Fanconi Anemia Genetic Fanconi anemia is a rare inherited blood disorder that affects the bone marrow’s ability to produce blood cells. It is caused by defects in the Fanconi DNA-repair pathway, leading to progressive bone marrow failure, congenital abnormalities, and a high risk of cancer. This genetic disorder needs lifelong management and supervision.[1]
What is Fanconi Anemia?: Fanconi Anemia Genetic
Fanconi anemia is a rare genetic disease, and it mainly affects bone marrow, the spongy tissue found inside the bones to form blood cells. In FA, the bone marrow will not produce sufficient blood cells (RBCs, WBCs, and platelets). The reason for this impaired production is that the genetic mutations prevent the body from repairing the damaged DNA.[2]
The disease has a global prevalence of about one in 130,000 live births, but is more common in some racial groups, as the Ashkenazi Jews and Afrikaners of South Africa. The prevalence of the condition is estimated to be 1 in 100,000-160,000 in the general population.[3]
It was named after Swiss pediatrician Guido Fanconi, who first described it in 1927. Fanconi anemia is distinct from Fanconi syndrome, which is a totally different kidney disease also named after Dr. Fanconi.
How Many People Are Affected by Fanconi Anemia?
In the United States, approximately 31 children are born with Fanconi anemia every year. Although precise world statistics are not available, in medical literature, about 2,000 cases have been reported.[4]
The condition is also common in both males and females, and it can be found in all ethnic groups. Nevertheless, some populations are at a greater risk because of carrier frequency within their populations.
Causes of Fanconi Anemia
Genetic Factors
Fanconi anemia is caused by some defects in the functions of proteins that participate in the repair of DNA in a process known as homologous recombination. The condition can be caused by mutations in over 20 different genes, and those genes encode proteins that participate in the Fanconi anemia pathway that assists in repairing damaged DNA.[5]
Inheritance Pattern
Fanconi anemia is primarily an autosomal recessive genetic disease, and that means two mutated copies of genes, one inherited from each parent, are needed to result in an individual developing the disease. In the case of transmission of an abnormal FA gene by both parents:[6]
- A quarter of their children will develop Fanconi anemia
- Their child has a 50% probability of being a symptomless carrier.
- One out of every four children will not have the disease or will be a carrier.
Approximately 2 percent of the cases are X-linked recessive, i.e, the mutated gene is located on the X chromosome so that male children of a carrier mother have a 50 percent probability of contracting the disease.
Most Common Gene Mutations
In 80 to 90 percent of Fanconi anemia cases, defects in one of three genes, FANCA, FANCC, and FANCG, cause the disorder. These genes contain instructions on assembling components that are necessary for repairing DNA. Approximately 60 percent of all cases are associated with the FANCA gene, which is linked tosubsequent bone marrow failure.[7]
Symptoms of Fanconi Anemia
The Fanconi anemia symptoms differ greatly between people. Approximately 75 percent of individuals with FA will have physical abnormalities, and the rest will have no apparent physical abnormalities in their childhood.[8]
Physical Deformities At Birth
A large number of children with Fanconi anemia are born with some unique physical appearance:
Skeletal Abnormalities
- Missing, malformed, or extra thumb
- Missing radius bone
- Malformation of the hip, legs, hands, and toes
- Curved spine (scoliosis)
- Stature and birth weight are low
Skin Changes
- Café au lait spots (birthmarks of coffee color)
- Patches of lighter skin (vitiligo)
- Abnormal skin pigmentation
Facial and Sensory Features
- Microcephaly (small head size)
- Small or abnormally shaped eyes
- Abnormal ear shape
- Deafness or hearing loss at birth
Organ Problems
- Abnormalities of the kidney, such as missing or malformed kidneys
- Heart defects, especially a ventricular septal defect
- GIT structural issues
Blood-Related Symptoms
Approximately 80 percent of affected people with FA develop bone marrow failure at age 20. In childhood, children with FA get bone marrow failure that deteriorates with age, resulting in reduced blood cell counts.
Anemia or Low Red Blood Cell
- Persistent fatigue and weakness
- Pale skin
- Shortness of breath
- Dizziness and lightheadedness
- Rapid or irregular heartbeat
- Headaches
Leukopenia (Low White Blood Cells)
- Frequent infections
- Slow healing of ailments
- Chronic health issues
Thrombocytopenia (Low Platelets)
- Easy bruising
- Petechiae
- Bleeding gums
- Frequent nosebleeds
- Sustained bleeding from minor injuries.
Developmental and Other Symptoms
Approximately 75 percent of individuals affected by FA experience some type of endocrine issue with different severity levels. Additional symptoms may include:
- Delayed growth and development
- Feeding difficulties in infancy
- Learning disabilities
- Delayed puberty
- Female and male infertility
- Early menopause in women
Fanconi Anemia Diagnosis
When to Suspect Fanconi Anemia?
FA must be suspected and tested in:
- Any infant with malformations of the thumb and arm
- One with aplastic anemia at any age
- Patients with squamous cell carcinoma of the head, neck, gastrointestinal, or gynecologic system at a young age
It is diagnosed at an average of 7 years; however, early diagnosis has grown as a result of increased awareness and prenatal screening. Fifty percent of the patients are diagnosed under the age of 10, and approximately 10 percent are diagnosed when they are adults.[9]
Medical History and Physical Examination
Diagnosis begins with a detailed review of personal medical history and family medical history.
The healthcare providers seek symptoms of bone marrow failure, physical anomalies, and family history, which would indicate inherited conditions.
Laboratory Tests
Complete Blood Count (CBC)
CBC in Fanconi Anemia (FA) shows Pancytopenia (a reduction in all major blood cell lines).[10]
- Hemoglobin: Low (Anemia)
- White Blood Cells: Low (Leukopenia)
- Platelets: Low (Thrombocytopenia)
- Red Blood Cells: Often macrocytic (larger than normal)
Chromosome Breakage Test
The chromosome breakage test is the gold-standard test of Fanconi anemia that evaluates the ability of cells to repair DNA damage properly. In this test, the patient cells are subjected to DNA-damaging agents such as diepoxybutane (DEB) or mitomycin C (MMC). FA patients have many more chromosome breaks than normal cells.[11]
Genetic Testing
Genetic tests may aid in determining which particular gene mutation is the cause of the disease, and these findings can at times affect treatment planning. Testing may involve:
- Next-generation sequencing to determine the existence of particular gene mutations.
- Complementation test to show the affected FA gene group.
- Testing of relatives of the carrier.
Imaging Studies
Further examinations assist in determining physical abnormalities:
- X-rays to assess the abnormalities in the skeletal structure.
- Kidney and organ ultrasound examination.
- Heart defect assessment using the echocardiogram.
- MRI or CT scans as needed.
Bone Marrow Examination
A bone marrow biopsy may help to:
- Determine the intensity of bone marrow failure.
- Determine abnormal cell development.
- Rule out leukemia/ myelodysplastic syndrome
Fanconi Anemia Treatment
Currently, there is no cure for Fanconi anemia, but you can manage your symptoms with some treatments to improve your quality of life and extend your survival.
Blood Product Support
Transfusions
One of the best support that provide immediate therapy is blood transfusion. But it’s better to do this transfusion with packed red blood cells and platelets, having direct effects. Here, an instruction is not to take blood from your family member to avoid the risks of alloimmunization and graft-versus-host disease.[12]
In case you receive frequent transfusions, it will help:
- Enhance oxygen-carrying capacity
- Reduce bleeding risk
- Improve energy levels and quality of life
Medication Therapies
Androgen Therapy
In another temporary therapy, there is the use of androgens and hematopoietic growth factors that can aid in bone marrow failure, yet it is not a cure. Androgens are good at boosting your blood count, but ultimately, they are not long-term and may present undesired side effects, notably liver disease, as well as hormonal changes.[13]
Some benefits of them are:
- Increases the manufacture of red blood cells
- May improve platelet counts
- Reduces transfusion dependency in some patients
Growth Factors
Leukopenia also responds to granulocyte colony-stimulating factor (G-CSF), but only in patients whose neutrophil count is very low. With the help of these artificial materials, the bone marrow can generate increased blood cells.
Hematopoietic Stem Cell Transplantation (HSCT)
Bone marrow transplantation is currently the only possibly curative treatment that kills the defective stem cells and substitutes them with healthy blood-forming stem cells, which are donated by the donors.[14]
A detailed view of a medical apheresis machine showing blood flow through tubes during a blood processing or transfusion procedure.
When is HSCT Recommended?
The care team can suggest BMT in cases when bone marrow failure is serious and needs blood transfusions or when the child acquires myelodysplastic syndrome or leukemia.
Success Rates and Outcomes
The overall survival of HSCT in aplastic anemia patients with Fanconi is greater after 5 years than that of patients with underlying myelodysplasia or acute leukemia. The 10 and 15-year survival rates were 90 and 79, respectively, among 157 patients who survived over 2 years after transplantation.[15]
Donor Selection
The best outcomes occur with:
- HLA-matched sibling donors
- Matched unrelated donors
- Reduced-intensity conditioning regimens designed specifically for FA patients
Fanconi Anemia Life Expectancy
Life expectancy of FA patients was around 22 years according to older sources.
The Italian Registry has shown the following statistics:[16]
- There were 88, 56, and 37 percent overall survival at 10, 20, and 30 years, respectively.
- TThe life expectancy is about 29 years old, and the survival rates are 91% at age 10, 72% at age 20, and 47% at age 30.
The survival rates of Fanconi anemia patients are about 80 percent to the age of 18 years or older.
Factors Affecting Survival
Medication therapy, supportive blood products and stem cell transplantation of aplastic anemia extend life expectancy beyond the estimated median life of about 30 years.[17]
Better outcomes are possible with:
- Early treatment and diagnosis
- A successful stem cell transplantation
- Fewer congenital abnormalities
- Availability of special FA care centers
- Prevention of cancer-causing substances
Cancer, hematological complications, and transplantation complications are the leading causes of death.
Fanconi Anemia Prognosis
Cancer Risk
The majority of patients with FA develop cancers. Most often, acute myelogenous leukemia, myelodysplastic syndrome, and liver cancer.[18]
High-Risk Cancers
- Acute myeloid leukemia (AML)
- Myelodysplastic syndrome (MDS)
- Squamous cell carcinoma of the head and neck
- Gastrointestinal cancers
- Gynecological cancers
- Skin cancer
- Liver tumors
About 10% of people with Fanconi anemia develop leukemia during childhood, with cancer risk increasing with age.
Quality of Life Considerations
Despite serious health challenges, many aspects of life remain normal:
- Even though most patients having Fanconi anemia are short with skeletal abnormalities, intelligence is typically normal. So promote education/career planning.
- Early intervention is possible through regular monitoring.
- Supportive care improves daily functioning
- Availability of specialized teams of care improves the outcomes.
Comparison of Aplastic Anemia with Fanconi Anemia
As the majority of patients develop aplastic anemia, you can differentiate between them with the help of the following table.[19]
| Feature | Aplastic Anemia | Fanconi Anemia |
|---|---|---|
| Cause | Autoimmune diseases, viral infections, medications, chemotherapy, exposure to chemicals, radiation, etc.; most of the cases are idiopathic. | Inherited genetic mutations |
| Genetic Pattern | Not inherited | Always inherited |
| Age of Onset | It may happen at any age; highest between the ages of 15-25 and above 60. | The diagnosis is made during childhood, half at an age younger than 10. |
| Physical Abnormalities | Usually, there are no congenital physical deformities. | Approximately three-quarters of them are born with characteristic defects (skeletal, skin, and organ defects). |
| DNA Repair | None of the known DNA repair deficiencies. | An essential malfunction in the DNA repair that results in instability of the chromosome. |
| Cancer Risk | Increased risk of leukemia | Very high risk of various types of cancer in life. |
| Chromose Stability | Normal on cytogenetic breakage test. | Chromosome breakage and instability on mitomycin C testing. |
| Treatment Sensitivity | Ability to tolerate normal dose chemotherapy and radiation. | Extremely sensitive to DNA-damaging agents |
| Diagnostic Test | The diagnosis can be made by clinical history, blood counts and bone marrow biopsy. | Idiopathic aplastic anemia is identified by a cytogenetic breakage study (mitomycin C test). |
Conclusion
Fanconi anemia is a complicated genetic disease that leads to bone marrow dysfunction and high cancer risk. Although in the past it was very serious, with the development of state-of-the-art diagnostics, such as chromosome breakage testing and treatment, such as hematopoietic stem cell transplantation, results have improved significantly.
A multidisciplinary team and genetic counseling of families can manage the condition. Through continued research and extensive treatment, it is now possible to have a large number of patients living into adulthood, though they require lifelong monitoring.
References
[1] Fanconi G (1927). Familiäre infantile perniziosaartige Anämie (perniziöses Blutbild und Konstitution). Jahrbuch für Kinderheilkunde. 117:257-280.
[2] Auerbach AD (2009). Fanconi anemia and its diagnosis. Mutation Research. 668(1-2):4-10. doi:10.1016/j.mrfmmm.2009.01.013
[3] Peake JD, Noguchi E. (2022). Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair. Human Genetics. 141(12):1811-1836. doi:10.1007/s00439-022-02462-9
[4] Rosenberg PS, Tamary H, Alter BP. (2011). How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. American Journal of Medical Genetics Part A. 155(8):1877-1883.
[5] Knies K, Schuster B, Ameziane N, et al. (2012). Genotyping of Fanconi anemia patients by whole exome sequencing: advantages and challenges. PLoS One. 7(12):e52648. doi:10.1371/journal.pone.0052648
[6] Bogliolo M, Surrallés J. (2015). Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Current Opinion in Genetics & Development. 33:32-40.
[7] Yamamoto K, Ishiai M, Matsushita N, et al. (2003). Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells. Molecular and Cellular Biology. 23(15):5421-5430.
[8] Faivre L, Guardiola P, Lewis C, et al. (2000). Association of complementation group and mutation type with clinical outcome in fanconi anemia. Blood. 96(13):4064-4070.
[9] Joenje H, Patel KJ. (2001). The emerging genetic and molecular basis of Fanconi anaemia. Nature Reviews Genetics. 2(6):446-457. doi:10.1038/35076590
[10] Soulier J. (2011). Fanconi anemia. Hematology. American Society of Hematology Education Program. 2011:492-497. doi:10.1182/asheducation-2011.1.492
[11] Auerbach AD, Wolman SR. (1976). Susceptibility of Fanconi’s anaemia fibroblasts to chromosome damage by carcinogens. Nature. 261(5555):494-496. doi:10.1038/261494a0
[12] Bagby GC, Lipton JM, Sloand EM, Schiffer CA. (2004). Marrow failure. Hematology. American Society of Hematology Education Program. 2004:318-336. doi:10.1182/asheducation-2004.1.318
[13] Velazquez I, Alter BP. (2004). Androgens and liver tumors: Fanconi’s anemia and non-Fanconi’s conditions. American Journal of Hematology. 77(3):257-267. doi:10.1002/ajh.20183
[14] MacMillan ML, Wagner JE. (2010). Haematopoietic cell transplantation for Fanconi anaemia – when and how? British Journal of Haematology. 149(1):14-21. doi:10.1111/j.1365-2141.2010.08078.x
[15] Bonfim C, Ribeiro L, Nichele S, et al. (2016). Long-term survival, organ function, and malignancy after hematopoietic stem cell transplantation for Fanconi anemia. Biology of Blood and Marrow Transplantation. 22(7):1257-1263. doi:10.1016/j.bbmt.2016.03.012
[16] Kutler DI, Singh B, Satagopan J, et al. (2003). A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 101(4):1249-1256. doi:10.1182/blood-2002-07-2170
[17] Giri N, Batista DL, Alter BP, Stratakis CA. (2007). Endocrine abnormalities in patients with Fanconi anemia. Journal of Clinical Endocrinology & Metabolism. 92(7):2624-2631. doi:10.1210/jc.2007-0135
[18] Rosenberg PS, Greene MH, Alter BP. (2003). Cancer incidence in persons with Fanconi anemia. Blood. 101(3):822-826. doi:10.1182/blood-2002-05-1498
[19] Young NS, Maciejewski J. (1997). The pathophysiology of acquired aplastic anemia. New England Journal of Medicine. 336(19):1365-1372. doi:10.1056/NEJM199705083361906