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'''Fanconi anemia''' (FA) is a [[Genetic disorder|genetic disease]] that affects children and adults from all ethnic backgrounds.<ref name="pmid29904161">{{cite journal| author=Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O et al.| title=From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia. | journal=Genet Med | year= 2018 | volume= | issue= | pages= | pmid=29904161 | doi=10.1038/s41436-018-0037-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29904161 }}</ref> 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|mitomycin C]]. | '''Fanconi anemia''' (FA) is a [[Genetic disorder|genetic disease]] that affects children and adults from all ethnic backgrounds.<ref name="pmid29904161">{{cite journal| author=Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O et al.| title=From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia. | journal=Genet Med | year= 2018 | volume= | issue= | pages= | pmid=29904161 | doi=10.1038/s41436-018-0037-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29904161 }}</ref> 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|mitomycin C]]. | ||
== History == | |||
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. | |||
== Classification == | |||
== Pathophysiology == | |||
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 [[Coagulation|common pathway]]. Up until the late 90s, nothing was known about the proteins encoded by FA genes.<ref name="pmid299041612">{{cite journal| author=Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O et al.| title=From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia. | journal=Genet Med | year= 2018 | volume= | issue= | pages= | pmid=29904161 | doi=10.1038/s41436-018-0037-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29904161 }}</ref><ref name="pmid29901137">{{cite journal| author=Kulanuwat S, Jungtrakoon P, Tangjittipokin W, Yenchitsomanus PT, Plengvidhya N| title=Fanconi anemia complementation group C protection against oxidative stress‑induced β‑cell apoptosis. | journal=Mol Med Rep | year= 2018 | volume= | issue= | pages= | pmid=29901137 | doi=10.3892/mmr.2018.9163 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29901137 }}</ref><ref name="pmid29907598">{{cite journal| author=Guan J, Fransson S, Siaw JTT, Treis D, Van den Eynden J, Chand D et al.| title=Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib. | journal=Cold Spring Harb Mol Case Stud | year= 2018 | volume= | issue= | pages= | pmid=29907598 | doi=10.1101/mcs.a002550 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29907598 }}</ref> | |||
*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 repair|DNA damage]] due to [[Cross-link|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. | |||
== Classification == | |||
There are at least 13 genes of which mutations are known to cause FA. | |||
===Common Genes=== | |||
*FANCA, FANCB, FANCC, FANCD1 (BRCA2). | |||
*FANCD2, FANCE, FANCF FANCG | |||
== Differentiating Fanconi's Anemia From Other Diseases == | |||
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.<ref name="pmid24237973">{{cite journal| author=Hartung HD, Olson TS, Bessler M| title=Acquired aplastic anemia in children. | journal=Pediatr Clin North Am | year= 2013 | volume= 60 | issue= 6 | pages= 1311-36 | pmid=24237973 | doi=10.1016/j.pcl.2013.08.011 | pmc=3894991 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24237973 }}</ref> | |||
*As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia. | |||
*Must be differentiated on basis on congenital anomalies and chromosomal breakage test.<ref name="pmid27069254">{{cite journal| author=Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al.| title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. | journal=Blood | year= 2016 | volume= 127 | issue= 20 | pages= 2391-405 | pmid=27069254 | doi=10.1182/blood-2016-03-643544 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27069254 }}</ref> | |||
==Epidemiology and Demographics== | |||
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.<ref name="pmid21974856">{{cite journal| author=Rochowski A, Rosenberg PS, Alonzo TA, Gerbing RB, Lange BJ, Alter BP| title=Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy. | journal=Leuk Res | year= 2012 | volume= 36 | issue= 1 | pages= 29-31 | pmid=21974856 | doi=10.1016/j.leukres.2011.09.009 | pmc=4008327 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21974856 }}</ref> | |||
*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 | |||
== [[Fanconi anemia risk factors|Risk Factors]] == | |||
== Screening == | |||
== Natural History, Complications and Prognosis == | |||
== Diagnosis == | |||
==== History and Symptoms ==== | |||
==== Physical Examination ==== | |||
==== Laboratory FIndings ==== | |||
==== Electrocardiogram ==== | |||
==== X-ray ==== | |||
==== CT ==== | |||
==== MRI ==== | |||
==== Ultrasound ==== | |||
==== Other Imaging Findings ==== | |||
==== Other Diagnostic Studies ==== | |||
== Treatment == | |||
==== Medical Therapy ==== | |||
==== Surgery ==== | |||
==== Primary Prevention ==== | |||
==== Secondary Prevention ==== | |||
==References== | ==References== | ||
Revision as of 22:26, 5 November 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds.[1] 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.
History
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.
Classification
Pathophysiology
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.[2][3][4]
- 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.
Classification
There are at least 13 genes of which mutations are known to cause FA.
Common Genes
- FANCA, FANCB, FANCC, FANCD1 (BRCA2).
- FANCD2, FANCE, FANCF FANCG
Differentiating Fanconi's Anemia From Other Diseases
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.[5]
- As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia.
- Must be differentiated on basis on congenital anomalies and chromosomal breakage test.[6]
Epidemiology and Demographics
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.[7]
- 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
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory FIndings
Electrocardiogram
X-ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
References
- ↑ 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.
- ↑ 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.
- ↑ Kulanuwat S, Jungtrakoon P, Tangjittipokin W, Yenchitsomanus PT, Plengvidhya N (2018). "Fanconi anemia complementation group C protection against oxidative stress‑induced β‑cell apoptosis". Mol Med Rep. doi:10.3892/mmr.2018.9163. PMID 29901137.
- ↑ Guan J, Fransson S, Siaw JTT, Treis D, Van den Eynden J, Chand D; et al. (2018). "Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib". Cold Spring Harb Mol Case Stud. doi:10.1101/mcs.a002550. PMID 29907598.
- ↑ Hartung HD, Olson TS, Bessler M (2013). "Acquired aplastic anemia in children". Pediatr Clin North Am. 60 (6): 1311–36. doi:10.1016/j.pcl.2013.08.011. PMC 3894991. PMID 24237973.
- ↑ Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254.
- ↑ Rochowski A, Rosenberg PS, Alonzo TA, Gerbing RB, Lange BJ, Alter BP (2012). "Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy". Leuk Res. 36 (1): 29–31. doi:10.1016/j.leukres.2011.09.009. PMC 4008327. PMID 21974856.