Fanconi Anemia

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Continuing Education Activity

Fanconi anemia is a rare genetic disorder, involving all three blood cell lines. It is the most common cause of inherited bone marrow failure characterized by pancytopenia. This activity reviews the evaluation and management of Fanconi anemia and highlights the role of the interprofessional team in improving care for patients with this condition.


  • Identify the etiology of Fanconi anemia.
  • Describe the appropriate evaluation of Fanconi anemia.
  • Outline the management options available for Fanconi anemia.
  • Summarize interprofessional team strategies for improving care coordination and communication to advance the care of Fanconi anemia and improve outcomes.


Fanconi anemia (FA) is a rare genetic disorder, involving all three blood cell lines. It is the most common cause of inherited bone marrow failure characterized by pancytopenia. Additionally, it affects almost all organs of the body.[1] Fanconi anemia is mainly based upon the molecular mechanism involving a defective homologous recombination DNA repair pathway, defects in proteins as well as other enzymes involved in the repair of damaged DNA following various alkylating agents, irradiation, and cytotoxic drugs. It is also referred to as the inherited form of aplastic anemia. The discovery of Fanconi anemia had implications far beyond the disease itself. An extensive study of other bone marrow failure syndromes and chromosome fragility diseases has enhanced the scientific understanding of the bone marrow failure in Fanconi anemia. It is mostly associated with other congenital deformities and is susceptible to hematological and solid tumors. It usually is more common during childhood, with the average age of diagnosis being 7 years. The advancement of molecular genetic studies has helped in the comprehensive study of Fanconi anemia.


Fanconi anemia is an inherited autosomal recessive disease, but about 2% is inherited by an X-linked recessive manner, with either homozygous or heterozygous mutations. DNA sequencing identified various pathogenic alleles, including point mutations, duplications, splicing defects, and deletions.[2] Mutation of FA genes results in impaired double-stranded DNA repair. To date, more than 23 FA complementation genes (FANC) have been recognized, and all of them are involved in the DNA repair pathway.[3] Most of them are autosomal recessive except a few such as FANCB that is X-linked, and FANCR (RAD51), which is autosomal dominant.[4][5]


Fanconi anemia is a very rare type of anemia. Overall, an average of 1 out of 136000 newborns has Fanconi anemia, and it varies from 1 in 100000 to 250000 births.[6] European registries and data reveal the prevalence of Fanconi anemia is just 4-7 per million live births.[7] It has been found in all races.[8] However, the rate is higher in the African population of South Africa, sub-Saharan Blacks, and Spanish Gitanos with rates of 1 in 40000 births.[9] Carrier frequency is higher among Ashkenazi Jews of the United States, i.e., 1 case per 100 people with a birthrate of 1 case per 30000.[10] There is a slight predilection of men more than women, but overall, 99% of cases are equal in both sex.


A defect in the homologous recombination of double-stranded DNA is the main mechanism of the pathogenesis of Fanconi anemia. Various FA proteins maintain genomic stability through DNA interstrand crosslinks (ICLs) repair. ICLs prevent DNA strand separation and maintain DNA integrity. Genetic defects in DNA repair are present in the FA pathway so that cells cannot properly repair especially detrimental types of DNA damage. It results in genomic instability and increased susceptibility to cytotoxic agents and predisposition to malignancies. Proteins encoded by FA genes include ubiquitin ligase, monoubiquitinated protein, helicase, and breast/ovarian cancer susceptibility proteins. These proteins are responsible for DNA repair and resistance against DNA damage insults. Some of the FA proteins are similar to the BRCA2 protein, such as FANCD1, which works in the FA-BRCA network. An interactive network of these FA proteins with other proteins are responsible for other rare genetic syndromes such as ataxia-telangiectasia, Bloom syndrome, breast-ovarian cancer, etc.[11][12][13] These FA proteins also have multiple other functions. The FA pathway involves FANC genes and their products to maintain genomic integrity. Fanconi cells show hypersensitivity to crosslinking agents like mitomycin C (MMC), diepoxybutane (DEB), and cisplatin. FA proteins are also involved in other stress response pathways. The inability of the affected cells to withstand normal oxidative stress and oxygen free radicals cause oxidative damage.[14]

Genetics and genomic instability: There is a large number of FA genes identified (see above). Proteins encoded by these genes have various roles in the DNA repair FA pathway. The formation of ICLs leads to FA core complex arrangement. Among them, the FANCD2 protein has a central role in this pathway. Core proteins FANC (A, B, C, E, F, G, L, M), more specifically, FANCL component acts as E3 ligase responsible for monoubiquitination, and other core proteins for phosphorylation, and translocation of FANCD2 proteins in nuclear foci.[6] Monoubiquitination and phosphorylation are the activation process after DNA damaged by various agents in the normal DNA repair pathway. Monoubiquitinated FANCD2 accumulates in nuclear foci with other proteins such as BRCA1, FANCD1/BRCA2, RAD51, FANCN/PALB2, which are involved in DNA repair and resistance against DNA crosslinking and damaging agents like ionizing radiation, hydroxyurea, and UV light irradiation.

FANCI is monoubiquitylated and phosphorylated after DNA damage, but its role is not prominent. Genetic defects of any component of this pathway result in decreased resistance against damaging agents and ultimately leads to chromosome fragility. Some of the FA core complex proteins FANCC and FANCE localize to nuclear foci along with FANCD2, FANCG with BRCA2, and RAD51. Nuclear foci formation and the monoubiquitination of FANCD2 proteins are the focal steps in the FA DNA repair pathway. FA core protein complex itself, and with the help of one of its proteins FANCM stimulated translocase and ATPase. ATPase causes hydrolysis of ATP that provides energy to translocase for moving FA core complex along the DNA strand, and another FAAP24 protein binds to ssDNA and branching structures at the damaged site. In addition, FANCM contains helicase and endonuclease domain, which separate the double-stranded DNA and cleave the phosphodiester bond at the damage site to repair the damaged part. FANCJ is also a helicase that binds and interacts with BRCA1. FA core complex with other proteins such as BLM, RPA, and topoisomerase III-alpha are also involved in the DNA repair pathway. Some of the FA proteins, for instance, FANCD1 with BRCA2 and FANCJ with BACH1 and BRIP1, work downstream on homologous recombination DNA repair. Ultimately, bone marrow failure and other complications are due to the defect in the DNA repair pathway, increased oxygen reactive species, and inflammatory cytokines.[15] Cancer predisposition has the same common reason of defective DNA repair system.[16]


Microscopic examination of a bone marrow biopsy shows hypoplasia and hypocellularity with fatty replacement characteristic of aplastic anemia. Hypocellularity is often out of proportion of cytopenias. Bone marrow biopsy at infancy may be normocellular. In some cases, islands of hyperplastic erythroblasts and erythroid dysplasia can be seen.

History and Physical

Fanconi anemia leads to pancytopenia. Thus, a history with a decrease of all three blood cell lines, including red blood cells (RBCs), platelets, and leukocytes, is evident in the blood work. Shortness of breath, chest pain, dizziness, and fatigability are common manifestations of anemia. A history of epistaxis, petechiae, and unstoppable bleeding from a wound site is common due to thrombocytopenia. The risk of recurrent infections increases with the severity of leukopenia, which presents with fever and flu-like illness. History of low birth weight is present in some cases, and a history of weight loss is important to elicit from patients for cases complicated by cancer. Family history and marriage history are important, particularly where the prevalence of the consanguinity marriage system is high.

Approximately 75% of Fanconi anemia is associated with birth defects. On physical examination, the stature of the child may be short, and there are light-brown skin pigmentation ("cafe-au-lait") lesions in more than 50% of cases.[17] Structural abnormalities of extremities are more common. Absent, bifid, supernumerary, low set, short or hypoplastic thumb, absent or hypoplastic radii, and dysplastic ulna are the usual upper limb abnormalities. Lower limb abnormalities include polydactyly, short toes, club foot, flat feet, hip dislocation, abnormal femur, and thigh osteoma. Other skeletal abnormalities consist of head and face anomalies, microcephaly and hydrocephaly, frontal bossing, flathead, micrognathia, sloped forehead, webbed and short neck, low hairline, spina bifida, scoliosis, abnormal ribs, and extra vertebrae. Hypogonadism is common in both sexes and includes less genitalia development, undescended and absent testis, phimosis, hypospadias, micropenis, and vaginal atresia.

Other additional anomalies include abnormal epicanthal fold, proptosis, ptosis, cataracts, blindness, epiphora, ear anomalies such as absent eardrums, small or large pinnae, and atresia of the ear canal. Physical signs of pancytopenia are sometimes visible, including pallor, petechiae and bruising, and coldness of the hands and feet. Gastrointestinal abnormalities such as imperforate anus, tracheoesophageal fistula, atresia of the intestine, Meckel diverticulum megacolon, and umbilical hernia are less common.


Diagnosis may be delayed until the bone marrow failure develops. Different studies have summed up the average age of diagnosis as 7 years, although earlier diagnosis has been increased due to disease awareness and prenatal screening diagnostic enhancement. Early diagnosis may prevent severe complications.

Patients presenting with signs and symptoms of pancytopenia should be evaluated. Complete blood count reveals the level of RBCs, white blood cells (WBCs), and platelets. Raised mean corpuscular volume (MCV) indicates macrocytosis, and there can be high fetal hemoglobin levels due to increased stress. Serum erythropoietin is increased due to the low level of blood cells and the low response of hematopoietic stem cells. Bone marrow aspiration and biopsy reveals hypocellularity, aplasia with fatty marrow, and absence of myeloid, erythroid, and megakaryocytes stem cell lines. Myelodysplastic cases show hypo- or hypergranularity, hyposegmentation of myeloid precursors, and hypolobulated or hyperlobulated megakaryocytes. Clonic malformations are seen in leukemic transformations.

The chromosomal breakage test is diagnostic testing and is indicated in those with severe pancytopenia, i.e., absolute neutrophil count (ANC) less than 100/mL, hemoglobin less than 10g/dL with reticulocyte less than 40000/mL, bone marrow cellularity less than 25%, and platelet count less than 50000/mL. Testing with DNA cross-linkers such as diepoxybutane or mitomycin C stimulates the breakage of DNA in the absence of a DNA repair system. These agents increase the chromatids' breaks, gaps, reduplications, or rearrangements. Cultured fibroblasts also show chromosome fragility. Skin fibroblast is preferred in such patients that show negative T-lymphocytes chromosome fragility test and in those who have already undergone hematopoietic cell transplantation.[18]

Cell cycle analysis flow cytometry is an alternative to the chromosomal breakage test. In this test, those cells with impaired DNA repair undergo G2 arrest following DNA cross-linking agent exposure. Immunoblotting of GANCD2 mutation is less commonly used. FA gene sequencing is recommended in patients with positive chromosomal breakage testing. The identification of genetic defects is confirmatory and excludes other chromosome breakage syndromes. Prenatally, abnormal chromosome breakage can be analyzed with amniotic fluid cells or chorionic villous biopsy. An elevated level of serum alpha-protein is a rapid screening diagnostic test, but it may not be identified in many cases.[19]

Additional surveys are done to evaluate the other structural and birth defect abnormalities. A skeletal survey is done to identify bone defects. X-rays can detect the site and type of the exact defect. The X-ray of the head shows a crewcut appearance. Ultrasound of the abdomen is done to monitor the liver and kidney size and shape. Magnetic resonance imaging (MRI) is crucial to identify CNS abnormalities, such as the absence of corpus callosum, cerebellar hypoplasia, and small pituitary.

Treatment / Management

Supportive treatment: Blood transfusions are the best supportive therapy for Fanconi anemia. Packed RBCs and platelet transfusions have an immediate effect. RBCs transfusion from family members should be avoided due to alloimmunization and graft-versus-host disease. Leukopenia has a good response to granulocyte-colony-stimulating factor, but this is reserved for those patients with ANC<200/mL. Extensive transfusion has poor outcomes in patients with hematopoietic cell transplantation.

Hematopoeitic stem cell transplantation (HCT): Cure of aplastic anemia and prevention of myelodysplastic syndrome can be achieved through bone marrow, peripheral blood cells, and cord blood transplantation. Bone marrow is the preferred method over the others from an HLA-matched sibling. It is essential to do chromosome breakage testing of siblings or other related donors to exclude FA in donors. This method is not accessible for everyone and is reserved only for patients with severe myelodysplastic syndrome and leukemia, and failure of medical treatment. 50% - 75% of patients respond, and it is a more permanent treatment.[20]

Androgen therapy: It is performed in those who are not suitable for HCT. Oxymetholone is the most commonly used androgen. Other androgens less commonly used are danazol and oxandrolone. Androgens stimulate the hematopoietic stem cell proliferation, but it is not curative. Oxymetholone is used with a starting dose of 2-5mg/kg/day, but it is tapered to avoid toxicity. Patients with severe bone marrow hypocellularity have a poor response to androgen therapy. RBCs respond well, but platelets and leukocytes are less likely to respond.

Surgical treatment: Surgery is performed only for the management of structural deformities. Splitting of anomalies of the hand should be repaired early in life to avoid functional delays. Other surgeries include congenital heart defect surgery, repair of trachea-esophagus fistulas, and imperforate anus. Surgery may be required for cancers as well.

Gene therapy: The replacement of an abnormal gene by a normal gene is the modern developing technique. The correction of CD34+ in affected cells is now feasible.[21]

Differential Diagnosis

Fanconi anemia resembles a large variety of diseases. Other hematological problems that manifest clinical features of FA and congenital structural defects that are associated with FA should be excluded.[22]

Acquired aplastic anemia: It is due to acquired hematopoietic stem cells' destruction of bone marrow following various toxicogenic agents. Pancytopenia is the cardinal feature of Fanconi anemia due to bone marrow failure. Hypocellularity of bone marrow is sufficient for the diagnosis of acquired aplastic anemia, which does not show chromosome fragility by chromosome breakage test. Fanconi anemia shows chromosome fragility test positive, and gene sequencing is required to confirm the diagnosis.[23][24]

Other inherited bone marrow failure syndrome: Because bone marrow failure is distinct in Fanconi anemia, differentiation of other causes of bone marrow failure is essential. Diseases with short telomerase such as dyskeratosis congenital is associated with bone marrow aplasia. Bone marrow aplasia caused by reticular dysgenesis is a combined immunodeficiency disease due to AK2 gene mutation. However, sensorineural hearing loss and adaptive immune deficiency in infancy is a prominent feature of reticular dysgenesis. Diamond-Blackfan anemia is pure red cell aplasia that typically presents with bone marrow abnormalities.[25] Schwachman-diamond syndrome is bone marrow aplasia primarily associated with neutropenia in 88% - 100% of cases.[26] Congenital amegakaryocytic thrombocytopenia principally affects platelets.[27] All these diseases may show trilineage aplasia in the bone marrow after an extended period of time.

Denovo myelodysplastic syndrome (MDS): It is a clonal myelodysplastic disease characterized by ineffective hematopoiesis and peripheral cytopenias. MDS is also associated with Fanconi anemia, but de novo MDS is not susceptible to chromosome breakage test, does not have FA mutation, or congenital anomalies. Suspected MDS patients with associated FA should be tested with skin fibroblasts chromosome breakage tests rather than peripheral lymphocytes.

Drug-induced or infection-associated pancytopenia: Exposure of many cytotoxic drugs, mainly cancer chemotherapy, viral and bacterial infections, and chemicals cause transient bone marrow hypoplasia and pancytopenia in children, but unlike FA, this pancytopenia lacks congenital anomalies and also pancytopenia is reversible with removal of the agents. The chromosomal breakage test is negative.

Paroxysmal nocturnal hemoglobinuria (PNH): It is due to mutations of PIGA gene encoding anchoring protein glycosylphosphatidylinositol (GPI), mainly in hematopoietic progenitor cells which leads to nocturnal hemolysis due to activation of the complement system in the acidic environment during shallow breathing at night. Patients are anemic, have an increased risk of thrombosis, hemoglobin in the urine, and jaundice. Bone marrow failure is mainly due to acquired autoimmunity rather than inherited. The abnormal chromosomal breakage test is absent.

Other rare chromosomal breakage syndromes (CBS): A number of chromosomal instability diseases in the presence of irradiation, DNA cross-linkers, and chemicals are evident but rare, which mimic FA and necessitates their exclusion for an accurate diagnosis and treatment plan. These disorders include Bloom syndrome,[28] LIG4 syndrome, Ataxia-telangiectasia,[29] Nijmegen breakage syndrome,[30] Seckel syndrome,[31][32] NHEJ1 deficiency, Warsaw breakage syndrome, and cohesinopathies such as Robert syndrome.[33] These diseases, like FA, show an abnormal chromosomal breakage test as well as congenital anomalies such as short stature, microcephaly, malignancy. So they can be quite difficult to differentiate. However, bone marrow failure is not typical of CBS, and also there are spectral differences in congenital anomalies and malignancies between FA and CBS. Therefore, genomic sequencing of mutation helps to differentiate FA from CBS.

Pertinent Studies and Ongoing Trials

Several clinical trials are ongoing to investigate the therapy and prevention of Fanconi anemia. Clinicians should be aware of these trials and refer their patients for ones for which they may qualify.


The prognosis of Fanconi anemia is poor. Severe aplastic anemia is the main cause of mortality that leads to death before 10 years of age in the absence of a diagnosis. Survival has been improved in developed countries due to a reduction in mortality by bleeding, or infection complications. However, living well into adulthood has increased the chances of cancer development. Most of the individuals eventually develop acute myelogenous leukemia. Regular monitoring of patients is needed for cancer in those who have undergone a bone marrow transplant. Most of the patients have other associated birth defects, such as developmental delay, kidney problems, and microcephaly.


The major complications of FA are aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and specific solid tumors.[34]

The propensity of cancer: FA is associated with various cancers as the defective FA gene is associated with a wide variety of cancers.[35] Defects of genes of the FA pathway responsible for DNA repair and cell cycle checkpoints are involved in the hypersensitivity of cancer cells to chemotherapeutic drugs, viruses, and radiation. Impairment of the DNA repair system and lack of stability in cell cycle checkpoints leads to the uncontrolled proliferation of cells. Common variants of cancer include squamous cell carcinomas of the head, neck, and upper esophagus and carcinomas of the vulva, anus, and cervix, which has a 50-fold higher risk as compared to the absence of FA association. Myelodysplastic syndrome is the most common malignancy, which has a 6000-fold higher chance as compared to the general population. Acute myelogenous leukemia is the second most common cancer, which has a 700-fold higher chance as compared to the general population. Clonal mosaicism in Fanconi anemia has been demonstrated in aging and cancers.[36]

Bone marrow failure: Fanconi anemia registries reveal around 90% of patients suffer from bone marrow failure by the age of 40 years.[37] Bone marrow failure ultimately leads to pancytopenia.[38]

Endocrine disorders: A wide range of endocrine disorders are either intrinsic to molecular defects or HCT-associated and androgen therapies. Structural disruption of the hypothalamus-pituitary axis may lead to short stature due to growth hormone deficiency, hypothyroidism is found in around 60% of patients,[39] adrenal dysfunction that responds to exogenous ACTH, and dysfunction of pancreatic islets associated with glucose intolerance, dyslipidemia, and infertility due to hypogonadism. Androgen therapy causes benign and malignant liver tumors and peliosis hepatis.[40]

Deterrence and Patient Education

Information and understanding of Fanconi anemia are essential for family members because of the genetic inheritance pattern of the disease, and the patient is usually a child at the time of clinical presentation and diagnosis. Genetic counseling for the disease helps the family members have enough patient education to increase the compliance and the patient-clinician relationship. Fanconi anemia in a child necessitates the testing of the disease in other family members, most importantly, siblings, to either catch the disease in the early stage or to prevent future childbirth with genetic defects.

It is also important to perform the abnormal chromosomal breakage test and HLA matching of siblings in order to evaluate for possible hematopoietic stem cell transplantation between the siblings. A level of knowledge regarding the disease process, signs and symptoms, and the treatment plan should be a part of the education of parents. Parents should be informed about any interventions to be made, the benefits of one over other options, and health hazards. After complete clarification, they should be provided the opportunity to choose the best treatment plan.

Enhancing Healthcare Team Outcomes

Fanconi anemia, like other diseases, requires an interprofessional team approach. Healthcare outcomes are enhanced by the teamwork of many healthcare providers. Disease extent determines the need for a number of health professionals from different specialties. Fanconi anemia, although mainly a hematological problem, is associated with multiple diseases, including birth defects, and solid as well as hematological cancers. It requires the care of primary clinicians, oncologists, hematologists, gynecologists, pathologists, radiologists, nurses, genetic analysts, pharmacists, physiotherapists, and the support and care of family and friends.



Yana Puckett


8/10/2022 3:15:26 PM



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