Fanconi Anemia: Practice Essentials, Etiology, Epidemiology (original) (raw)

Fanconi anemia is the most frequently reported of the rare inherited bone marrow failure syndromes (IBMFSs). 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). [1, 2] Fanconi anemia must be tested for using chromosome breakage in blood or fibroblasts, or germline mutation analysis. Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia. [3, 4, 5]

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.” [6]

Complications of Fanconi anemia

Possible complications of Fanconi anemia include hemorrhages, infections, leukemia, myelodysplastic syndrome, and liver tumors and other cancers. [7, 8] (See Prognosis.)

Cancer risk [9, 10, 11]

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, VACTERL-H (the highest incidence in the FANCD1/BRCA2 genotype), regardless of hematologic status, must be evaluated for Fanconi anemia. [10]

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.)

A study by Altintas et al looking at the Fanconi anemia/BRCA DNA repair pathways found that the Fanconi anemia phenotype was less severe in individuals with variants in the upstream complex pathway, with these patients lacking the features of VACTERL-H and/or PHENO (Pigmentation, small-Head, small-Eyes, Neurologic, Otologic, Short stature). The VACTERL-H phenotype was associated with the ID complex pathway. The investigators also found better survival in the upstream complex patients than in individuals with variants in the ID complex or downstream complex. [12]

Signs and symptoms of Fanconi anemia

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%).

Workup in Fanconi anemia

Chromosome breakage in blood or fibroblasts, or germline mutation analysis, is used to test for Fanconi anemia.

Tests in Fanconi anemia reveal the following:

Management of Fanconi anemia

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).

Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) may cure aplastic anemia and prevent myelodysplastic syndrome or leukemia. [3, 4, 5] It should be considered for those who have a human leukocyte antigen (HLA)–matched sibling donor (survival rate is >80%).

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.

Hand surgery and splinting may be indicated for thumb and radial anomalies. Congenital heart defects may require surgery. Gastrointestinal (GI) anomalies, such as tracheoesophageal fistulas and imperforate anus, are also treated surgically.