Management and prognosis of Fanconi anemia

INTRODUCTION — 

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by pancytopenia, cancer predisposition, and physical abnormalities, including short stature, microcephaly, developmental delay, café-au-lait skin lesions, and malformations belonging to the VACTERL-H association.

FA is usually diagnosed in childhood, but diagnostic delays and variable disease manifestations are common, and some individuals are not diagnosed until adulthood.

The management of FA is challenging. Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure and hematologic neoplasms but not the nonhematologic features of FA. Because of their vulnerability to deoxyribonucleic acid (DNA) damage, patients with FA receive reduced-intensity conditioning therapy for HCT and lower-intensity treatments for cancers. Patients with FA require increased surveillance for both hematologic and nonhematologic malignancies.

This topic review discusses the management and prognosis of FA.

Clinical manifestations and diagnosis of FA are discussed separately. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

OVERVIEW — 

Major issues in managing FA include the following:

●Determining what therapeutic interventions are indicated for bone marrow failure and the appropriate timing of their use. (See 'Bone marrow failure' below.)

●Ensuring that appropriate schedules are followed to screen for hematologic neoplasms and nonhematologic malignancies, and treating these as they arise. (See 'Hematologic neoplasms' below and 'Solid tumors' below.)

●Coordinating subspecialty follow-up for complications related to congenital anomalies, endocrinologic disorders, and treatment-associated morbidities. (See 'Organ dysfunction' below.)

We screen siblings to identify affected individuals with milder phenotypes who might benefit from more comprehensive evaluations and to assess their suitability as potential donors for hematopoietic cell transplantation. (See 'Testing of siblings and management of heterozygotes' below.)

Immunosuppressive therapy, which is used frequently in patients with acquired aplastic anemia, has no role in the treatment of FA because this disease is not immune-mediated.

Our approach to management is consistent with Fanconi Anemia Guidelines for Diagnosis and Management [1].

BONE MARROW FAILURE — 

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for bone marrow failure (BMF) and for myelodysplastic syndromes/neoplasms (MDS) and acute leukemias that develop in patients with FA.

Transplant outcomes in patients with FA have improved dramatically since the development of FA-specific reduced toxicity approaches to conditioning and an improved understanding of the supportive care needs of these patients. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)

Patients with evidence of BMF should be promptly referred to a specialized transplantation center to discuss the risks and benefits of HCT and initiate an evaluation of potential graft donors.

While we do not advocate for HCT in individuals with adequate bone marrow function (to avoid the toxicity of the conditioning therapy and because some of these patients will not develop BMF), it may also be appropriate to refer such individuals with FA to a specialized transplant center to discuss these issues. (See 'Allogeneic HCT' below.)

Monitoring bone marrow function — Our approach to monitoring bone marrow function is stratified according to the severity of BMF (table 1) and the presence of clonal hematopoietic neoplasms:

●Mild BMF – For mild BMF, defined as an absolute neutrophil count (ANC) of ≥1000 to 1500/microL, platelet count ≥50,000 to 150,000/microL, and hemoglobin (Hb) ≥10 g/dL, we monitor the complete blood count (CBC) and differential count every three to four months, for as long as the blood counts remain stable.

Bone marrow examination is performed annually, including cytogenetics and a fluorescence in situ hybridization (FISH) panel.

If the blood counts change without an apparent explanation (eg, infection), the frequency of CBC monitoring is increased and bone marrow studies are repeated, regardless of the date of the last study.

●Moderate BMF – For moderate BMF (ANC ≥500 to <1000/microL, platelet count ≥30,000 to 50,000/microL, Hb 8 to 10 g/dL) whose counts continue to decline, we initiate HCT planning for allogeneic HCT.

The preferred donor is a human leukocyte antigen (HLA)-matched sibling donor (MSD) who has been determined to not have FA, or an HLA-matched unrelated donor (MUD). Other acceptable options include a closely HLA-MUD, a haploidentical donor, or an umbilical cord blood (UCB) graft. (See 'Allogeneic HCT' below.)

Androgen therapy may be a reasonable option to improve blood counts for some patients, including those with moderate BMF 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. (See 'Androgens' below.)

Alternatively, if the patient is asymptomatic with stable cell counts and no clonal abnormality, it is reasonable to monitor the CBC every three to four months and perform a bone marrow examination annually, as done for mild BMF.

Blood count monitoring and a bone marrow examination should be more frequent if there is a cytogenetic abnormality associated with adverse-risk MDS but no other MDS-defining features. As an example, a CBC should be performed every one to two months and a bone marrow examination every one to six months, while pursuing the best available transplant donor. Examples of poor-risk clonal hematopoiesis in FA include +3q, -7/del7q, and cryptic RUNX1 mutations [2]. (See 'Allogeneic HCT' below.)

●Severe BMF – For severe BMF (ANC ≤500/microL, platelet count ≤30,000/microL, Hb <8 g/dL) or transfusion dependence, we promptly pursue allogeneic HCT with the best available donor.

The preferred graft donor is an MSD who has been determined not to have FA or a MUD. Other donor options include a closely HLA-MUD, a haploidentical donor, or a UCB graft.

For individuals who are not candidates for HCT (eg, medically ineligible, no suitable donor, cost of transplantation), we encourage enrollment in a gene therapy clinical trial or other experimental approaches. (See 'Therapies under development' below.)

Androgen therapy, transfusions, and growth factor support may be used while awaiting allogeneic HCT, but limiting transfusion exposure and opportunistic infections are important for optimal transplant outcomes. (See 'Supportive care' below.)

We promptly proceed to allogeneic HCT in young children with FA who have moderate to severe BMF because transplant outcomes are better in young children than in adolescent and young adult (AYA) patients. Supportive strategies are acceptable for older patients who develop moderate to severe BMF because they are already in the high-risk category for transplant outcomes.

A European transplant consortium study reported that overall survival (OS) after transplantation for FA was >80 percent at 36 months in young children but <50 percent in AYA patients [3]. A report from the Center for International Bone Marrow Transplant Research (CIBMTR) and single-center studies have also consistently demonstrated worse outcomes for patients >10 years with FA [4,5].

Allogeneic HCT — Allogeneic HCT is the only curative therapy for severe BMF, transfusion-dependent anemia or thrombocytopenia, MDS, or acute myeloid leukemia (AML) in patients with FA [6]. We urgently refer these patients for HCT.

Patients with FA require lower toxicity conditioning regimens. Potential related donors must undergo genetic testing or evaluation for chromosomal breakage to ensure that they do not also have FA. This testing is necessary because family donors who are asymptomatic and healthy may have FA but lack the classic findings due to mosaicism, incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease manifestations.

HCT is curative for BMF and can cure hematopoietic neoplasms, but it does not alter 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. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Solid tumors'.)

Pretransplant evaluation, donor selection, conditioning regimen, stem cell source (eg, bone marrow rather than peripheral blood), and post-transplant care are discussed separately. (See "Hematopoietic cell transplantation for aplastic anemia in adults" and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)

Supportive care

Androgens — Androgen therapy may be appropriate for patients with BMF who lack a suitable transplant donor or those for whom HCT is not pursued due to family/caregiver preference or medical eligibility [7,8]. Androgen therapy is also sometimes used to support blood counts for a period of weeks to months while parents attempt in vitro fertilization (IVF) with prenatal genetic diagnosis and until the resulting HLA-matched donor is able to donate.

●Choice of androgen – Danazol is our preferred androgen for use in FA [9-12]. Oxandrolone and oxymetholone have been removed from the market.

●Toxicity – Adverse effects (AEs) associated with androgen therapy include virilization, growth abnormalities, behavioral changes, hypertension, and liver tumors.

The most concerning AEs of androgens in patients with FA involve the liver, including transaminitis, cholestasis, peliosis hepatis, and liver tumors. In a series in which androgens were administered to 36 patients with FA and 97 patients with other conditions, such as acquired aplastic anemia, those with FA were more likely to develop androgen-associated liver tumors at a younger age than those without FA [10]. Of the 36 liver tumors reported overall, 21 were hepatocellular carcinomas and 13 were adenomas. In the German experience mentioned above, liver adenoma was reported in the records of 12 of 26 patients (46 percent) [13]. Given these concerning risks, patients receiving androgen therapy should have liver chemistry profiles monitored every 1 to 2 months, with liver ultrasounds performed every 6 to 12 months.

●Efficacy – Approximately one-half of patients with FA will respond to androgen therapy [14].

Patients with severe bone marrow aplasia are less likely to respond than those with residual bone marrow function, and responses can take weeks to months. Thus, the recommended time to initiate a trial of androgen therapy is when a patient has developed moderate to severe BMF (table 1) but is not consistently transfusion-dependent. Androgen therapy has the most dramatic effect on the erythroid lineage and can improve Hb levels within a few weeks of initiation. Responses in the platelet count are generally slower and less complete, and neutropenia may not completely resolve [15,16]. If blood counts stabilize or improve after initiation of an androgen, the daily dose may be tapered to the minimum effective dose to avoid nonhematologic toxicity. If no response is seen after three months, the androgen should be discontinued.

A retrospective series of 70 patients treated with an androgen (mostly oxymetholone) from 1974 to 2014 reported that two-thirds of patients had an improvement in Hb level, while one-third had trilinear responses (ie, improvements in Hb, white blood cell [WBC] count, and platelet count) [13]. The median time to response was 12 to 14 weeks. In most cases, these responses were sufficient to convert the patient from transfusion-dependent to transfusion-independent. Liver adenoma was reported in 12 of 26 patients (46 percent). There was evidence of clonal evolution to MDS or AML in 12 patients, all of whom underwent subsequent HCT. OS of the cohort at approximately 10 years was 76 percent.

A 2020 retrospective analysis from the Canadian Inherited Marrow Failure Registry of 29 patients receiving danazol or oxymetholone, including 10 patients with FA, demonstrated similar efficacy between the two androgens, with fewer and less severe side effects experienced with danazol, particularly less virilization and lower growth disturbance [12]. Treatment of nine patients with oxandrolone was associated with 78 percent hematologic response, none had clinical virilization, and none developed liver tumors, with median follow-up of nearly two years [11]. Oxandrolone and oxymetholone are no longer available.

Transfusions and growth factors — Transfusions and growth factors can be given while awaiting allogeneic HCT, but their use should be limited to avoid complications.

Granulocyte colony-stimulating factor (G-CSF) and thrombopoietin mimetics should be used judiciously because extensive use and high doses of growth factors have been associated with increased development of MDS and AML in patients with inherited BMF syndromes [6,17].

●RBCs – Red blood cell (RBC) transfusion is indicated for patients 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) [18].

Directed donations by family members should be avoided to reduce the risk of graft rejection due to alloimmunization in patients who subsequently undergo HCT with a related donor. (See "Red blood cell transfusion in infants and children: Selection of blood products" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)

Chronic RBC transfusions can lead to an iron overload, which can lead to significant morbidity and mortality. An approach to assessing and treating transfusional iron overload (eg, with phlebotomy or chelation therapy) is presented separately. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)

●Platelets – Platelet transfusion is indicated in patients with platelet counts <10,000/microL and in any patient with severe bruising, bleeding, or invasive procedures (see "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure'). 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.

The thrombopoietin mimetic eltrombopag is being evaluated as a therapy to improve platelets and other blood lineages in patients with FA (NCT03206086).

●G-CSF – We generally reserve G-CSF for patients with ANC <200/microL or those with an active invasive fungal or bacterial infection and an ANC <1000/microL. Although G-CSF can raise the neutrophil count in most neutropenic patients with FA, there are concerns that it might increase the risk of MDS or AML in patients with BMF syndromes [19-22].

The starting dose of G-CSF is 5 mcg/kg daily, and the dose is adjusted towards a target ANC of 1500 to 2000/microL. If possible, the administration of G-CSF is adjusted to every other day to minimize the frequency of administration. If there is no improvement in the neutrophil count after eight weeks, treatment should be discontinued.

Patients with neutropenia and fever should be evaluated urgently, cultures obtained, and broad-spectrum antibiotics administered until the fever resolves or cultures are negative. However, we do not give routine prophylactic antibiotics to patients with FA, as there are no studies to indicate clinical benefit from this practice, and it may potentially increase the risk of fungal infections and antibiotic resistance. (See "Management of children with non-chemotherapy-induced neutropenia and fever" and "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Aplastic anemia' and "Management of the adult with non-chemotherapy-induced neutropenia".)

Therapies under development

●Gene therapy – Gene therapy has the potential to improve bone marrow function in individuals with FA since the origin of BMF is a deficiency of an FA gene function. Gene-corrected CD34-positive stem cells from FA patients have been engrafted in immune-deficient mice [23,24]. The gene therapy platform developed in clinical trials for patients with FA utilizes a lentiviral-based, gene-modified autologous transplant, performed without chemotherapy or radiation. Thus, gene therapy has the advantage, compared with allogeneic HCT, of avoiding exposure to cytotoxicity that can lead to short- and long-term complications. However, to date, hematopoietic correction following gene therapy for FA patients with FANCA mutations has been inconsistent. In the FANCOLEN-1 study, while correlative studies demonstrated impressive gene correction, gene therapy failed to halt progressive thrombocytopenia [25]. In follow-up studies using the same approach, only 7 of 12 patients achieved hematopoietic stabilization, and even responders failed to normalize blood counts [26].

●Metformin – In a mouse model of FA (FANCD2 gene knockout), metformin produced modest increases in WBC counts, Hb levels, and platelet counts; reduced p53-dependent tumor formation, and evidence of decreased susceptibility to DNA damage [27].

Metformin was safe and tolerable and was associated with improved blood counts in one-third of the 15 nondiabetic patients with FA [28].

HEMATOLOGIC NEOPLASMS — 

Clonal hematopoiesis is common in patients with FA.

For newly diagnosed patients who have not had a bone marrow evaluation, we obtain a unilateral bone marrow aspirate and biopsy (>1 cm) for morphologic review. Flow cytometry analysis should be performed if dysplasia or increased myeloblasts are seen. Cytogenetic analysis should also be performed, and at minimum, should include G-banding analysis of at least 20 metaphases to assess for acquired chromosomal aberrations. Fluorescence in situ hybridization (FISH) analysis for specific aberrations associated with transformation to myelodysplastic syndromes/neoplasms (MDS; eg, +1q, +3q, -7, -7q) and whole genome single nucleotide polymorphism (SNP) array with copy number analysis may increase sensitivity and the ability to detect subtle chromosome aberrations. If adequate cytogenetic analysis was not done prior to the diagnosis of FA, we perform a bone marrow examination to obtain cytogenetics.

Greater intensity monitoring and other interventions are generally based on the presence of dysplasia, blast count, and specific cytogenetic findings. Our approach is as follows:

●As noted above, an initial bone marrow aspirate and biopsy with cytogenetics is done in all patients diagnosed with FA. This is usually repeated annually as long as no concerning features are noted. (See 'Monitoring bone marrow function' above and "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetic testing'.)

●Patients with morphologic features concerning a hematologic neoplasm, including multilineage dysplasia and/or excess blasts, and those with poor-risk cytogenetic features (eg, -7, +3q, cryptic RUNX1 mutations [29,30]) should be promptly referred for hematopoietic cell transplantation (HCT) with the best available donor.

Pre-HCT chemotherapy cycles are not advised in these patients because of the risk of prolonged aplasia and the lack of evidence for a survival benefit, even in young patients without FA who develop MDS [31]. Regardless of the pre-HCT cytoreduction approach, it is critical to identify the HCT donor prior to initiating chemotherapy for MDS or acute myeloid leukemia (AML) in patients with FA because of the risk of chemotherapy-induced aplasia.

●Patients with advanced MDS (eg, bone marrow blast count >10 to 15 percent) or AML may be treated with a course of chemotherapy followed by HCT. One piloted strategy used a single cycle of reduced-intensity FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF]) three weeks prior to the initiation of HCT conditioning (without waiting for hematologic recovery from the FLAG regimen); this may be an effective approach, as all six patients in a study using this approach were alive and disease free at a follow-up of 28 months [32]. However, the use of pretransplant cytoreduction remains highly controversial and is best discussed with experts in FA prior to initiation [33].

●Certain cytogenetic abnormalities, such as +1q, del(20q), and del(5q), are not associated with poor-risk MDS for patients with FA. For patients with these findings who do not have another indication for HCT, such as severe bone marrow failure (BMF), dysplasia, or acute leukemia, we monitor the complete blood count closely (eg, once per month) and repeat the bone marrow examination every one to six months until the stability (or instability) of the clone is established.

●Patients with biallelic BRCA2 (FANCD1) mutations (and perhaps also those with FANCN mutations) present a special challenge, as they have a very high risk of MDS or AML, in addition to the risk of T cell malignancies, in the absence of BMF at an early age.

Some experts consider pre-emptive HCT in this setting to preclude the development of MDS or AML in childhood [34], but this should only be pursued after discussion with an expert in HCT for patients with FA.

SOLID TUMORS — 

As noted above, individuals with FA are at increased risk for a number of types of solid tumors, and this risk is likely to be increased in those who have undergone hematopoietic cell transplantation (HCT). (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Solid tumors'.)

Surveillance and prevention — We screen for the following, with referrals, as appropriate:

●Skin cancer – A full skin examination should be performed, and all concerning skin lesions should be evaluated by a dermatologist.

●Head and neck squamous cell carcinoma (HNSCC) – We advise patients with FA to avoid tobacco and alcohol since these are known risk factors for HNSCC. We also advise good oral hygiene and regular dental care, including a thorough examination of the oral cavity every six months, since poor oral hygiene is also a risk factor for HNSCC in patients with FA. In addition, all patients older than 10 years of age and patients under 10 years who have undergone HCT and have a history of graft-versus-host disease (GVHD) should have a laryngoscopic examination of the nasopharynx and oropharynx by an otolaryngologist at least annually.

Any lesions suspicious for oral leukoplakia should be evaluated by an oral surgeon. Patients with difficulty swallowing or similar complaints should undergo esophagoscopy.

●Liver tumors – Patients who are receiving androgen therapy or have received androgens in the past should be screened for liver tumors as outlined above. (See 'Androgens' above.)

●Gynecologic and anogenital cancer – Human papillomavirus (HPV) vaccination should be given to all patients prior to the onset of puberty.

We administer HPV vaccination to patients with FA, but we recognize that FA-associated squamous cell carcinoma (SCC) does not consistently demonstrate HPV based on DNA sequencing. FA-SCC instead appears to be driven by acquired TP53 loss-of-function mutations and structural cytogenetic changes [35]. HPV vaccine administration is discussed separately. (See "Human papillomavirus vaccination".)

Adolescent girls should have a visual examination of the external genitalia beginning at menarche and a comprehensive gynecologic evaluation, including a Pap test, once they become sexually active or by the age of 18 years, whichever comes first.

Routine anoscopy is indicated for patients with prior anogenital dysplasia due to an increased risk of anal SCC.

●Breast cancer – Breast self-examination should be performed monthly beginning in the early 20s, and routine physical examinations should include an evaluation for breast masses. Screening mammography may be initiated as early as age 25, particularly if self-examination or physician examination identifies any concerning lesions.

●Gastrointestinal cancer – Screening for gastrointestinal cancers by upper endoscopy and colonoscopy should begin around age 20 years.

Management with chemotherapy dose reductions — For patients with FA who develop a malignancy that requires chemotherapy and/or radiation therapy, treatment is complicated by the extreme sensitivity to genotoxic agents, especially radiation and alkylating agents, such as cyclophosphamide.

Dose reduction of these agents or switching to alternative regimens may be necessary depending on the type of tumor and stage of disease. Chemotherapy regimens to treat solid tumors should be discussed with experts in the management of patients with FA prior to their initiation. Additionally, patients who have not undergone HCT and are treated with intensive chemotherapy or radiation therapy for solid tumors are at high risk for developing therapy-related bone marrow failure, and discussion with a center with both FA and HCT expertise is indicated before chemotherapy is initiated.

ORGAN DYSFUNCTION — 

All patients with FA require regular follow-up with subspecialists to address issues related to endocrine, musculoskeletal, and other organ dysfunction (table 2). A number of specialists are likely to be involved; coordination among these individuals and support for the needs of the patient and family/caregiver should be a priority [1].

We perform the following evaluations for all patients with FA:

●Examination for anomalies and referral to an orthopedist if any radial ray/thumb or other musculoskeletal abnormalities are identified.

●Examination of the oral cavity by a dental health professional for leukoplakia or other concerning dysplasia, should begin as early as age 3. These exams should include the education of patients and families to perform effective parental or self-examination [36].

●An endocrine evaluation that includes the following:

•Regular screening for thyroid function.

•Pituitary magnetic resonance imaging (MRI; recommended in patients with evidence of significant endocrinopathy).

•Growth assessments, including height, weight, and thyroid function studies. If there is evidence of growth failure, testing for etiologies should include an assessment of growth hormone (GH) deficiency (eg, with IGF-1, IGBP3, bone age, GH stimulation testing).

•Adrenal function by ACTH (corticotropin) stimulation testing if there is evidence of other pituitary hormone deficiency.

•Metabolic testing for insulin resistance with fasting glucose and insulin levels, lipid profile, and HgbA1C. If these are abnormal, oral glucose tolerance testing may be appropriate.

•Gonadal function assessment using tanner staging, and, if abnormal for age, assessment of bone age, LH, FSH, estradiol, and/or testosterone. One retrospective study of patients of FA who have been through computed tomography suggests that inhibin B in males and anti-Mullerian hormone in females are the most predictive markers of testicular and ovarian failure [37]. (See "Delayed puberty: Approach to evaluation and management".)

•Bone health assessment using 25-OH vitamin D levels, with dual-energy x-ray absorptiometry (DXA) scanning for those with symptomatic osteopenia, including atypical fractures. (See "Overview of dual-energy x-ray absorptiometry".)

The involvement of a consulting endocrinologist with experience managing patients with FA is strongly encouraged. Insulin resistance, bone health disorders, and other endocrinopathies may be exacerbated by hematopoietic cell transplantation (HCT) and require close lifelong monitoring [38].

●Baseline evaluation of visual acuity and anatomic eye anomalies, and annual screening for all patients with known ophthalmologic issues and for those who have undergone HCT.

●Hearing test and/or formal audiogram. If screening is abnormal, assessment by an otolaryngologist for causes for conductive hearing loss (most common), auditory canal stenosis, or sensorineural hearing loss.

●Gynecologic examination for females and examination of males for hypospadias and cryptorchidism. Additional testing for reproductive function may be indicated in those trying to conceive a child.

●Baseline kidney ultrasound to evaluate for renal anomalies, with baseline serum electrolytes and creatinine. Referral to a urologist is indicated if urologic anomalies are identified (eg, undescended testes, hypospadias, hypogenitalism). Referral to a gynecologist for a routine examination is appropriate for postpubertal females.

●Liver function tests and bilirubin to assess for anatomic or functional abnormalities, including hepatitis. We emphasize a nutritional evaluation for patients with failure to thrive.

●Echocardiogram and electrocardiogram are useful if any VACTERL-H findings (see "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Congenital anomalies') or cardiac abnormalities are present on the physical examination. A yearly echocardiogram and electrocardiogram are appropriate for all patients who have undergone HCT.

TESTING OF SIBLINGS AND MANAGEMENT OF HETEROZYGOTES — 

Once a patient is diagnosed with FA, all first-degree siblings should be tested, as the phenotype is variable within families, and it is common to see more than one child with FA in a family. Additionally, since siblings are potential donors for hematopoietic cell transplantation (HCT), it is important to exclude siblings with FA as potential HCT donors. Testing for known familial mutations can also be pursued for other interested family members in addition to siblings.

Testing family members of an affected individual by genetic testing (if the familial mutation has been characterized) or by testing peripheral blood lymphocytes or fibroblasts for chromosomal breakage (if the mutation is not yet known), as described above. (See 'Allogeneic HCT' above.)

Testing of family members should be accompanied by counseling with a genetic counselor or clinician with expertise in FA and the management of heterozygotes. Counseling and testing of siblings should be done as soon as possible after proband diagnosis so that alternative donor strategies can be pursued if there are no unaffected siblings who are a human leukocyte antigen match.

Prenatal testing is possible using cells obtained by chorionic villus sampling, amniocentesis, or cordocentesis. In vitro fertilization with prenatal genetic testing, as discussed above, is another method utilized to detect disease or carrier status prior to implantation of sibling embryos. (See 'Allogeneic HCT' above.)

Prenatal screening for FANCC mutation in Ashkenazi Jews is discussed separately. (See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Fanconi anemia group C'.)

Carrier status for an FA mutation may have implications for reproductive decision-making. For most individuals who are heterozygous for an FA mutation, there may be a slightly increased risk of cancer, but the absolute risk appears to be relatively small, and there are no specific recommended screenings for individuals who are heterozygous carriers. Exceptions include the following:

●Individuals who are heterozygous for a mutation in FANCD1/BRCA2 or FANCS/BRCA1 have a high risk of developing breast and ovarian cancers. As a consequence, mothers of patients with either of these mutations should be referred to adult oncologists for discussions of high-risk screening and prevention strategies. Heterozygous siblings and fathers should also be offered genetic counseling and cancer screening as appropriate. The magnitudes of BRCA-associated cancer risks are discussed separately. (See "Cancer risks in BRCA1/2 carriers", section on 'Cancer risks in BRCA1/2 carriers'.)

●Males with a mutation in FANCB (which is X-linked recessive) and any patient with a mutation in FANCR (RAD51), which is autosomal dominant, are treated as affected individuals rather than carriers. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)

PROGNOSIS — 

Prior to the year 2000, the median survival of individuals with FA was 21 years of age. Since that time, there has been a dramatic improvement in survival for patients with FA who live in the developed world. This is largely due to fewer deaths from bleeding or infectious complications due to pancytopenia.

Bone marrow failure can often be cured, and myelodysplastic syndromes/neoplasms or acute myeloid leukemia can often be cured or prevented with hematopoietic cell transplantation in most patients [39-41]. However, as many more individuals are living well into adulthood, the cumulative incidence of solid tumors continues to rise, and new phenotypes (eg, neurologic or liver abnormalities) are emerging in adult patients with FA [42-44]. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Solid tumors'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

●Description – Fanconi anemia (FA) is an inherited bone marrow failure (BMF) syndrome characterized by pancytopenia and BMF, predisposition to malignancy, and characteristic but variable physical abnormalities (table 2).

●Management – Patients with FA are stratified according to the severity of BMF (table 1) and the presence of clonal hematopoietic neoplasms. Our approaches to management are consistent with Fanconi Anemia Guidelines for Diagnosis and Management. (See 'Monitoring bone marrow function' above.)

●Transplantation – Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for FA-associated BMF and associated myelodysplastic syndromes/neoplasms (MDS) and leukemias. All patients with evidence of BMF, high-risk MDS, or acute leukemia should be referred to a specialized center to discuss transplantation and initiate an evaluation of potential HCT donors. (See 'Allogeneic HCT' above.)

Additional information about HCT in children with FA is presented separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)

●Androgens – Androgen therapy may be appropriate for patients awaiting HCT or those who cannot undergo HCT. (See 'Androgens' above.)

●Supportive care – Transfusions and growth factor support may alleviate progressive BMF and associated complications. We favor a judicious approach, as extensive transfusions may be associated with worse outcomes with HCT, and extensive use of growth factors has been associated with increased risks of developing MDS and acute myeloid leukemia (AML) in other BMF syndromes. Directed donations from potential HCT donors should be avoided. (See 'Transfusions and growth factors' above.)

●Clonal hematopoiesis (CH) – CH is common in FA. The intensity of monitoring and specific testing for MDS and hematologic neoplasms are discussed above. (See 'Hematologic neoplasms' above.)

●Solid tumors – (See 'Solid tumors' above.)

•Surveillance/prevention – Individuals with FA are at increased risk for developing solid tumors. Routine cancer surveillance and preventive interventions (eg, human papillomavirus [HPV] vaccination) are listed above. (See 'Surveillance and prevention' above.)

•Management – Dose reductions or alternative regimens of chemotherapy and/or radiation therapy are needed for treatment of cancer in a patient with FA. Chemotherapy regimens should be discussed with experts in the management of patients with FA and HCT. (See 'Management with chemotherapy dose reductions' above.)

●Organ function – All patients with FA require regular follow-up with subspecialists to address endocrine, musculoskeletal, and other organ dysfunction. (See 'Organ dysfunction' above.)

●Siblings and relatives – All first-degree siblings of an affected patient should be tested for FA, accompanied by genetic counseling. (See 'Testing of siblings and management of heterozygotes' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Akiko Shimamura, MD, PhD; Alison Bertuch, MD, PhD; and Donald H Mahoney, Jr, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff acknowledges the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.