Fanconi anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds.^[1] 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.

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.

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.

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.

There are two major diagnostic studies of choice for Fanconi anemia. These include chromosomal breakage analysis and mutational analysis.

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. ^[2] 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.

There are no other radiologic findings associated with Fanconi anemia.

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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

• In 1927, Guido Fanconi, a Swiss pediatrician, noticed that three male children from a family had pancytopenia and birth defects. These children were between the ages of 5 and 7.^[1] He published his observations of his findings from this family.^[2] This was the first clinical report of Fanconi anemia.^[3] Guido Fanconi noted that the various findings of Fanconi anemia were different than pernicious anemia. He reported that the major criteria for Fanconi anemia were small stature, pancytopenia, hyperpigmentation, skeletal abnormalities, familiar occurrence, and urogenital abnormalities.^[1]
• In 1931, Erwin Uehlinger, a German Pathologist, published article showing that findings of Guido Fanconi are different from pernicious anemia this type of constitutional anaemia was often associated with pancytopenia and that congenital malformations.^[4]
• In 1931, Otto Naegeli, a Swiss hematologist, introduced the name Fanconi’s Anaemia^[5]
• In 1937, Guido Fanconi described the renal Fanconi syndrome based on observation of de Toni and Debre, characterized by growth retardation, aminoaciduria, glycosuria and hypophosphataemic rickets. ^[6]
• In 1967, Guido Fanconi described Fanconi anemia findings as separate entity than pernicious anemia.^[7]
• In 1975, S.A. Latt and colleagues showed that chromosome breaks and rearrangements in Fanconi anemia may be due to defective DNA repair.^[3]
• In 1980, Gluckman and colleagues reported on the adverse outcomes of a handful of patients with Fanconi anemia undergoing bone marrow transplantation (allogeneic transplant from an HLA-matched sibling donor with standard dose cyclophosphamide). This regimen had been used successfully in other bone marrow failure conditions such as aplastic anemia.^[8] He therefore proposed to lower the dose of cyclophosphamide by 10-fold and add radiation to the conditioning regimen, which resulted in improved survival.
• In 1982, Rockefeller University created the International Fanconi Anemia Registry (IFAR), which comprised a database base of clinical and genetic features of approximately 1300 patients with Fanconi anemia.^[8]
• In 1985, the standard conditioning regimen that was used for patients with Fanconi anemia was low-dose cyclophosphamide and low-dose irradiation.^[8]
• In 1990, it was noted that the main reason for failure of unrelated donor allo-transplant for Fanconi anemia was graft failure.
• In 1992, the FANCC gene was first cloned.^[3]
• In 2013, it was found that Fanconi anemia genes were altered in 40% of cancers based on The Cancer Genome Atlas (TCGA) data.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

Fanconi anemia is currently classified by complementation group.

Fanconi anemia is a heterogenous disease from a genetic standpoint. Fanconi anemia is currently classified by complementation group. The four subtypes of Fanconi anemia can be discerned by somatic cell hybridization studies.^[1] This concept is based on the fact that at least four different genes function in concert to support normal hematopoiesis in healthy persons.^[1] The four subclasses of Fanconi anemia are:

• FA-A
• FA-B
• FA-C: This class of Fanconi anemia is characterized by a gene that encodes for a protein with unknown function, though it is known to localize to the cytoplasm. Six variants have been found in FA-C, and these are associated with disease.^[1] Approximately 8% of people with Fanconi anemia belong to complementation group C.
• FA-D

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

• The FANC complex: 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 1990s, little information 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. Following assembly, the protein core complex activates FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2. It was previously thought that BRCA1, with its zinc finger ubiquitin ligase domain was responsible for the post-transcriptional modification of FANCD2. However, this has since been invalidated and BRCA1 interaction with the FA protein complex is still being investigated. Ubiquinated FANCD2, also know as FANCD2-L, then goes on to interact with a BRCA1/BRCA2 complex. Again, details of this interaction have yet to be discovered. However, it is already known that similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability. With a crippling mutation in any FA protein in the complex, DNA repair has been shown to be much less effective, as can be seen from the damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C.

• Other FA protein interactions: Although the above described pathway seems to be the most integral part of the DNA damage response in cells and explains the pathology of FA, novel approaches have determined that most FA proteins have an alternate role. Recent investigations on FANCC, one of the intensively studied proteins, have shown that it plays an important role in cellular responses to oxidative stress. For example, it has been found to interact with NADPH cytochrome P450 reductase, associated with increased production of ROS, and glutathione S-transferase, responsible for production of the anti-oxidant glutathione. These two enzymes are both involved in either triggering or detoxifying ROS. Not surprisingly, mice with Cu/Zn superoxide dismutase and FANCC mutations demonstrate defective haemopoiesis. FANCC was also shown to bind STAT1 and help receptor docking and phosphorylation of STAT135, which helps in tumor suppression. This leads to the conclusion that FANCC participates in cell growth arrest and cell cycle progression, inhibiting apoptosis, a possible cause of bone marrow failure due to depletion of haemopoietic progenitors. Another FA protein linked to protection against oxidative damage is FANCG. This protein interacts with cytochrome P450 2E1 suggesting a possible role in detoxifying cytochrome ROS, produced readily by the members of this superfamily36. Furthermore, FANCG is identical to post-replication repair protein XRCC9, hinting at the possibility that FANCG also interacts directly with DNA by means of its internal leucine zipper. Thus it is readily seen that FA proteins also acts outside of the Fanconi pathway, either by helping neutralize ROS or by taking part in DNA repair. Such mechanisms help understand the causes behind bone marrow failure, where reoxygenation-induced oxidative stress is very common. Furthermore, it is known that cross-linking agents produce ROS and it is possible that FA cell hypersensitivity to cross-linkers is not due directly to them, but rather to the cell’s impaired ability to cope with increased ROS production.

The pathophysiology of Fanconi anemia largely stems from mutations that predispose cells to impaired DNA damage response, leading to bone marrow failure and increasing the risk for various cancers.^{[1][2][3][4][5][6][7][8][9]} In tissues and bone marrow, in which successful cell replication is vital, there can be increased susceptibility to DNA-damaging agents. Cellular function will be severely affected by FA protein dysfunction where FA leads to decreased hematopoiesis and bone marrow failure due to progenitor and stem cell senescence. In another pathway responding to ionizing radiation, FANCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks, and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistant DNA synthesis, the hallmark of a defect in the S phase checkpoint, in patients with FA-D1 or FA-D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of AML in these patients.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

Fanconi anemia an autosomal recessive genetic disorder that is caused by mutations in various genes of the FANC family.

There are no environmental-related causes of Fanconi anemia. The cause of Fanconi anemia is a genetic mutation in the hematopoietic stem cell. There are at least 13 genes of which mutations are known to cause FA.^{[1][2][3][4][5]} In the past, the genetic cause was unknown, but the advent of DNA sequencing led to the discovery of multiple genes associated with the disease.

• FANCA
• FANCB
• FANCC
• FANCD1 (BRCA2)
• FANCD2
• FANCE
• FANCF
• FANCG

• FANCI
• FANCJ (BRIP1)
• FANCL
• FANCM
• FANCN (PALB2)
• FANCP (SLX4)
• FANCS (BRCA1)
• RAD51C
• XPF

For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia. The presence of a mutation in one of the above genes results in chromosomal instability and ineffective DNA damage response, resulting in the clinical manifestations of the disease.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

• Fanconi anemia must be differentiated from other diseases (as noted below).^[1][2]

Clinical manifestations			Pathophysiology	Para-clinical findings			Gold standard	Additional findings
				Lab Findings	Imaging	Histopathology
Disease	Symptom	Physical exam		Blood profile	Anamalies
Fanconi Anemia	Short stature, delicate features, upper limbs absent or hypoplastic thumbs, supernumerary, bifid clinodactyly infection, petechia, pallor	Skin – Generalized hyperpigmentation; hypopigmented areas; large freckles, café-au-lait spots Head – Microcephaly or hydrocephaly; birdlike face, mid-face hypoplasia, Sprengel’s deformity of neck, Eyes- Microphthalmia, ptosis, epicanthal folds, strabismus	Inherited defect in DNA Repair causes loss of HSC that leads to bone marrow failure.	Anemia: normocellular or hypercellular bone marrow	Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation, Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis		FA gene sequencing	Increased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
Acquired Aplastic Anemia	Infections, mucosal hemorrhage, menorrhagia	Pallor and petechiae The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis	No known causes 70% cases, known cases are caused by drugs, virus, radiation	Anemia normocellular or hypercellular bone marrow	Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation, Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis		Hypocellular bone marrow	Rapid onset
Paroxysmal nocturnal hemoglobinuria (PNH)	Fatigue ●Dyspnea ●Hemoglobinuria Abdominal pain ●Bone marrow suppression ●Erectile dysfunction ●Chest pain ●Thrombosis ●Renal insufficiency		Acquired mutation in PIGA gene –> problem in synthesis of DGI —> complement mediated Intravascular hemolysis	Anemia normocellular or hypercellular bone marrow		●Hypo/Hyper /Normo cellular,	Flow cytometry
Other inherited bone marrow failure syndromes (Dyskeratosis congenita and other short telomere syndromes)	Bone marrow failure Classic mucocutaneous and additional dermatologic findings •Skin dyspigmentation •Nail irregularities •Leukoplakia •Premature graying/hair loss •Hyperhidrosis – 15 percent ●Ophthalmologic/Epiphora  (excessive tearing/lacrimal duct stenosis) ●Neurologic/Cognitive •Developmental delay •Ataxia/cerebellar hypoplasia – approximately •Microcephaly ●Pulmonary disease (pulmonary fibrosis) ●Endocrine/Growth/Urologic  features •Short stature •Intrauterine growth retardation •Hypogonadism/Undescended  testes •Urethral stricture/phimosis  •Osteoporosis and related complications	Unlike Fanconi anemia, individuals with DC do not appear to have impaired fertility ●Dental manifestations (caries) ●Gastroenterologic/Hepatologic  manifestations •Esophageal strictures •Liver disease (cirrhosis, fibrosis) or gastroenteropathy ●Cancer	(DC) and telomere related disorders, mutations in genes that maintain telomere length in rapidly dividing cells that lead to premature cell death, senescence, or genomic instability, which in turn results in impaired function and cellular homeostasis in many organs and tissues.	Reticular dysgenesis			Flow cytometry	– chromosomal breakage test.
Drug-induced or infection-associated pancytopenia
Rare syndromes, Nijmegen breakage syndrome (NBS), Bloom syndrome (BLM), ataxia telangiectasia (ATM), LIG4 syndrome (LIG4), NHEJ1 deficiency (NHEJ1), Seckel syndrome (ATR),  cohesinopathies Roberts syndrome (ESCO2) Warsaw breakage syndrome (DDX11).	Microcephaly, short stature increased malignancy		NBS: chromosomal instability disorder caused by mutations in the nibrin (NBN) gene DNA breaks are not efficiently repaired in the absence of fibrin. oxidative/alkylating stress damages the cells	No specific findings	Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation, Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis		Abnormal chromosomal breakage test	No bone marrow failure
De novo myelodysplastic syndrome (MDS)	MDS can arise de novo or secondary to another bone marrow disorder			Bone marrow failure		Positive chromosomal breakage tests		Negative chromosomal breakage tests

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2] Pervaiz Laghari, MD[3]

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.

Fanconi anemia is rare overall, but it is one of the most common inherited bone marrow failure syndromes. Historically, the heterozygote frequency for pathogenic Fanconi anemia mutations has been estimated to be 1:300 in the United States and Europe and 1:100 in Ashkenazi Jews and South Africans. A 2011 study using demographic data from the Fanconi Anemia Research Fund estimated a higher carrier frequency in the United States (within the range of 1:156 to 1:209) and in Israel (within the range of 1:66 to 1:128)^[1][2][3]

• 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 was estimated to be 1 in 129,600 births.^[4]
• SEER data were used to estimate the age-adjusted annual probability of AML, in persons 0–18 years, as 0.72/100,000.

• Patients of all age groups may develop FA.
• The age of onset of bone marrow failure in patients with FA is highly variable, even among siblings. 
• 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. 
• An analysis of 754 patients in the International Fanconi Anemia Registry (IFAR) suggested that the average age of onset is 7.6 years.^[5] However, that study analyzed patients who mainly had defects in the FANCA, FANCC, and FANCG genes, which are the most frequently mutated FA genes; therefore, the results may not be representative of patients with rarer gene defects.
• In adults as compared to children, FA is less commonly diagnosed due to primary bone marrow failure; instead, the diagnosis of FA more commonly occurs as a consequence of presentation with cancer or with severe toxicity after chemotherapy treatment for a malignancy.
• Severe, usually transient, bone marrow failure can also develop in non-transplanted female patients with FA during pregnancy.

• There is no racial predilection to FA. It is found is all races and ethinic group.
• Ethinic groups with higher than average prevalence of FA include Jews, Spanish Gypsies and Black and Afrikaner population from South Africa. These increases prevalence are due to specific founder mutations. Other countried where found founder mutation include Tunisia, Japan, Korea and Brazil.

• FA slightly more common in males than females with a ratio of 1.2:1 (M:F)

• The FA cases are more prevalent in Middle East parts of the World where tribal and/or local customs with respect to marriage make consanguinity, and thus higher probability of inheriting an autosomal recessive disease more common.

There is no particular relation of FA with developed countries.

There is no particular relation of FA with developing countries.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

The major risk factor for Fanconi anemia is genetic inheritance. It is inherited in an autosomal recessive pattern.

The major risk factor for Fanconi anemia is genetic inheritance. It is inherited in an autosomal recessive pattern, meaning that both parents must harbor the gene mutation to have an affected child. There are no other particular risk factors for Fanconi anemia. This is a genetic disorder that is caused by a mutation in genes involved in DNA damage response. Patients with Fanconi anemia are more susceptible to malignancy such as acute myeloid leukemia, and a risk factor for development of malignancies includes exposure to radiation and carcinogens.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

There are no recommendations on screening for Fanconi anemia.

There are no recommendations on screening for Fanconi anemia. Screening for Fanconi anemia is not routinely done during pregnancy. This is in contrast to other disorders such as sickle cell disease or thalassemia, in which robust screening programs are in place. One study in Korea suggested that a nationwide screening program be implemented via treatment of cells with mitomycin C or diepoxybutane, which are DNA damaging agents.^[1] However, this study included a very small number of patients and is not universally applicable to other populations. The costs and risks of screening likely outweigh the benefits.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

The natural history of Fanconi anemia involves progressive bone marrow failure, which can result in clinical manifestations such as fatigue, infections, and bleeding. The diagnosis of Fanconi anemia is typically made during childhood, with a median age of diagnosis of 7-8 years. However, decreased blood counts can remain undetectable for many years due to the insidious natural history of the disease.^[1] The natural history involves a gradual reduction in the hematopoietic stem cell pool.^[1] Children will usually present with signs and symptoms of bone marrow failure. These signs and symptoms include:

• Fatigue: Severe fatigue can arise in the setting of low hemoglobin levels. In some cases, transfusion of packed red blood cells may be required.
• Infections: In some cases, significant infections can occur in patients with Fanconi anemia. This is a result of low white blood cell counts. The spectrum of infections can encompass bacterial, viral, or fungal organisms. Patients may need antibiotics, antiviral, or antifungal medications.
• Bleeding: In some cases, bleeding and bruising can occur, which is a result of low platelet counts. Patients may need platelet transfusions if clinically significant bleeding occurs.

The complications of Fanconi anemia range from iron overload, which can be readily treated, to the development of acute leukemia, which can be fatal. Complications include overt bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and iron overload from frequent transfusions. The complications can be broadly divided into systemic complications and bone marrow-related complications.

• Cardiovascular collapse: This refers to failure of the heart to produce a sufficient blood pressure to maintain normal homeostasis and oxygen delivery. This can lead to death from hypoxia and hypoxemia within a short period of time. The reason for this is severely decreased hemoglobin concentration, which results in impaired ability of the heart to meet the oxygen demands of peripheral tissue.
• Exacerbation of cardiopulmonary conditions: Fanconi anemia can result in high-output cardiac failure, which refers to the inability of the circulatory system to meet the demands of exercising tissue, despite a high cardiac output. Fanconi anemia can also exacerbate lung disease, since the capillary beds in the pulmonary circulation function to load oxygen onto hemoglobin for delivery to tissue beds.
• Exacerbation of neurologic conditions: Fanconi anemia can contribute to cerebrovascular disease, or strokes, since the brain requires oxygen for survival of neurons.
• Myocardial infarction: Myocardial infarction, or heart attack, occurs if the anemia is severe such that the oxygen-carrying capacity is reduced to the coronary tissue. For this reason, patients with coronary artery disease should be transfused packed red blood cells if hemoglobin is less than 8 g/dl, compared to the conventional threshold of 7 g/dl for the general population.
• Transfusion dependence: This occurs when a patient requires repeated transfusions with packed red blood cells in order to maintain hemoglobin within an acceptable range, such as greater than 7 g/dl. Complications of transfusion include:
  • Transfusion-associated circulatory overload (TACO)^[2] For this reason, a restricted transfusion strategy is preferred over a liberal strategy.^[3]
  • Transfusion-related acute lung injury (TRALI)^[2]
  • Iron overload, or hemosiderosis: After frequent transfusions of packed red blood cells, patients can develop iron deposition in the skin, liver, pancreas, heart, and metacarpophalangeal joints. In some cases, iron chelation therapy may be needed.
  • Transfusion reaction due to ABO blood group incompatibility

• Myelodysplastic syndrome: Myelodysplastic syndrome, formerly known as pre-leukemia, is a condition in which immature myeloid cells in the bone marrow cannot differentiate into functional cell types. Myelodysplastic syndrome shares many of the morphologic features of AML with some important differences. First, the percentage of undifferentiated progenitor cells, blasts cells, is always less than 20% (based on World Health Organization classification of myeloid neoplasms) and there is considerably more dysplasia, defined as cytoplasmic and nuclear morphologic changes in erythroid, granulocytic and megakaryocytic precursors, than what is usually seen in cases of AML. These changes reflect delayed apoptosis or a failure of programmed cell death.^[4] When left untreated, MDS can lead to AML in about 30% of cases. Due the nature of the FA pathology, MDS diagnosis cannot be made solely through cytogenic analysis of the BM. Indeed, it is only when morphologic analysis of BM cells is performed, that a diagnosis of MDS can be ascertained. Upon examination, MDS-afflicted FA patients will show many clonal variations, appearing either prior or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent being monosomy 7 and partial trisomies of chromosome 3q 15. Observation of monosomy 7 within the BM is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years.^[5]
• Acute myeloid leukemia: Patients with Fanconi anemia also have elevated risks of developing AML, defined as presence of 20% or more of myeloid blasts in the BM, 20% or more of myeloid blasts in the peripheral blood, or presence of characteristic chromosomal rearrangements that typically define AML. All of the subtypes of AML can occur in FA with the exception of promyelocytic. However, myelomonocytic (French-American-British (FAB) M4 group) and acute monocytic (FAB M5 group) are the most common subtypes observed. It is also interesting to note that many MDS patients will evolve into AML given they survive long enough.^[6] This is due to clonal evolution, which has been well-described over the recent years. Furthermore, the risk of developing AML increases with the onset of BM failure. While the risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40. Even with BM transplant, about one fourth of patients will die from MDS/AML related causes within 2 years.
• Overt bone marrow failure: The last major haematological complication associated with FA is BM failure, defined as inadequate blood cell production. Several types of BM failure are observed in FA patients and are generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible BM transplant. While most FA patients are initially responsive to androgen therapy and haemopoietic growth factors, these have been shown to promote leukemia, especially in patients with clonal cytogenic abnormalities, and have severe side effects, including hepatic adenomas and adenocarcinomas. The only treatment left would be BM transplant; however, such an operation has a relatively low success rate in FA patients when the donor is unrelated (30% 5-year survival) 16.^[7] It is therefore imperative to transplant from HLA-identical sibling. Furthermore, due to the increased susceptibility of FA patients to chromosomal damage, pre-transplant conditioning cannot include high doses of radiations or immunosuppressants, and thus increase chances of patients developing graft-versus-host disease. If all precautions are taken, and the BM transplant is performed within the first decade of life, 2-year probability of survival can be as high as 89%. However, if the transplant is performed at ages older than 10, 2-year survival rates drop to 54%.

The prognosis of Fanconi anemia is variable and develops upon the complications that arise. The median survival of patients with FA was 21 years of age prior to the 21st century. Currently, however, the prognosis is significant improved, given advances in therapeutics and reduction in the risk of death due to bleeding or infectious complications. Bone marrow failure can often be cured by allogeneic stem cell transplant. However, many patients eventually develop acute myelogenous leukemia (AML), and prognosis can be quite poor. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.^[8] The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi’s have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head).^[9] Quality, comprehensive care is available for treating Fanconi anemia. Since research is on-going, there is hope that as knowledge gained through clinical trials and research grows, a cure may be developed.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

• 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

Fanconi anemia might not be diagnosed at birth since these physical characteristics can be indicative of other conditions, and since some patients may have no obvious physical traits of FA.

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.

Congenital anomalies: Congenital malformations are the most common presenting features of FA. Malformations are reported in 60 to 75 percent of patients, but many in the field believe this represents an underestimate, as many patients with FA do not manifest with classical findings.^[1] Young adults with more subtle clinical findings increasingly may be identified from genomic sequencing. Despite the high frequency of malformations, only a small percentage of patients with FA (<5 percent) are diagnosed within the first year of life based on classic congenital anomalies. Thus, while the presence of these findings provides an important clue to the diagnosis, their absence does not eliminate the possibility of FA. In a series of 370 patients enrolled in the International FA Registry and a review of over 2000 patients reported in the literature from 1927 to 2009, the most common developmental abnormalities included the following.

• Skin findings (approximately 40 to 60 percent), including hyper– or hypopigmentation or café-au-lait spots
• Short stature (40 to 60 percent)
• Thumb or other radial ray abnormalities (50 percent)
• Thumbs absent or hypoplastic, bifid/duplicated, rudimentary, triphalangeal (35 percent)
• Radii absent or hypoplastic (7 percent)
• Hands/other such as flat thenar eminence, clinodactyly, polydactyly, missing first metacarpal, dysplastic ulnae (6 percent)
• Axial skeletal abnormalities (25 percent), especially microcephaly, triangular facies, short/webbed neck, vertebral anomalies
• Eye malformations (20 to 40 percent), including strabismus and hypo/hypertelorism
• Renal and urinary tract malformations (approximately 20 to 30 percent) including horseshoe, ectopic, dysplastic, or absent kidney; hydronephrosis; hydroureter
• Gonadal/Genital malformations
• In males, hypospadias, micropenis, undescended/absent testes, infertility (25 percent)
• In females, uterus malformation, small ovaries, hypogenitalia (<5 percent)
• Ear abnormalities (10 to 20 percent) with conductive hearing loss due to middle ear anomalies or atretic ear canal
• Congenital heart disease (approximately 5 percent) such as patent ductus arteriosus, ventricular septal defect, aortic coarctation, truncus arteriosus
• Gastrointestinal anomalies (approximately 5 percent) such as tracheoesophageal fistula, esophageal atresia, intestinal atresia, imperforate anus
• Central nervous system abnormalities (<5 percent) involving the pituitary gland (eg, small, interrupted pituitary stalk syndrome), hydrocephalus, cerebellar hypoplasia, or absent corpus callosum.

Cytopenias/bone marrow failure: Cytopenias in FA include thrombocytopenia, macrocytic anemia, or pancytopenia. Bone marrow failure eventually occurs in the majority of patients, though the time to onset can be quite variable. Progression to pancytopenia may occur rapidly after initial cytopenias are noted or may take months or years to develop, or (rarely) may not develop at all.

• Cytopenias may only be mild upon presentation or may develop later in the disease course if the FA diagnosis is made based on congenital anomalies. In some cases only a single cell line will be involved (typically thrombocytopenia), particularly early in life. Mild to moderate thrombocytopenia may be misdiagnosed as immune thrombocytopenia (ITP). The anemia is typically macrocytic, and some individuals may have macrocytosis without anemia. The degree of cytopenia may be used to characterize the degree of bone marrow failure as mild, moderate, or severe. Most patients eventually develop symptomatic anemia, although contrary to the name Fanconi “anemia,” symptomatic anemia is often the last severe cytopenia to develop. Severe neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet count <30,000/microL) are often more problematic, as they can lead to potentially life-threatening infections and bleeding. Definitions of disease severity based on the bone marrow cellularity and blood counts is discussed in more detail separately.
• Regarding bone marrow failure, in a 2003 report from the International FA Registry that included 754 patients, 601 (80 percent) had bone marrow failure at the time of enrollment; the cumulative incidence was 90 percent by age 40.^[2] In the small percentage of patients in whom bone marrow failure does not develop, specific genetic factors may protect from bone marrow aplasia. Patients with biallelic FANCD2/BRCA2mutations appear less likely to develop bone marrow failure, though the high rate and early onset of malignancies, coupled with the short lifespan in this population may contribute to this perceived effect. In addition, up to 25 percent of patients with FA may develop acquired somatic mosaicism through gene conversion events (in compound heterozygous patients), back mutation, or even compensatory deletions/insertions, which lead to correction of the chromosomal breakage sensitivity phenotype.^{[3] [4] [5][6]} While many patients may have somatic mosaicism detectable only in lymphocytes, patients with mosaicism in hematopoietic stem cells (HSCs) or progenitor cells have been shown to have an ameliorated bone marrow phenotype. However, these individuals remain at risk for hematologic malignancy and other non-hematologic complications.
• Findings on bone marrow examination may be indistinguishable from findings seen in other causes of bone marrow failure such as aplastic anemia or myelodysplastic syndrome (MDS). For patients diagnosed with FA in infancy due to congenital anomalies, screening bone marrow biopsies are often normocellular. By the onset of cytopenias, the marrow may reveal severe hypocellularity out of proportion to the degree of cytopenias. Erythroid dysplasia, including hyperplastic erythroblast islands and megaloblastic features, is commonly seen in many, but not all, bone marrow aspirates from patients with FA, and should not be interpreted in isolation as MDS in the absence of other dysplastic features, increased blasts, or cytogenetic changes. On the other hand, dysplasia in the myeloid series, increased myeloblasts, and with somewhat less specificity dysmegakaryopoiesis, should be considered to be concerning evidence for onset of clonal abnormalities consistent with MDS.^[7][8]
• MDS and leukemia are common in patients with FA; in many cases, MDS or acute myeloid leukemia (AML) is the presenting finding. Patients with FA have been estimated to have a 6000-fold and 700-fold greater risk than the general population for developing MDS and AML, respectively.^[9] By age 50, up to 40 percent of patients with FA will develop MDS and up to 15 percent will develop AML. Lymphoid malignancies including acute lymphoblastic leukemia (ALL) and Burkitt lymphoma are also seen, although they are much less common.^[10] A period of bone marrow hypoplasia precedes the development of hematologic malignancies in some but not all cases.^[11]
• Leukemia risk is even higher in patients with biallelic mutations in FANCD1/BRCA2. These individuals have a cumulative incidence of leukemia of 80 percent by age 10.^[12] Most develop AML, although some may develop T cell ALL. Patients with mutations in BRCA2 involving the IVS7 site have particularly early risk of leukemia, with most developing AML by three years of age.
• Karyotypic abnormalities are common in patients with FA who develop MDS or AML, including translocations of chromosome 1p, monosomy 7, and gains of chromosome 3q ^[13]. In one study of 53 patients, 18 had 3q amplification, which was associated with shorter survival and increased risk for development of AML. A 2012 literature review identified 46 cases of AML in patients with FA in whom cytogenetics were available and found the most common cytogenetic abnormalities to be chromosomal gains of 1q, 3q, or 13q, along with loss of chromosome 7 (or more specifically, 7q) ^[14]. In contrast, cytogenetic lesions common in de novo AML including t(8;21), trisomy 8, and inv(16) were not seen in any of the patients with FA.
• Cytogenetic clones should be interpreted within the context of the bone marrow morphology. Some cytogenetic clones of unclear clinical significance may remain stable or become undetectable over time, whereas loss of part or all of chromosome 7 necessitates consideration of hematopoietic cell transplant (HCT) prior to leukemia progression. With any cytogenetic abnormality, close monitoring of the bone marrow and the blood counts is warranted.

Solid tumors: A number of solid tumor types have been reported to occur at increased frequency in individuals with FA, and these appear at a much younger age than the age at which these tumors are seen in unaffected individuals. As an example, a 2003 study involving a cohort of 1300 individuals with FA estimated the median age of cancer development to be approximately 16 years, compared with 68 years in the general population.^[15] In many late-onset cases of FA, malignancy is the presenting finding.

• The cumulative incidence of solid tumors is increasing as individuals with FA are living longer, due to cure of bone marrow failure by HCT. In addition, HCT may increase the risk of solid tumors in some individuals with FA, likely due to a combination of factors including exposure to DNA damaging agents or radiation in the conditioning regimen and the development of graft-versus-host disease (GVHD). This trend was demonstrated in a study that compared the rates of cancer between 117 individuals with FA who underwent HCT with 145 who did not. The age-specific hazard of squamous cell cancer was 4.4-fold higher in individuals who had a transplant, and the tumors occurred at a younger age (median age, 18 versus 33 years). In another series of 37 individuals with FA who underwent HCT, the 15-year incidence of head and neck cancers was 53 percent.^[16]
• Unlike for AML, where risk in patients with FA reaches a plateau between 30 to 40 years of age, the annual risk of developing a solid tumor continues to increase significantly with age, particularly in FA patients greater than age 30. A 2003 study from the International FA Registry estimated the cumulative incidence of solid tumors by the age of 40 years at 28 percent [18]. This study followed 754 patients for over 20 years and identified 79 solid tumors. The most common were squamous cell cancers (SCCs) of the head, neck, esophagus, anus, and urogenital region; these accounted for 39 of the solid tumors (49 percent). There were also 18 liver tumors, accounting for 23 percent of tumors; as well as six renal tumors, five brain tumors, three breast cancers, and other tumor types including germ cell tumors and sarcomas. Similar findings have been reported in other cohorts. ^[17][18]
• Despite this high incidence of malignancy, solid tumors are rare in childhood, with the exception of those harboring biallelic FANCD1/BRCA2mutations, in whom the likelihood of at least one malignancy is greater than 97 percent by seven years of age.^[19] For patients with FANCD1/BRCA2 mutations, brain tumors occur in over 50 percent by five years of age (second only to leukemia in frequency), although new onset brain tumors are rare beyond this age [86]. Wilms tumor is also common in patients with biallelic FANCD1/BRCA2 mutations, and less frequently other solid tumors of childhood are seen, including rhabdomyosarcoma and neuroblastoma ^[20]
• The role of human papilloma virus (HPV) infection in patients with FA who develop SCC is unclear. A 2003 report from a United States cohort suggested that the high incidence of SCC of the head/neck and anal/urogenital regions in patients with FA were due to increased susceptibility to genomic instability produced by HPV, as >80 percent of these tumors were HPV-positive. Many of the tumors in the European cohort demonstrated p53 mutations.^[21] Thus, whether patients with FA have increased indication to receive vaccination to HPV compared to the general public remains unknown. We give the HPV vaccine to all patients with FA since uncertainty remains regarding this issue.

Endocrine manifestations: Individuals with FA may have a range of endocrine disorders. In many cases, endocrine abnormalities result from anatomical disruption of the hypothalamic-pituitary axis during development, including common abnormalities such as pituitary stalk interruption syndrome and septo-optic dysplasia. In other cases, specific organ dysfunction, either intrinsic to the disease or as a consequence of HCT-associated therapies (eg, conditioning regimen, therapy for GVHD) leads to endocrine abnormalities.

• Short stature is seen in the majority of patients, but some patients have normal or even above-average height regardless of genotype.^[22] In many cases, short stature is driven by growth hormone deficiency.
• Primary hypothyroidism is seen in over 60 percent of patients with FA, usually due to central hypothalamic or intrinsic thyroid dysfunction rather than autoimmunity.
• Adrenal dysfunction occurs in a subset of patients due to low ACTH secretion, although these patients will generally have a normal response to exogenous ACTH stimulation.^[23]
• Altered glucose metabolism, including diabetes mellitus and impaired glucose tolerance, occurs in nearly 50 percent of patients with FA due to dysfunction of pancreatic islet cells.^[24]
• Patients with FA are also at increased risk for dyslipidemia and other aspects of metabolic syndrome.
• Infertility and delayed or abnormal progression of puberty are also very frequent in FA. In males, infertility may result from gonadal dysfunction and/or developmental defects in genital tract formation. In females fertility is possible; however, premature ovarian failure occurs in over 75 percent of patients.^[25]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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).

• 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.

• 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.

• Head and face – Microcephaly, hydrocephalus, micrognathia, peculiar face, bird face, flat head, frontal bossing, scaphocephaly, sloped forehead, choanal atresia.
• Eyes – Small, strabismus, epicanthal folds, hypertelorism, ptosis, slanted, cataracts, astigmatism, blindness, epiphora, nystagmus, proptosis, small iris
• Ears – Deaf (usually conductive), abnormal shape, atresia, dysplasia, low-set, large, small, infections, abnormal middle ear, absent drum, dimples, rotated, canal stenosis

• Neck – Sprengel abnormality, short, low hairline, webbed

• No significant chest findings present usually.

• No significant CVS findings present usually.

GI system – High-arch palate, atresia (eg, esophagus, duodenum, jejunum), imperforate anus, tracheoesophageal fistula, Meckel diverticulum, umbilical hernia, hypoplastic uvula, abnormal biliary ducts, megacolon, abdominal diastasis, Budd-Chiari syndrome

BACK

Neck – Sprengel abnormality, short, low hairline, webbed.

Spine – Spina bifida (thoracic, lumbar, cervical, occult sacral), scoliosis, abnormal ribs, sacrococcygeal sinus, Klippel-Feil syndrome, vertebral anomalies, extra vertebrae.

• Gonads may display the following abnormalities:
• Males – Hypogenitalia, undescended testes, hypospadias, abnormal or absent testis, atrophic testes, azoospermia, phimosis, abnormal urethra, micropenis, delayed development
• Females – Hypogenitalia; bicornuate uterus; aplasia of uterus and vagina; atresia of uterus, vagina, or ovary/ovaries

Neuromuscular findings are non significant.

Upper limb abnormalities can include the following features:

• Thumbs – Absent or hypoplastic, supernumerary, bifid, rudimentary, short, low set, attached by a thread, triphalangeal, tubular, stiff, hyperextensible^[1]
• Radii – Absent or hypoplastic (only with abnormal thumbs [ie, terminal defects]), absent or weak pulse
• Hands – Clinodactyly, hypoplastic thenar eminence, 6 fingers, absent first metacarpal, enlarged abnormal fingers, short fingers
• Ulnae – Dysplastic

• Feet – Toe syndactyly, abnormal toes, flat feet, short toes, clubfoot, 6 toes
• Legs – Congenital hip dislocation, Perthes disease, coxa vara, abnormal femur, thigh osteoma, abnormal legs.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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. ^[1] Flow cytometry of hematopoietic cells may show cell cycle arrest in G2/M phase.

In Fanconi anemia, the complete blood count (CBC) may reveal trilineage pancytopenia or may only show RBCs that are macrocytic for age. Macrocytosis, thrombocytopenia, and/or leukopenia may precede full-blown aplasia.

• Chromosome breakage is usually examined in short-term cultures of peripheral blood mitogen–stimulated T lymphocytes in the presence of DNA cross-linkers, such as diepoxybutane (DEB) or mitomycin C (MMC).^[2] These agents lead to increased numbers of breaks, gaps, rearrangements, and quadraradii in Fanconi anemia homozygote cells. It is considered as screening test for Fanconi anemia.
• Some patients may have hematopoietic somatic mosaicism, with correction of the Fanconi anemia defect in the blood. In these cases, skin fibroblasts may be needed for the chromosome breakage test.
• FA gene sequencing is generally suggested for all patients with a positive result from chromosomal breakage testing. The reason is that identification of the genetic defect definitively confirms the diagnosis and eliminates other chromosomal breakage disorders as the cause of the abnormal screening test. Furthermore, sequencing allows screening of family members for the purposes of identifying HCT donors, performing prenatal testing, and genetic counseling, given that heterozygous carriers will not have abnormal chromosomal breakage analysis.

Flow cytometry of Fanconi anemia cells cultured with nitrogen mustard and other clastogens demonstrates an arrest in G2/M. Flow cytometry for cell cycle analysis can be performed through propidium iodide staining, Hoechst staining, or pyronin Y staining.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

There are no specific electrocardiogram findings in Fanconi anemia.

There are no specific electrocardiogram findings in Fanconi anemia. However, patients with Fanconi anemia can present with the VACTERL syndrome, which consists of Vertebral anomalies, Anal atresia, Cardiac abnormalities, Tracheo-Esopheageal fistula, Renal abnormalities, and radial Ldefects. If the cardiac defects are severe enough to disturb the conduction system of the heart, EKG abnormalities can result.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

Many of the congenital anomalies can be detected on imaging studies. These include:

• Growth disturbances: Intrauterine growth retardation, short stature, delayed ossification.^[1]
• Central nervous system: Hydrocephalus, single ventricle, absent septum pellucidum/corpus callosum, vascular malformations, moyamoya, Chiari malformations/absent septum pellucidum/corpus callosum.
  • Skull: Microcephaly, craniosynostosis, micrognathia, frontal bossing, small or absent external auditory canal, absent tympanic membrane, microtia, fused ossicles.
• Spine: Spina bifida, Klippel-Feil anomaly, vertebral body anomalies, sacral agenesis or hypoplasia, kyphosis, scoliosis.^[2]
• Radial ray anomalies: Thenar hypoplasia; dislocation of the radial head; radioulnar synostosis; absence or hypoplasia of the radius, scaphoid, trapezium, and/or thumb; floating thumb; bifid thumb; digitalized thumb; and abnormal thumb placement.^[3]
• Extremities (other): Brachydactyly, arachnodactyly clubfoot, dysplastic or absent ulna, humeral abnormalities, absent clavicles, Sprengel deformity, congenital hip dysplasia/dislocation, Legg-Calve-Perthes disease, leg length discrepancy, soft-tissue syndactylism of the toes, metatarsus varus, medial deviation of the toes, hammer toes.
• Gastrointestinal: Esophageal atresia, tracheoesophageal fistula, duodenal atresia, duodenal web, malrotation, foregut duplication cyst, anal atresia. Biliary atresia, annular pancreas.
• Renal anomalies: Renal aplasia, horseshoe kidney, low-lying kidney(s), renal ectopy, hydronephrosis, hydroureter, urethral stenosis, reflux.^[4]
• Genital anomalies: Hypogenitalism, cryptorchidism, hypospadias, bicornate uterus, aplasia or hypoplasia of vagina and uterus, atresia of vagina, hypoplasic uterus, hypoplastic/absent ovary.
• Cardiopulmonary: Patent ductus arteriosus, ventricular septal defect, pulmonic or aortic stenosis, coarcation of the aorta, double aortic arch, cardiomyopathy, tetralogy of Fallot, pulmonary atresia.
• Osteoporosis: This can be visualized on X-ray to a certain extent, but a better test is dual-energy X-ray absorptiometry (DEXA).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Pervaiz Laghari, MD[3]

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.

Active surveillance involves monitoring of bone marrow function without pursing specific pharmacologic intervention. The initial approach of monitoring bone marrow function is classified according to the severity of bone marrow failure and the presence or absence of clonal hematopoietic neoplasms. This monitoring T schedule and management approach is consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Management from the Fanconi Anemia Research Fund.

• Mild bone marrow failure: This is described as absolute neutrophil count (ANC) between 1000 and 1500/microL, platelet count between 50,000 and 150,000/microL, and hemoglobin ≥10 g/dL. CBC with differential should be monitored every 3-4 months as the blood count remain stable. A bone marrow examination with cytogenetics should be done annually. If there are any changes in blood count without an apparent cause (e.g: infection) we should increase the frequency of CBC monitoring and the bone marrow studies repeated regardless of the date of last study.
• Moderate bone marrow failure: This is described as ANC between 500 and 1000/microL, platelet count between 30,000 and 50,000/microL, hemoglobin between 8 and 10 g/dL. For patients whose counts continue to decrease, stem cell transplant planning should begin with an HLA-matched related donor (first choice) or closely matched unrelated donor. Androgen therapy may be an alternate option to improve blood counts for some patients including those with moderate bone marrow failure for whom no donor is available, those who do not meet medical eligibility criteria for HCT due to pre-existing organ dysfunction or ongoing infection, and those who decline HCT. If a patient is asymptomatic with stable cell counts and no clonal abnormality, it may be reasonable to monitor the CBC every three to four months and perform a bone marrow examination annually as done for mild bone marrow failure. If cytogenetic abnormalities suggest poor risk MDS in the absence of other MDS-defining feature, CBC and bone marrow should be monitored more frequently (eg, CBC every 1-2 months, Bone marrow every 1-6months), and should be proceed with the best available donor.
• Severe bone marrow failure: This is defined as ANC ≤500/microL, platelet count ≤30,000/microL, hemoglobin <8 g/dL), and/or transfusion dependence. Patients should undergo stem cell transplant with the best available donor, an HLA-matched sibling/family member who has been determined not to have FA would be preferable, second choice should be closely matched unrelated donor. If neither of above options available then we should start trial of androgen therapy while pursuing other alternative donor such as cord blood or haploidentical HCT, with attempt to avoid transfusion exposure and opportunistic infection during the androgen trial.

Allogenic HSCT (HCT) is the only accepted curative therapy for Fanconi anaemia with severe bone marrow failue, MDS or AML, transfusion dependent anaemia or thrombocytopenia. Patients with FA are at risk for significant toxicity from standard chemotherapy doses which are used for HCT conditioning. Strategies revised at the Minnesota University and other centres that incorporate reduced dose of cyclophosphamide have been extremely effective in matched sibling donor HCT for FA. Rates of engraftment associated with these approaches are greater than 90%, and overall post-HCT survival is greater than 95% in most series reported since 2005.^[1] Additional developments have also improved outcomes from unrelated donors, including matching with high-resolution HLA genotyping, T cell depletion, and conditioning regimens with lower toxicity. Thus, even though unrelated donor HCT may carry a higher risk of long-term toxicity, it is likely to be critical to delaying HCT while attempting to use non-curative supportive care approaches to rising blood counts. Although HCT is curative for bone marrow failure and potentially for hematopoietic neoplasms, it does not cure other manifestations of FA. As noted above, HCT appears to increase the risk of squamous cell cancers, especially in individuals with severe graft-versus-host disease. Additionally, insulin resistance, bone health disorders, and other endocrinopathies may be worsened by HCT, and require close lifelong monitoring.^[2]

• Sibling donor transplant: The recommended source of stem cells is the bone marrow (rather than peripheral blood stem cells) from an eligible sibling who is HLA matched at 10 of 10 alleles of the four most commonly tested HLA genes (HLA -A, -B, -C, and DRB1) or a closely matched unrelated donor. It is essential that all sibling or other related donors must go through chromosomal breakage testing or genetic testing to confirm that they do not also have FA. If they also have Fanconi anemia, their cells cannot be used as donor cells. This testing is very important because family donors those are apparently asymptomatic and healthy may have FA genetically but lack classic findings due to mosaicism, incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease manifestations. HCT performed with a family donor who also turns out to have FA, even if mosaic and/or asymptomatic, would possess a very high risk of graft failure. Alternatively, siblings who are only carriers of one heterozygous mutation in an autosomal recessive FA-associated gene are eligible as donors. Options for patients with FA who lack a closely matched related or unrelated donor but still require HCT for bone marrow failure include the following.
• Unrelated cord blood transplant (CBT): This seems to be less effective than matched unrelated donor bone marrow for patients with FA. This was demonstrated in a 2007 series of 93 patients with FA who underwent CBT, in which overall survival was 40 percent.^[3] Use of cord blood units with higher stem cell doses and incorporation of fludarabine into CBT conditioning regimens may improve outcomes in the future.
• Haploidentical donor transplant: HCT using a parental or other related donor is still under investigation at several centers. This approach shows promise, although outcomes are not as good as those seen with closely matched unrelated donors. ^[4] [5] Based on the above conclusion, CBT or haploidentical HCT should only be performed for patients with FA in the context of active clinical trials.

Those parents who are interested in having additional children, in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) approaches are an established method that not only ensures that future children will not have FA, but also can select for an HLA-matched sibling that can be used as a donor. While not always effective and also associated with challenging ethical and emotional dimensions that must be addressed, this method has facilitated successful matched sibling donor HCT in a number of patients with FA dating back to 2001.^[6] This approach is not optimal for somebody with FA who have an urgent need for HCT (eg, those who require transfusions or have severe neutropenia despite optimal supportive care), since it may take one to two years before a healthy sibling donor is available.

Androgen therapy can be a reasonable option for those who lack a closely matched related donor for HCT, or for whom HCT is not pursued due to family preference or medically eligibility.^[7] Androgen therapy is used to increase blood count for a period of weeks to month while parents attempt to IVF with PGD and until resulting HLA-matched related donor is available. It is not a curative treatment. Only half of patents with FA will respond to androgen therapy.^[8] Patients with severe bone marrow aplasia are less likely to respond than those with residual bone marrow function, and response can take weeks to months. Androgen therapy has the most dramatic effect on the erythroid lineage and can improve hemoglobin within a few weeks of initiation. Responses in the platelet count are generally slower and less complete, and neutropenia may not completely resolve. Androgen therapy can be associated with virilization, growth abnormalities, behavioral changes, and hypertension. The most concerning side effects of androgens in patients with FA involve the liver and include transaminitis, cholestasis, peliosis hepatis, and liver tumors.

• Oxymetholone: This is the most commonly used androgen in FA. If no response is seen after three months, oxymetholone should be discontinued.
• Danazol: This androgen is sometimes also used in anemia related to MDS.
• Oxandrolone: This is rarely used currently but can be tried if other measures are ineffective.^[9] If the blood counts stabilize or improve, the daily dose may be tapered to the minimum effective dose to avoid non-hematologic toxicity. A 2014 study was the first to report outcomes of FA patients treated with low-dose oxandrolone, an anabolic steroid with a potentially favorable toxicity profile compared to oxymetholone. Of nine patients with a median follow-up of nearly two years, 78 percent had a hematologic response, none had clinical virilization, and none developed liver tumors.^[10] More experience with this agent is needed.

Transfusion and growth factor support may be essential due to progressive bone marrow failure and associated complications in patients with FA. However, increasing evidence supports a judicious approach, as extensive transfusions may be associated with worse outcomes with HCT, and extensive use and high doses of growth factors such as G-CSF and thrombopoietin mimetics in patients with other bone marrow failure syndromes have been associated with increased risks of developing MDS and AML.

• Packed RBCs: Red blood cell (RBC) transfusion is indicated for any patient with symptomatic anemia (eg, decreased activity level, excessive fatigue, shortness of breath, and poor growth) or anemia with hemodynamic instability. Only leukoreduced, irradiated units of RBCs should be used, to minimize the risk of cytomegalovirus transmission, alloimmunization, and transfusion-associated graft-versus host disease (ta-GVHD). Directed donations by family members should be avoided to reduce the risk of graft rejection due to alloimmunization in patients who subsequently undergo HCT.  Chronic RBC transfusions can lead to iron overload, which, if not treated, can lead to significant morbidity and mortality.
• Platelets: Platelet transfusion is indicated in patients with platelet counts below 10,000/microL and in any patient with severe bruising, bleeding, or invasive procedures. The use of single donor pheresis platelets minimizes exposure to multiple donors, and all products should be irradiated to prevent ta-GVHD. As with RBCs, directed platelet donations from family members should be avoided.
• Granulocyte colony-stimulating factor (G-CSF): This raises the neutrophil count in most neutropenic patients.^[11]

The workup for hematologic malignancies for FA includes bone marrow aspirate and biopsy for morphologic review. Flow cytometry analysis should be performed if dysplasia or increased myeloblasts are seen. Cytogenetic analysis should also should be performed. Fluorescence in situ hybridization (FISH) analysis for specific aberrations associated with transformation to myelodysplastic syndrome. This includes assessment for gain of 1q, gain of 3q, deletion of 7, and deletion of 7q).

• Management of multilineage dysplasia with excess blasts: These patients should be referred for urgent stem cell transplant.
• Management of poor-risk cytogenetics: These patients should be referred for urgent stem cell transplant.
• Management of advanced MDS or AML: These patients can be treated with induction chemotherapy followed by stem cell transplant. For example, FLAG chemotherapy (reduced intensity (fludarabine, araC, and G-CSF) can be used.^[12]
• Management of biallelic BRCA2 (FANCD1) mutations: These patients harbor a very high risk of presenting early in childhood with MDS or AML in the absence of bone marrow failure. These patients might benefit from early stem cell transplant.^[13]

Since patients with FA are at increased risk for development of certain cancers aside from hematologic malignancies, it is important to perform screening for certain types of these cancers.

• Breast cancer: Monthly breast self-examination should be performed starting in the early 3rd decade of life.
• Skin cancer: A detailed skin examination should be performed annually by a dermatologist.
• Head and neck cancer: These patients should avoid exposure to tobacco and alcohol, since these are known risk factors for HNSCC. Good oral hygiene and regular dental care is especially important.
• Liver tumors: Patients who are receiving androgen therapy may have increased risk for development of liver tumors.
• Gynecological and anogenital cancer: Human papilloma virus (HPV) vaccination is indicated for boys and girls prior to the onset of puberty.
• Stomach and colon cancer: A workup for a gastrointestinal malignancy should be performed in any patient with FA who presents with persistent abdominal discomfort, pain, or other attributable symptom that is not explained by other evaluation. Upper and/or lower endoscopic evaluations should be done.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

There is no surgical treatment of Fanconi anemia.

There is no surgical treatment of Fanconi anemia. However elective splenectomy and bone marrow transplant are end-stage therapies for Fanconi anemia, as is true for any other aplastic anemia.^[1][2][3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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 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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

There are two major methods of secondary prevention in Fanconi anemia. These involve reducing the risk of development of secondary malignancies.

There are two major methods of secondary prevention in Fanconi anemia. These involve reducing the risk of development of secondary malignancies, such as acute myeloid leukemia.

• Avoidance of radiation: Radiation can induce DNA damage in cells, and radiation can serve as a second-hit to a cell that is already predisposed to malignant transformation due to DNA repair defects. Patients with Fanconi anemia are advised to avoid radiation. This includes radiation for treatment of other conditions, such as lymphoma or breast cancer.
• Avoidance of chemicals: Chemicals and carcinogens are induce cancer readily in patients with Fanconi anemia. If a patients with Fanconi anemia has another malignancy, caution should be exercised when determining the chemotherapeutic regimen, since this chemotherapy can cause cancer.^[1][2]

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Therapies under development

● Gene therapy – Gene therapy has the potential to improve bone marrow function in individuals with FA since the origin of bone marrow failure is deficiency of an FA gene function. Gene-corrected CD34+ stem cells from FA patients have been engrafted in immune-deficient mice, but successful clinical applications of gene therapy for FA have not yet been demonstrated.^[1]

Major inclusion and exclusion criteria for gene therapy in patients with biallelic FANCA germ-line mutations as proposed by International Fanconi Anemia Gene Therapy Working Group.^[2]

Inclusion Criteria	1. FA demonstrated by a positive test for increased sensitivity to chromosomal breakage with MMC/DEB and determination of FA complementation group A by somatic cell hybrids, molecular characterization, western blot analysis, direct FANCA sequencing, or acquisition of mitomycin C resistance after in vitro transduction with a vector bearing the FANCA cDNA.
	2. Bone Marrow analysis demonstrating normal karyotype.
Exclusion Criteria	1. Uncontrolled infection (viral, bacterial, or fungal).
	2. Patients with an HLA identical sibling donor.

● Metformin – In a mouse model of FA (FANCD2 gene knockout), metformin produced modest increases in white blood cell (WBC) counts, hemoglobin levels, and platelet counts.^[3] There was also reduced p53-dependent tumor formation and a suggestion of decreased susceptibility to DNA damage. Metformin has not been evaluated in patients with FA.