Fanconi anemia overview
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Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. It is causes by mutations in DNA repair proteins that lead to increased susceptibility to DNA breakage, which in turns leads to ineffective erythropoiesis and increased risk for malignancies. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C. Treatment involves allogeneic stem cell transplant or supportive measures like transfusions and growth factor support.
The discovery of Fanconi anemia is largely the work of the Swiss pediatrician Guido Fanconi who observed various findings of the disease to be different than pernicious anemia. Over the coming decades, multiple advances in diagnostics have been made by various groups. Bone marrow transplant was optimized for Fanconi anemia in the 1980s. Most recently, in the 2010s, various new genomic alterations have been associated with Fanconi anemia.
Fanconi anemia is currently classified by complementation group.
In order to understand the pathophysiology, it is important to understand normal physiology of DNA repair. There are eight FANC family members that are activated during times of DNA damage. These proteins function in repairing damaged genetic material. In patients with Fanconi anemia, there is impaired DNA damage response due to mutations in the FANC family genes, and this leads to chromosomal instability and susceptibility to cross-linking agents. These cross-linking agents can lead to the generation of reactive oxygen species.
Fanconi anemia an autosomal recessive genetic disorder that is caused by mutations in various genes of the FANC family.
Differentiating Fanconi Anemia from Other Diseases
Fanconi anemia must be differentiated from aplastic anemia, paroxysmal nocturnal hemoglobinuria, chromosomal breakage syndromes, and hereditary bone marrow failure syndromes (dyskeratosis congenita and other short telomere syndromes). Each disease has a different pathophysiology, exam findings, and histopathology.
Epidemiology and Demographics
Fanconi anemia is rare overall, but it is one of the most common inherited bone marrow failure syndromes. It is typically diagnosed in children with a median age of diagnosis of 7.6 years. There is no racial predilection for Fanconi anemia. It is slightly more common in males than females with a ratio of 1.2:1.
The major risk factor for Fanconi anemia is genetic inheritance. It is inherited in an autosomal recessive pattern.
There are no recommendations on screening for Fanconi anemia.
Natural History, Complications and Prognosis
The natural history of Fanconi anemia involves progressive bone marrow failure, which can result in clinical manifestations such as fatigue, infections, and bleeding. Complications of Fanconi anemia include cardiovascular failure, iron overload from frequent transfusions, myelodysplastic syndrome, acute myeloid leukemia, overt bone marrow failure. The prognosis of Fanconi anemia is poor in the absence of allogeneic stem cell transplant. The prognosis is especially poor if Fanconi anemia evolves into acute myeloid leukemia. After allogeneic transplant, however, the prognosis can be quite favorable and cure can be achieved.
Diagnostic Study of Choice
There are two major diagnostic studies of choice for Fanconi anemia. These include chromosomal breakage analysis and mutational analysis.
History and Symptoms
The majority of patients with Fanconi anemia present with congenital anomalies. Sometimes, FA may be suspected at birth by one or more of these physical traits. The clinical features of Fanconi anemia encompass congenital anomalies, cytopenias/bone marrow failure, development of solid tumors, and endocrine manifestations.
The most common presenting features of FA are congenital malformations. Cytopenias are also common, and many patients eventually develop bone marrow failure. Common malignancies include myelodysplastic syndrome (MDS), leukemia, and solid tumors, especially squamous cell cancers (SCC).
The laboratory findings in Fanconi anemia include decreased hemoglobin on CBC and increased chromosomal breakage with mitomycin C or diepoxybutane. There may also be single-lineage or multi-lineage cytopenias.  Flow cytometry of hematopoietic cells may show cell cycle arrest in G2/M phase.
There are no specific electrocardiogram findings in Fanconi anemia.
X-ray can show a variety of abnormalities in patients with Fanconi anemia. Although non-specific, some of the features include radial ray anomalies of the thumb, absent thumb, or triphalangeal thumb. A skeletal survey can be done to identify all developmental defects involving bone. Care should be taken to ensure that radiation doses are limited in patients with Fanconi anemia, since the DNA damage response is impaired and these patients can develop cancers due to radiation exposure. Care should be taken to avoid unnecessary radiation in patients with a cancer predisposition.
There are no specific CT findings in Fanconi anemia. However, certain anatomic defects associated with Fanconi anemia can be visualized with CT.
There are no specific MRI findings in Fanconi anemia. However, certain anatomic defects associated with Fanconi anemia can be visualized with MRI.
There are no specific ultrasound findings in Fanconi anemia. However, certain anatomic defects associated with Fanconi anemia can be visualized with ultrasound, including renal and cardiac anomalies.
Other Imaging Findings
There are no other radiologic findings associated with Fanconi anemia.
Other Diagnostic Studies
Other diagnostic studies in Fanconi anemia include fetal hemoglobin assessment, adenosine deaminase study, and erythropoietin assay.
There is no single universalized medical therapy for Fanconi anemia. Treatment for Fanconi anemia is diverse and largely depends on severity of disease and the risk assessment for future malignancies. The most conservative management strategy involves active surveillance with routine laboratory monitoring every three months. Allogeneic transplant is a more intense treatment that can be used for curative purposes, though the toxicity is higher. Androgens, transfusions, and growth factor support can help improve anemia. Given the risk of both hematologic malignancies and solid tumors in patients with Fanconi anemia, it is important to understand screening and management strategies for these.
There is no surgical treatment of Fanconi anemia.
There are no specific methods of primary prevention for Fanconi anemia. However, genetic counseling can be done for people with Fanconi anemia who would like to reduce the likelihood of having a child with Fanconi anemia.
There are two major methods of secondary prevention in Fanconi anemia. These involve reducing the risk of development of secondary malignancies.
- Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O; et al. (2018). "From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia". Genet Med. doi:10.1038/s41436-018-0037-1. PMID 29904161.
- Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD (1993). "The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry". Pediatrics. 91 (6): 1116–20. PMID 8502512.