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◉ What is Fanconi anemia?
Fanconi anemia (FA) is an inherited disorder caused by defects in the ability of cells to repair damaged DNA secondary to inactivating mutations in 1 of the 23 genes of the FA DNA repair pathway.
It is a multisystem disease that affects multiple organs, and the clinical manifestations are very variable, including bone marrow failure, congenital abnormalities, and a predisposition to malignancies such as leukemia and squamous cell carcinoma.
◉ Other Names
- Fanconi hypoplastic anemia
- Fanconi pancytopenia
- Fanconi panmyelopathy
◉ Frequency
First described in 1927 by the Swiss pediatrician Guido Fanconi, this rare disorder has an incidence of 1 in 100,000 to 350,000 births. However, the frequency is increased in certain ethnic populations such as Ashkenazi Jews and Afrikaners in South Africa.
The median survival age was only 14 years in the 1980s, but has improved to 30-40 years with modern management of bone marrow failure and screening for malignancies.
◉ Causes
Fanconi anemia follows an autosomal recessive pattern of inheritance. This means that both parents must be carriers of a mutation in the same FANC gene and pass down that mutation to the affected child. When the child inherits two mutated copies of the gene, one from each parent, they develop FA.
To date, mutations in 23 different FANC genes (FANC-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, -N, -O, -P, -Q, -R, -S, -T, -U, -V, -W, Y) have been identified that can lead to Fanconi anemia. The proteins encoded by these genes cooperate in the Fanconi anemia pathway, which regulates DNA repair and cell cycle progression.
When this pathway is defective, DNA repair is compromised leading to chromosomal breakage, cell death, and clinical features of Fanconi anemia.
Note: a small number of cases can result from a dominant negative mutation in a FANC gene on one allele.
◉ Symptoms and Signs
The clinical presentation of fanconi anemia is highly variable, ranging from severe congenital anomalies and very early onset of bone marrow failure to subtle physical abnormalities and onset of hematologic manifestations later in life.
Many different organ systems can be affected:
1- Hematologic abnormalities are a hallmark of fanconi anemia and manifest as pancytopenia (anemia commonly appears first, followed by neutropenia and thrombocytopenia) resulting from progressive bone marrow failure (aplastic anemia).
2- Characteristic physical findings include:
- Short stature.
- Skin pigmentation abnormalities like café-au-lait spots.
- Thumb and arm anomalies such as hypoplastic or absent thumbs and radial defects.
- Small head size (microcephaly).
- Renal structural abnormalities.
- Developmental delay.
- Microphthalmia (small eyes).
- Hearing deficits.
- Other skeletal malformations
3- Endocrine abnormalities are common, including:
- Hypogonadism
- Delayed puberty
- Short stature
- Abnormalities in glucose/insulin metabolism
4- Gastrointestinal manifestations, such us:
- Esophageal atresia
- Pyloric stenosis
- Anal abnormalities may be seen
5- Liver dysfunction and elevation of liver enzymes can occur.
6- Malignancies develop in a sizable portion of patients with Fanconi anemia, including hematologic cancers like acute myeloid leukemia and solid tumors such as squamous cell carcinomas of the head/neck, gynecologic system, and anogenital region.
◉ Diagnosis
The average age of diagnosis as 7 years, milder or atypical cases may escape early diagnosis, only coming to light later when bone marrow failure, malignancies, or infertility issues arise.
When FA is suspected based on clinical presentation, the diagnosis is confirmed by demonstrating increased chromosomal breakage and/or pathogenic variants in a FANC gene
◉ Physical Exam and History
The diagnosis starts with a complete physical exam, looking carefully for characteristic features like short stature, radial ray defects of the arms, café-au-lait spots, or microcephaly.
Medical history will inquire about cytopenias, developmental issues, pubertal development, and family history of fanconi anemia or related cancers. Ethnic background may provide clues, as certain populations have higher incidence of FA.
◉ Complete Blood Count
A complete blood count is done to check for cytopenias. Low red blood cell, white blood cell, and/or platelets suggest bone marrow failure. However, blood counts may sometimes be normal early in the disease.
◉ Chromosomal Breakage Testing
This test analyzes chromosomes from peripheral blood cells to check for spontaneous or mutagen-induced breaks. Fanconi anemia cells show increased breakage compared to normal cells.
The diagnostic test involves culturing blood cells with and without exposure to a DNA crosslinking agent such as diepoxybutane (DEB) or mitomycin C. In FA, excess breakage is observed after exposure to the mutagen.
◉ Mutation Analysis
Sequencing of FANC genes can identify the disease-causing mutations. Targeted mutation panels for common FANC mutations are available, as well as broader next-generation sequencing panels that cover all 22 FANC genes. Prenatal testing is also possible if the family's pathogenic mutations are known.
◉ Other Tests
Cell cycle analysis may show excessive accumulation of cells in the G2 phase. Testing for biomarkers of DNA damage response defects may support an FA diagnosis. Skin fibroblast culture can also be used to assess chromosomal breakage.
Note: Early diagnosis may prevent severe complications.
◉ Treatment and Management
While there is no cure for FA, the goals of treatment are to monitor blood counts, transfuse for cytopenias, delay bone marrow failure, prevent malignancies, and otherwise maximize quality of life.
1- Supportive Care
Once diagnosed, patients need frequent monitoring of blood counts to watch for cytopenias. Transfusions of red cells and platelets can treat anemia and bleeding episodes. Blood products should be irradiated and leukoreduced to prevent transfusion reactions. Iron chelation therapy is used to remove excess iron from transfusions. Granulocyte colony-stimulating factor (G-CSF) may help raise neutrophil counts.
2- Androgens
Androgenic steroids like oxandrolone and danazol can stimulate erythropoiesis in some patients. However, long-term use has risks including liver toxicity and masculinization.
3- Hematopoietic Cell Transplantation
The only definitive cure for the hematologic manifestations of FA is allogeneic stem cell transplant, ideally from a human leukocyte antigens (HLA)-matched sibling donor. Transplant aims to regenerate the bone marrow before severe cytopenias or malignancies develop. Outcomes have improved with better HLA matching, less toxic conditioning regimens, and enhanced supportive care.
4- Gene Therapy
Introducing functional FANC genes into patient hematopoietic stem cells via viral vectors is a promising investigational approach currently undergoing clinical trials. This could potentially cure the hematologic deficits without the risks of allogeneic transplantation.
5- Cancer Screening
Because of the high risk of malignancies, annual screening beginning in early adolescence is recommended. This includes complete physical exams, blood counts, tumor marker blood tests, and imaging studies appropriate for the most common cancers. Early detection of cancers like squamous cell carcinoma improves outcomes.
6- Other Supportive Care
Management also focuses on supportive multidisciplinary care such as surgery for anatomic abnormalities, growth hormone for short stature, hormone replacement for hypogonadism, and social/educational support. Avoidance of alcohol, smoking and environmental toxins is advised.
◉ Conclusion
Fanconi anemia is a complex inherited syndrome leading to bone marrow failure, congenital anomalies, and cancer predisposition. It is caused by defective DNA repair due to pathogenic variants in FANC genes.
Diagnosis involves blood counts, chromosomal breakage testing, and genetic testing. Treatment is aimed at supportive care, transfusion support, allogeneic HCT, cancer surveillance, and emerging gene therapies.
With improved treatments, survival has increased significantly. However, FA remains a serious lifelong illness requiring comprehensive medical management and social support. Continued research to better understand FA biology and translate genetic advances into targeted therapies is critical to keep improving prognosis in this challenging disorder.
