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Synonyms and Keywords: Fanconi anaemia; Fanconi hypoplastic anemia; Fanconi panmyelopathy; Fanconi pancytopenia; FA
Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. 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.
The discovery of fanconi anemia is largely the work of Swiss pediatrician Guido Fanconi who observed various finding of fanconi anemia to be different then pernicious anemia and led to its discovery.
Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 90s, nothing was known about the proteins encoded by FA genes.
- However, more recently, studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M assemble to form a core protein complex in the nucleus.
- This complex has also been suggested to exist in cytoplasm and its translocation into the nucleus is dependent on the nuclear localization signals on FANCA and FANCE.
- Assembly is thought to be activated by DNA damage due to cross-linking agents or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage.
There are at least 13 genes of which mutations are known to cause FA.
- FANCA, FANCB, FANCC, FANCD1 (BRCA2).
- FANCD2, FANCE, FANCF FANCG.
Fanconi Anemia must be differentiated from Aplastic Anemia, Paraoxysomal Nocturnal Hemoglobinuria, and Chromosomal breakage syndrome and Hereditary Bone marrow failure syndrome (Dyskeratosis congenita and other short telomere syndromes).
- Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, Congenital anomalies, and associated with malignancy such as Aplastic Anemia, Rare chromosomal breakage syndrome and inherited bone marrow failure.
- As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia.
- Must be differentiated on basis on congenital anomalies and chromosomal breakage test.
FA is rare overall, but it is one of the most common inherited bone marrow failure syndromes.
- The incidence of FA is approximately 1 in 100,000 to 250,000 births.
- Approximately 10 to 20 children are born with FA each year in the United States.
- The probability of FA in the US population, FA, was estimated to be 1 in 129,600 births
- Most children are diagnosed between six and nine years of age, concurrent with the onset of bone marrow failure . Rarely, marrow failure from FA can present in infants and small children
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:
- Skin discolorations, Hand, arm and other skeletal anomalies, Kidney problems, Small head or eyes.
- Low birth weight, Gastrointestinal problems (bowel), Small reproductive organs in males, Heart defects.
Since these physical characteristics can be indicative of other conditions, and since some patients may have no obvious physical traits of FA, the condition may not be diagnosed at birth. They may exhibit symptoms such as:
- Unexplained fatigue, Recurrent colds or viral infections, Recurrent nosebleeds.
- Easy bruising, Blood in the stool or urine, Shortness of breath, Poor growth / short stature.
In rare cases, symptoms do not occur until early adulthood.
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)
Physical Examination[edit | edit source]
- Congenital malformations are the most common presenting features of FA.
- Patients with FA usually present with hypo/hyperpigmentation, café-au-lait spots, short staure and thumb or other radial abnormalities.
- Vital Signs Usually normal sometime patients present with fever due to superimposed infection.
- Skin abnormalities in Fanconi anemia can include generalized hyperpigmentation on the trunk, neck, and intertriginous areas, the aforementioned café au lait spots, and hypopigmented areas. Delicate features can also be characteristic of patients.
The diagnosis of Fanconi anemia is not based on routine laboratory tests; it must be considered and tested for using chromosome breakage in blood or fibroblasts, or germline mutation analysis. Siblings who do not apparently have Fanconi anemia need to be screened for occult Fanconi anemia.
Any patient with single-lineage or multi-lineage cytopenias without known cause who also has one or more congenital malformations strongly associated with FA.
Laboratory findings consistent with the diagnosis of Fanconi Anemia include Pancytopenia, Chromosomal breakage test positive, and Flow cytometry shows arrest in G2/M phase.
Although non-specific, these are one of the best described features and include:
- radial ray anomalies: including absent thumb.
- triphalangeal thumb.
Perform a skeletal survey to identify all developmental defects involving bone. Keep in mind that radiation doses should be limited in patients with Fanconi anemia. Care should be taken to avoid unnecessary radiation in patients with a cancer predisposition.
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|Suspected clinical FA|
|Chromosome breakage test on peripheral film|
|Repeat Chromosome breakage test|
|Highly suspected FA||Not highly suspected FA|
|Chromosome breakage test on skin fibroblast|
|Consider other IBMFS|
|Diagnosis of FA|
|Genetic testing for Korean|
mutations FANCAexon 27 & 37
FANCGintron 3 & exon 8
|Other FA associated genes|
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