cardiac, tracheal, esophageal, and limb (VACTERL) association.[1, 13, 14]

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.

Upper limb abnormalities can include the following features:

  • 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 may display the following abnormalities:

  • 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 can include the following features:

  • 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

Additional abnormalities found in Fanconi anemia can include the following characteristics:

  • 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

  • GI 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

 

DDx

Diagnostic Considerations

Patients with Fanconi anemia with characteristic birth defects (eg, radial ray anomalies, poor growth, genitourinary abnormalities) are often treated by various medical specialists during infancy. The diagnosis of Fanconi anemia must first be considered and can only be established if specific tests are ordered.

Failure to diagnose aplastic anemia or leukemia may lead to delays in treatment. The diagnosis of Fanconi anemia 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.

Patients who have tumors that are characteristic of Fanconi anemia but who present without the usual risk factors for those tumors need to be screened for Fanconi anemia (eg, head and neck cancer in a 20-year-old woman who does not smoke or drink).

Mild forms of Fanconi anemia may be missed, placing future pregnancies in that family at risk for Fanconi anemia. Possible probands with characteristic birth defects, undiagnosed cytopenias, or macrocytosis should be evaluated for Fanconi anemia.

Differentials to consider in the diagnosis of Fanconi anemia, aside from those in the next section, include the following conditions:

  • 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 should also be considered in the diagnosis.

Go to Pediatric Chronic Anemia, Anemia of Prematurity, Donath-Landsteiner Hemolytic Anemia, Pediatric Acute Anemia, and Pediatric Megaloblastic Anemia for complete information on these topics.

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of Fanconi anemia is not made using 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.

Prenatal Fanconi anemia 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 Fanconi anemia gene mutations in DNA extracted from fetal cells.

Preimplantation genetic diagnosis can be established using molecular methods, resulting in implantation of an embryo without Fanconi anemia mutations and, if so desired, who is human leukocyte antigen (HLA)–matched with an affected child with Fanconi anemia. Cord blood from the delivery can be used for hematopoietic stem cell transplantation, resulting in the cure of the sibling's aplastic anemia or leukemia.

CBC Count, Chromosome Breakage Test, and Flow Cytometry

CBC count

In Fanconi anemia, the complete blood count (CBC) may reveal trilineage pancytopenia or may only show RBCs that are macrocytic for age. Macrocytosis, thrombocytopenia, and/or leukopenia may precede full-blown aplasia.

Chromosome breakage test

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 quadraradii in Fanconi anemia homozygote cells.

Some patients may have hematopoietic somatic mosaicism, with correction of the Fanconi anemia defect in the blood. In these cases, skin fibroblasts may be needed for the chromosome breakage test.

Flow cytometry

Flow cytometry of Fanconi anemia cells cultured with nitrogen mustard and other clastogens demonstrates an arrest in G2/M.

Additional Studies

Fetal hemoglobin study

Fetal hemoglobin (HbF) may be increased for age as a manifestation of stress erythropoiesis.

Adenosine deaminase study

Red cell adenosine deaminase (ADA) is increased in approximately 85% of patients with Diamond-Blackfan anemia (DBA) but appears to be normal in Fanconi anemia.

Serum erythropoietin study

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.

Skeletal survey

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.

Ultrasonography

Perform initial abdomen ultrasonography to document the size and location of the kidneys, and perform follow-up ultrasonography annually to monitor for liver tumors or peliosis hepatis.

Perform cardiac ultrasonography to evaluate for congenital anomalies.

MRI

Central nervous system (CNS) magnetic resonance imaging (MRI) is indicated to identify any structural defects, such as absence of the corpus callosum, small pituitary, or cerebellar hypoplasia.

Complementation group and gene analysis

Complementation groups can be identified by using cell-fusion techniques. This approach will determine the affected allele but will not provide the specific mutation. However, mutations in specific Fanconi anemia genes can often be identified.

These tests are generally performed only in research laboratories, with the exception of the relatively common Fanconi anemia mutation found in Ashkenazi Jews (IVS4 +4 A to T).

Fanconi anemia lymphocytes are treated with vectors containing normal clones of the known Fanconi anemia 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.

Bone marrow aspiration and biopsy

Bone marrow aspiration 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. However, certain clonal abnormalities such as specific 3q amplifications have been suggested to portend a high likelihood of leukemic transformation.

 

Treatment

Approach Considerations

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. Patients should be referred to centers with experience in the care of patients with Fanconi anemia as new information is likely to change the treatment approach.

Related transplant donors must be proven not to have Fanconi anemia in order for a transplantation to succeed.

Go to Pediatric Chronic Anemia, Anemia of Prematurity, Donath-Landsteiner Hemolytic Anemia, Pediatric Acute Anemia, and Pediatric Megaloblastic Anemia for complete information on these topics.

Consultations

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

Supportive Care

Supportive care for patients with symptomatic Fanconi 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). 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.

Transfusions may be given as inpatient or outpatient treatment.

Hematopoietic Stem Cell Transplantation and Androgen Therapy

Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia.[15, 16, 17] 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 had been reserved for patients with leukemia or myelodysplasia and did not have HLA-matched related donors and for patients either unable to tolerate or refractory to standard medical treatment; this practice is changing as new, less toxic conditioning regimens and more precise HLA typing are developed and as the size of the donor pool increases.[18]

In any case, transplants must take place at institutions with experience in the treatment of patients with Fanconi anemia. Hematopoietic stem cell transplantation is currently an inpatient procedure.

A study by MacMillan et al reported that alternative donor hematopoietic cell transplantation had a high success rate in patients with Fanconi anemia who did not have a history of opportunistic infections or transfusions and who underwent conditioning with single fraction total body irradiation 300 cGy, cyclophosphamide, fludarabine, and antithymocyte globulin. Survival probability in these patients was 94% at 5 years, according to the investigators. The study, which involved 130 patients, also found that adding fludarabine to conditioning caused three-fold enhancement of hematopoietic cell engraftment.[19]

A study by Wang et al suggested that in patients with Fanconi anemia, the 1-year overall survival rate following unrelated-donor hematopoietic stem cell transplantation is poor in those with clonal or complete copy gains in the q arm of chromosome 3 or with abnormalities in three or more chromosomes.[20]

Androgen therapy

Although the only therapy that can cure the pancytopenia is stem cell transplantation, androgens, to which approximately 50-75% of patients respond, are used for those in whom transplantation is not an option.

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 Fanconi anemia.

Activity Restriction, Management of Complications, and Monitoring

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.

Inpatient care of Fanconi anemia may be needed for complications of bone marrow failure (eg, bleeding, infection).

Hospitalization may be needed for treatment of other complications (eg, leukemia, tumors).

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.

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.

 

Medication

Medication Summary

Fanconi anemia is one of the few forms of aplastic anemia in which the response to androgens is more than 50%. Hematopoietic growth factors are occasionally helpful in Fanconi anemia.

Androgenic agents

Class Summary

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 blood 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. Recent studies suggest that the less potent androgen, danazol, may be effective in delaying the onset of clinically significant cytopenias in patients with Fanconi anemia.

Oxymetholone (Anadrol-50)

This is an anabolic and androgenic derivative of testosterone in an oral formulation.

17 Alpha-ethynyl testosterone (Danazol, Danocrine)

A parenteral fat-soluble androgen has been studied experimentally and is sometimes selected because it is less virilizing, although the results of a large ongoing trial are not published. The risk of hepatic tumors compared with other androgens has not been determined. As with oxymetholone, the lowest effective dose should be used.

Antifibrinolytic agents

Class Summary

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

Aminocaproic acid (Amicar)

This medication competitively inhibits activation of plasminogen to plasmin.

Hematopoietic growth factors

Class Summary

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.

Filgrastim (G-CSF, Neupogen)

Filgrastim is a G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.