Management and prognosis of Fanconi anemia

INTRODUCTION — Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by pancytopenia, predisposition to malignancy, and physical abnormalities including short stature, microcephaly, developmental delay, café-au-lait skin lesions, and malformations belonging to the VACTERL-H association. Diagnosis is usually made in childhood, although diagnostic delays and variable disease manifestations are common, and some individuals may be diagnosed with FA in adulthood.

Management of patients with FA is challenging because hematopoietic stem cell transplantation (HCT) is curative for bone marrow failure and hematologic neoplasms but not for the non-hematologic features. Patients also require increased surveillance for both hematologic and non-hematologic malignancies, and reduced-intensity therapy is typically used for HCT and cancer treatment.

This topic review discusses the management and prognosis of FA. The clinical manifestations and diagnosis of FA is discussed in detail separately. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

Separate topic reviews discuss the diagnosis and management of other inherited bone marrow failure syndromes:

●Dyskeratosis congenita (DC) – (See "Dyskeratosis congenita and other telomere biology disorders".)

●Shwachman-Diamond syndrome (SDS) – (See "Shwachman-Diamond syndrome".)

OVERVIEW OF MAJOR MANAGEMENT ISSUES — 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 non-hematologic 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 'Identification and management of organ dysfunction' below.)

We also screen siblings in order 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.)

Our approach discussed in the following sections is consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Management, published through the FA Research Fund [1].

BONE MARROW FAILURE — Allogeneic hematopoietic stem cell transplantation (HCT) is the only established curative therapy for bone marrow failure (and for myelodysplastic syndrome [MDS] and acute leukemia) in patients with FA. HCT outcomes in patients with FA have improved dramatically since 2000, a trend made possible by the development of FA-specific reduced intensity approaches to conditioning and improvements in the understanding of supportive care needs for these patients. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)

We refer all patients with FA who have evidence of bone marrow failure to a specialized HCT center to discuss the risks and benefits of HCT and to initiate evaluation of potential HCT donors. It may also be appropriate to refer individuals with FA who do not have bone marrow failure to an HCT center to discuss these issues. However, we do not advocate performing HCT in individuals with adequate bone marrow function, with the rationale that some individuals with FA, including those with mild cytopenias, will not develop bone marrow failure. Additionally, HCT prior to the onset of bone marrow failure may require increased conditioning intensity and thus carries risks of increased toxicity. (See 'Allogeneic HCT' below.)

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

●For those with mild bone marrow failure, defined as an absolute neutrophil count (ANC) between 1000 and 1500/microL, platelet count between 50,000 and 150,000/microL, and hemoglobin (Hb) ≥10 g/dL, we monitor the complete blood count (CBC) with differential every three to four months as long as the blood counts remain stable, and we perform a bone marrow examination with cytogenetics annually.

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

●For those with moderate bone marrow failure (ANC between 500 and 1000/microL, platelet count between 30,000 and 50,000/microL, Hb between 8 and 10 g/dL) whose counts continue to decline, we initiate HCT planning with an HLA-matched related donor (first choice) or closely matched unrelated donor. (See 'Allogeneic HCT' below.)

Androgen therapy may be a reasonable 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. (See 'Androgens' below.)

Alternatively, if the 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 there is a cytogenetic abnormality known to be associated with poor-risk MDS in the absence of other MDS-defining features, the CBC and bone marrow should be monitored more frequently (eg, CBC every one to two months; bone marrow every one to six months), and the best-available donor HCT should be pursued. (See 'Allogeneic HCT' below.)

●For those with severe bone marrow failure (ANC ≤500/microL, platelet count ≤30,000/microL, Hb <8 g/dL), and/or transfusion dependence, we pursue HCT with the best available donor. An HLA-matched sibling who has been determined not to have FA is preferable, with the second choice being a closely matched unrelated donor. If neither of these options are available, a trial of androgen therapy may be attempted while (or prior to) pursuing other alternative donors such as cord blood or haploidentical HCT, with attempts to limit transfusion exposure and opportunistic infections during the androgen trial. For individuals who do not have access to HCT for whatever reason (eg, medically ineligible, lack of donor, cost), androgen therapy or investigational approaches such as gene therapy may be used. (See 'Androgens' below and 'Therapies under development' below.)

This monitoring schedule and management approach is consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Management from the Fanconi Anemia Research Fund [1].

Of note, immunosuppressive therapy (IST), which is used frequently in patients with acquired aplastic anemia, has no role in the treatment of FA because the disease is not immune-mediated.

Allogeneic HCT — Allogeneic HCT is the only established curative therapy for patients with FA and severe bone marrow failure, transfusion-dependent anemia or thrombocytopenia, MDS, or AML [2]. We urgently refer these patients for HCT. The preferred approach is to use bone marrow (rather than peripheral blood stem cells) from an eligible sibling who is HLA-matched at 8 of 8 alleles of the four most commonly tested HLA genes (HLA -A, -B, -C, and DRB1) or a closely matched unrelated donor.

HCT is curative for bone marrow failure and potentially for hematopoietic neoplasms, but 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 (see "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Solid tumors'). Additionally, insulin resistance, bone health disorders, and other endocrinopathies may be worsened by HCT, and require close lifelong monitoring [3]. (See 'Identification and management of organ dysfunction' below.)

Potential donor sources include:

●Related donors – It is critical that all potential sibling or other related donors 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 apparently asymptomatic and healthy may have FA, but lack classic findings due to mosaicism, incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease manifestations. For potential related donors who have nonhematologic features of FA, but in whom chromosomal breakage testing performed on a blood sample is normal, chromosomal breakage testing should be performed on a fibroblast sample to exclude the possibility of testing a hematologic revertant. HCT performed with a family donor who also turns out to have FA, even if mosaic and/or asymptomatic, would carry a very high risk of graft failure. On the other hand, siblings who are only carriers of one heterozygous mutation in an autosomal recessive FA-associated gene are eligible as donors.

●Unrelated donors – Although unrelated donor HCT carries a substantial risk of long-term toxicity, we consider it preferable to delaying HCT while attempting to use non-curative supportive care to increasing blood counts. Individuals with FA are at risk for significant toxicity from standard chemotherapy doses used for HCT conditioning. Strategies developed at the University of Minnesota and other centers that incorporate reduced doses of cyclophosphamide (20 to 60 mg/kg total dose; representing 50 to 90 percent reduction compared with conventional cyclophosphamide conditioning doses), in combination with immunosuppressive but otherwise low-toxicity agents such as fludarabine and antithymocyte globulin, have been extremely effective in matched sibling donor HCT for FA. Rates of engraftment associated with these approaches are >90 percent, and overall post-HCT survival by five years is >94 percent in most series reported since 2005 [4,5]. Matching with high-resolution HLA genotyping, T cell depletion, and conditioning regimens with lower toxicity have also improved outcomes from unrelated donors. Issues related to HCT are discussed in more detail separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)

●For patients with FA who lack a closely matched related or unrelated donor, if the parents are interested in having additional children, in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) can be considered. This approach can ensure that future children will not have FA and also select for an HLA-matched sibling that can be used as a future donor. While not always effective and associated with challenging ethical, emotional, and financial dimensions, this approach has facilitated successful matched sibling donor HCT [6]. This approach is not optimal for individuals 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. (See "Preimplantation genetic testing", section on 'Potential candidates for PGT-M'.)

●We consider use of an alternative donor source only in the context of a clinical trial. Examples include:

•Umbilical cord blood (UCB) HCT appears to be less effective than matched unrelated donor bone marrow for patients with FA. In a series of 93 patients with FA who underwent UCB HCT, overall survival was 40 percent [7]. Another report of alternative donor HCT at the University of Minnesota (1995 and 2012) showed an increased risk of neutrophil and platelet engraftment failure and severe GVHD, and a trend toward increased risk of mortality in 31 recipients of UCB HCT compared to 73 patients receiving HLA-matched, T cell-depleted unrelated donor bone marrow transplant [8]. Use of UCB units with higher stem cell doses and incorporation of fludarabine into conditioning regimens may improve outcomes in the future.

•Haploidentical HCT using a parent or other related donor is under investigation at several centers. This approach shows promise, although outcomes are not as good as those seen with closely matched unrelated donors [9-12].

Pre-transplant evaluation, donor selection, conditioning regimen, optimal 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'.)

Androgens — Androgen therapy is not curative, but it may be appropriate for patients who lack a closely matched related donor for HCT, or for those for whom HCT is not pursued due to family/caregiver preference or medical eligibility [13,14]. Androgen therapy is also increasingly used to support blood counts for a period of weeks to months while parents attempt IVF with PGD and until the resulting HLA-matched donor is able to donate.

●Choice of androgen – Danazol is our preferred androgen for use in FA [15-18]. 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 side effects of androgens in patients with FA involve the liver, and include 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 [16]. Of 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) [19]. Given these concerning risks, patients receiving androgen therapy should have liver chemistry profiles monitored every one to two months, with liver ultrasounds performed every 6 to 12 months.

●Efficacy – Approximately one-half of patients with FA will respond to androgen therapy [20].

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 bone marrow failure (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 [21,22]. 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 a trilinear responses (ie, improvements in Hb, white blood cell [WBC] count, and platelet count) [19]. 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, all of whom underwent subsequent HCT. Overall survival 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 a similar efficacy between the two androgens, with fewer and less severe side effects experienced with danazol, particularly less virilization and lower growth disturbance [18]. 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 [17]. Oxandrolone and oxymetholone are no longer available.

Transfusions and growth factors — Transfusion and growth factor support may be necessary 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 granulocyte colony-stimulating factor (G-CSF) and thrombopoietin mimetics in patients with other bone marrow failure syndromes have been associated with increased risks of developing MDS and AML.

●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) [23]. 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 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.

●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 concerns it might increase the risk of MDS or AML in patients with bone marrow failure syndromes [24-27].

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.

Importantly, patients with neutropenia and fever should be evaluated urgently, cultures obtained, and broad-spectrum antibiotics administered until the fever resolves or cultures are negative, to reduce the risk of life-threatening infections. 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 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 [28,29].

●Metformin – In a mouse model of FA (FANCD2 gene knockout), metformin produced modest increases in WBC counts, Hb levels, and platelet counts [30]. There was also reduced p53-dependent tumor formation and a suggestion of decreased susceptibility to DNA damage. Metformin is now being evaluated in a pilot study for patients with FA (ClinicalTrials.gov identifier: NCT03398824).

HEMATOLOGIC NEOPLASMS — Clonal hematopoiesis is quite 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 also should 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 syndrome (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 on a bone marrow performed prior to the diagnosis of FA, we repeat the bone marrow 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 for hematologic neoplasm, including multilineage dysplasia and/or excess blasts, or those with poor-risk cytogenetic features (eg, -7, +3q) even in the absence of dysmorphology, should be referred for urgent 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 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 acute myeloid leukemia (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 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 pre-transplant 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, dysplasia, or acute leukemia, we monitor the complete blood count (CBC) closely (eg, once per month) and repeat the bone marrow 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 these patients have a very high risk of presenting early in childhood with MDS or AML in the absence of bone marrow failure. A 2015 study using a theoretical survival analysis approach suggested that some patients with biallelic BRCA2 mutations might benefit from pre-emptive HCT because of the nearly 80 percent actuarial risk of leukemia by 10 years of age [34].

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 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 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.)

●Gynecological and anogenital cancer – Human papilloma virus (HPV) vaccination should be given to all patients prior to the onset of puberty. Information on HPV vaccine administration is presented in detail 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 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 increased risk of anal squamous cell carcinoma.

●Breast cancer – Breast self-examination should be performed monthly beginning in the early 20s, and routine physical examinations should include 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 – Stomach and colon cancers are not common in FA; however, any patient with FA who has abnormal upper or lower gastrointestinal bleeding, discomfort, pain, or other attributable symptom that is not explained by other evaluations should undergo upper and/or lower endoscopic evaluation.

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 who 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.

IDENTIFICATION AND MANAGEMENT OF 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.

●An oral cavity examination by a dental health professional for leukoplakia or other concerning dysplasia. These exams should include education of patients and families to perform effect parental or self-examination [35].

●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, thyroid function studies. If there is evidence of growth failure, testing for etiologies should include assessment of growth hormone (GH) deficiency (eg, with IGF-1, IGBP3, bone age, GH stimulation testing).

•Adrenal function by ACTH 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. (See "Approach to the patient with delayed puberty".)

•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".)

Involvement of a consulting endocrinologist with experience in managing patients with FA is strongly encouraged.

●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 hematopoietic cell transplantation (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 renal 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 gynecologist for a routine examination is appropriate for post-pubertal 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 physical examination. 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, if the mutation is not yet known, by testing peripheral blood lymphocytes or fibroblasts for chromosomal breakage, 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 an HLA match.

Prenatal testing is possible using cells obtained by chorionic villus sampling, amniocentesis, or cordocentesis. In vitro fertilization with PGD 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 slight 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 and management of BRCA1/2 carriers without cancer", 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. In large part this is due to a reduction in deaths due to bleeding or infectious complications that arise in the setting of pancytopenia. Bone marrow failure can often be cured, and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) can often be cured or prevented with hematopoietic cell transplantation in most patients [36-38]. However, as many more individuals are living well into adulthood, the cumulative incidence of solid tumors continues to rise, a phenomenon that may limit life expectancy until new approaches to treatment for these tumors are developed. (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

●Fanconi anemia (FA) – Patients with FA can have highly variable clinical manifestations, including characteristic physical abnormalities (table 2), bone marrow disorders, and increased risk for malignancies.

●Bone marrow failure (BMF) – Patients with FA are stratified according to the severity of BMF (table 1) and the presence or absence of clonal hematopoietic neoplasms. Our approaches to management are consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Management, published through the FA Research Fund. (See 'Monitoring bone marrow function' above.)

●Transplantation – Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for FA-associated BMF, myelodysplastic syndromes (MDS), and leukemia. All patients with evidence of BMF, high-risk MDS, or acute leukemia should be referred to a specialized center to discuss transplantation and initiate 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 have been associated with increased risks of developing MDS and 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 papilloma virus [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 'Identification and management of 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.