eMedicine Specialties > Pediatrics: General Medicine > Hematology

Anemia, Fanconi

Blanche P Alter, MD, MPH, FAAP, Adjunct Faculty, Medical Genetics Fellowship Program, National Human Genome Research Institute; Adjunct Professor of Pediatrics, George Washington University School of Medicine and Health Scieces; Visiting Professor of Pediatrics, Johns Hopkins School of Medicine; Senior Clinician, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Jeffrey M Lipton, MD, PhD, Professor, Elmezzi Graduate School of Molecular Medicine, Director, Patient Oriented Research, Feinstein Institute for Medical Research; Director, Pediatric Hematology/Oncology and Stem Cell Transplantation, Schneider Children's Hospital; Director of Hematology-Oncology and Stem Cell Transplantation, Children's Health Network, North Shore/Long Island Jewish Health System

Updated: Sep 9, 2009

Introduction

Background

Fanconi anemia (FA) is the most frequently reported of the rare inherited bone marrow failure syndromes, with close to 2000 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 Fanconi anemia 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 Fanconi anemia and aplastic anemia without birth defects and the diagnosis of Fanconi anemia in patients without aplastic anemia but with abnormal physical findings. 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.

Most recently, the advent of molecular diagnostics has further improved the specificity of Fanconi anemia diagnosis (see Other Tests). Fanconi anemia comprises 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.

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 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.)

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.)

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.)

Pathophysiology

Fanconi anemiais 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 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), FANCG (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 Fanconi anemia 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 Fanconi anemia 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 Fanconi anemia 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 Fanconi anemia 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 Fanconi anemia 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 Fanconi anemia who have received bone marrow transplantation; transplantation (especially if graft versus host disease occurs) appears to further increase the risk of these cancers.

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 is higher in FANCG compared with FANCA and in FANCC compared with FANCA.

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 Fanconi anemia.

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 head and neck squamous cell carcinomas appears to be higher in patients who have received a bone marrow transplant.⁴

Race

Fanconi anemia has been reported in all races, although "founder" effects are recognized, which result in higher carrier frequencies in Ashkenazi Jews,⁵ South African Afrikaaners,¹ sub-Saharan Blacks, and Spanish Gypsies.²  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

Fanconi anemia 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

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 Fanconi anemia 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 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

• 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
• 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
• 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 Fanconi anemia pathway. The exact link between mutations and phenotype is not clear, although patients who are homozygous for null mutations appear to have more severe Fanconi anemia than those with altered proteins. Various aspects of pathophysiologic research include the following:

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

Differential Diagnoses

Dyskeratosis Congenita
Holt-Oram Syndrome
Myelodysplastic Syndrome
Pearson Syndrome
Shwachman-Diamond Syndrome
Thrombocytopenia-Absent Radius Syndrome

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

Laboratory Studies

• In Fanconi anemia (FA), 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 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 of Fanconi anemia 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 Fanconi anemia.
• 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 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.

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 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 a hematopoietic stem cell transplantation, resulting in the cure of the sibling's aplastic anemia or leukemia.

Treatment

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 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 (see Medication).

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). 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.^6,7 It should be considered for those who have an human leukocyte antigen (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 who have 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. In any case transplants should take place at institutions with experience in the treatment of patients with Fanconi anemia.

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.

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

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.

Oxymetholone (Anadrol-50)

Anabolic and androgenic derivative of testosterone in an PO formulation.

Dosing

Adult

2-5 mg/kg/d PO

Pediatric

Administer as in adults

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

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

Precautions

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, possible; insulin or PO hypoglycemic dosage may need adjustment; may cause suppression of clotting factors II, V, VII, and X; may cause increase in PT
Cholestatic hepatitis, peliosis hepatitis, liver tumors, and blood lipid changes that increase risk of atherosclerosis possible; monitoring includes liver function tests and liver ultrasound examinations

Nandrolone decanoate (Deca-Durabolin)

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.

Dosing

Adult

1-2 mg/kg/wk IM

Pediatric

Administer as in adults

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

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

Precautions

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

Antifibrinolytic agents

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

Aminocaproic acid (Amicar)

Competitively inhibits activation of plasminogen to plasmin.

Dosing

Adult

30 g/d PO/IV in divided doses q3-6h; not to exceed 30 g/d

Pediatric

100-200 mg/kg PO/IV loading dose; followed by 200-400 mg/kg/d PO divided q6h for 7-10 d.
Renal impairment: 50 mg/kg/d PO qd

Interactions

Coadministration with estrogens may cause increase in clotting factors, leading to hypercoagulable state

Contraindications

Documented hypersensitivity; hematuria; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with DIC, differentiate between hyperfibrinolysis and disseminated intravascular coagulation

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Decrease dose to 50 mg/kg/d PO qd in severe renal impairment; caution in cardiac or hepatic disease

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.

Filgrastim (G-CSF, Neupogen)

G-CSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

Dosing

Adult

2-10 mcg/kg SC qd/qod

Pediatric

Administer as in adults

Interactions

Caution in coadministration with drugs that may potentiate release of neutrophils (eg, lithium)

Contraindications

Documented hypersensitivity

Precautions

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

May cause bone pain, flulike symptoms, nausea, or vomiting; do not dilute to concentrations <5 mcg/mL; do not dilute with saline; potential risk of evolution to leukemia

Epoetin alfa (Epogen, Procrit)

Stimulates division and differentiation of committed erythroid progenitor cells; induces release of reticulocytes from bone marrow into blood stream.

Dosing

Adult

100-250 U/kg SC 3 times/wk

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity (including hypersensitivity to human albumin, hypersensitivity to mammalian cell-derived products); uncontrolled hypertension

Precautions

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; use lowest dose possible to achieve Hgb no greater than 10-12 g/dL; decrease dose/discontinue if Hgb rises too rapidly (ie, >1 g/dL within 2 wk) or if achieve target Hgb

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.

Prednisone (Deltasone, Liquid Pred)

Elicits anti-inflammatory properties and causes profound and varied metabolic effects. Modifies the body's immune response to diverse stimuli.

Dosing

Adult

5-10 mg PO qod

Pediatric

5 mg PO qod

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase methylprednisolone levels; phenobarbital, phenytoin, and rifampin may decrease methylprednisolone levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May increase risk of serious or fatal infection in individuals exposed to viral illnesses such as chickenpox or measles; hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications

Follow-up

Further Inpatient Care

• Inpatient care of Fanconi anemia (FA) 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 human leukocyte adhesion (HLA)-match and does not have Fanconi anemia.

Complications

• Possible complications include hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors, and other cancers.
• Leukemia was reported in more than 150 patients with Fanconi anemia (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 Fanconi anemia following bone marrow transplantation.
• Patients with Fanconi anemia 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 Fanconi anemia 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 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 excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Miscellaneous

Medicolegal 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. Fanconi anemia 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 Fanconi anemia in order for a transplantation to succeed.
• 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.

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

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.)

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.)

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.)

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.)

References

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17. [Guideline] Langlois S, Wilson RD. Carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. J Obstet Gynaecol Can. Apr 2006;28(4):324-43. [Medline].

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20. 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].

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Keywords

Fanconi anemia, FA, constitutional aplastic anemia, bone marrow failure, inherited bone marrow failure syndrome, aplastic anemia, leukemia, myelodysplastic syndrome, liver adenoma, hepatoma, radial ray anomalies, poor growth, genitourinary problems, short stature, skin pigmentation, café au lait spots, petechiae, bruises, bruising, pallor, fatigue, infections, thumb anomalies, thumb and radial anomalies, abnormal male gonads, microcephaly, eye anomalies, structural renal defects, low birth weight, developmental delay, abnormal ears, abnormal hearing, Estren Dameshek Fanconi anemia, pancytopenia, treatment, diagnosis

Contributor Information and Disclosures

Author

Blanche P Alter, MD, MPH, FAAP, Adjunct Faculty, Medical Genetics Fellowship Program, National Human Genome Research Institute; Adjunct Professor of Pediatrics, George Washington University School of Medicine and Health Scieces; Visiting Professor of Pediatrics, Johns Hopkins School of Medicine; Senior Clinician, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Blanche P Alter, MD, MPH, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American Federation for Medical Research, American Pediatric Society, American Society for Clinical Investigation, American Society of Hematology, International Society of Hematology, New York Academy of Sciences, Phi Beta Kappa, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey M Lipton, MD, PhD, Professor, Elmezzi Graduate School of Molecular Medicine, Director, Patient Oriented Research, Feinstein Institute for Medical Research; Director, Pediatric Hematology/Oncology and Stem Cell Transplantation, Schneider Children's Hospital; Director of Hematology-Oncology and Stem Cell Transplantation, Children's Health Network, North Shore/Long Island Jewish Health System
Jeffrey M Lipton, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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