Fanconi Anemia 

Fanconi anemia is the most frequently reported of the rare inherited bone marrow failure syndromes (IBMFSs), with greater than 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.

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, liver tumors, and other cancers. (See Prognosis.)

Leukemias were reported in 175 patients with Fanconi anemia (out of more than 2000 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 45 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 25 patients had multiple cancers. Close to 20 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 1 of these cancers of 95% by age 65 years.

Additional characteristics

Characteristics of the kidneys and cardiovascular system in Fanconi anemia can include the following abnormalities:

• Kidneys - ectopic or pelvic, horseshoe, hypoplastic or dysplastic, absent, hydronephrosis or hydroureter, infections, duplicated, rotated, reflux, hyperplasia, no function, and abnormal artery
• 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, and cardiomyopathy

Other anomalies include developmental delay, hyperreflexia, Bell palsy, CNS arterial malformation, stenosis of the internal carotid, and small pituitary gland. (The clinical presentation of Fanconi anemia is discussed under Physical Examination.)

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 one of the 15 genes known to be responsible for Fanconi anemia. The cloned genes are FANCA, B, C, D1, D2, E, F, G, I, J, L, M,N, O, and P. Although most are unique genes, several were previously known, including FANCD1 (BRCA2), FANCG (XRCC9), FANCI (KIAA1794), FANCJ (BRPI1/BACH1), FANCL (PHF9/POG), FANCM (Hef), FANCN (PALB2), FANCO (RAD51C), and FANCP (SLX4). 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 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.

Research into Fanconi anemia includes investigations into the following possibilities:

• 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

Historically, the carrier frequency in the United States has been estimated to be approximately 1 case per 300 people, leading to an expected birthrate of approximately 1 case per 360,000 people. A more recent analysis suggests that this may be an underestimate, likely due to incomplete ascertainment of cases.^[2] More current data indicate a carrier frequency in the United States of roughly 1 case per 181 persons (range, 156 to 209), leading to an expected birthrate of approximately 1 case per 130,000 people.^[2] .

The general carrier frequencies internationally are similar to those in the United States, depending on the population and the prevalence of founder mutations.

Fanconi anemia has been reported in all races. However, due to founder effects, the heterozygote frequency is greater in South African Afrikaners,^[3] sub-Saharan Blacks, and Spanish Gypsies^[4] than in the overall world population, leading to expected birthrates in these subpopulations of around 1 per 40,000. Among Ashkenazi Jews in the United States, the carrier frequency is approximately 1 per 90 people, with a projected birthrate of 1 per 30,000 people.^[5]

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

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.

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. 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.

The most common malignancies are AML, head and neck squamous cell carcinoma (HNSCC), liver tumors (adenomas and hepatomas; primarily but not exclusively in patients who had aplastic anemia that was treated with oral androgens), vaginal squamous cell carcinoma (SCC), and brain tumors. The risks of AML, HNSCC, and vulvar SCC compared with the general population were approximately 600-, 500-, and 3000-fold, respectively. The relative risk of MDS in Fanconi anemia patients is greater than 5000-fold. An even more increased incidence of HNSCC, particularly of the tongue, occurring at an earlier age, has been reported in patients with Fanconi anemia who have received bone marrow transplantation, especially if graft versus host disease was present.^{[6, 7]}

Thus, 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.

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.