Management and Prognosis of Fanconi Anemia

20/11/23, 15:07 Management and prognosis of Fanconi anemia - UpToDate
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Management and prognosis of Fanconi anemia

AUTHOR: Timothy S Olson, MD, PhD
SECTION EDITOR: Peter Newburger, MD
DEPUTY EDITOR: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2023.

This topic last updated: Jun 08, 2022.
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".)
https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 1/23

● 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 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
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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.
Use of UpToDate is subject to the Terms of Use.
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13. Alter BP. Inherited Bone Marrow Failure Syndromes. In: Nathan and Oski's Hematology of I
nfancy and Childhood, Nathan DG, Orkin SH, Ginsburg D, Look AT (Eds), W.B. Saunders, Phil
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MDS in children. Br J Haematol 2011; 154:185.
32. Talbot A, Peffault de Latour R, Raffoux E, et al. Sequential treatment for allogeneic
hematopoietic stem cell transplantation in Fanconi anemia with acute myeloid leukemia.
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33. Peffault de Latour R, Soulier J. How I treat MDS and AML in Fanconi anemia. Blood 2016;
127:2971.
34. Khan NE, Rosenberg PS, Lehmann HP, Alter BP. Preemptive Bone Marrow Transplantation
for FANCD1/BRCA2. Biol Blood Marrow Transplant 2015; 21:1796.
35. Pivovar A, Furquim CP, Bonfim C, Torres-Pereira CC. Mouth examination performance by
children's parents and by adolescents in Fanconi anemia. Pediatr Blood Cancer 2017; 64.
36. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi
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Topic 109777 Version 21.0

GRAPHICS
Severity of bone marrow failure in patients with Fanconi anemia
Absolute neutrophil Hemoglobin

Platelet count
count concentration
(per microL)
(per microL) (g/dL)
Mild ≥1000 ≥50,000 ≥10
Moderate 500 to 1000 30,000 to <50,000 8 to 10
Severe <500 <30,000 <8
Refer to UpToDate for additional information regarding the severity of bone marrow failure and its
implications for treatment.
Adapted from Fanconi anemia: Guidelines for diagnosis and management, 3rd edition. Eiler ME, Frohnmayer D, Frohnmayer
L, et al, Eds, Eugene OR, 2008. Available at:
http://www.fanconi.org/images/uploads/other/Guidelines_for_Diagnosis_and_Management.pdf.
Graphic 57755 Version 7.0

Common clinical findings in Fanconi anemia
Frequency
Anomaly
(percent)
Any physical abnormality 60 to 75%
Skin – Generalized hyperpigmentation; hypopigmented areas; large freckles, 40 to 60%

café-au-lait spots
Short stature, delicate features 40 to 60%
Upper limbs – Absent or hypoplastic thumb, supernumerary, bifid, clinodactyly 35 to 50%
Gonads – Hypogenitalia, undescended/absent testes, hypospadias; bicornuate 25% (males)

or malpositioned uterus
<5% (females)
Head – Microcephaly or hydrocephaly; birdlike face, mid-face hypoplasia, 20 to 25%

Sprengel's deformity of neck
Eyes – Microphthalmia, ptosis, epicanthal folds, strabismus 20 to 40%
Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; 20 to 30%

hydronephrosis
Ears – Deafness (usually conductive); low set ears, abnormal shape, narrow 10 to 20%
canal
Developmental delay 10%
Cardiopulmonary anomalies – Congenital heart disease (patent ductus 6%

arteriosus, atrial or ventricular septal defects, coarctation, situs inversus)
Gastrointestinal anomalies – Atresias, imperforate anus, tracheoesophageal 5%

fistula, malrotation
Refer to UpToDate for details. These frequencies were derived from studies of patients with classic
presentations and may be an underestimate. Individuals with more subtle findings may be identified
from genetic sequencing.
FA: Fanconi anemia.
Adapted from:
1. Alter BP, Young NS. Bone marrow failure syndromes. In: Hematology of Infancy and Childhood, Nathan DG, Orkin SH
(Eds), WB Saunders, Philadelphia 1998. p.238.
2. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood
Reviews 2010; 24:101.
Graphic 71159 Version 6.0

Contributor Disclosures
Timothy S Olson, MD, PhD Consultant/Advisory Boards: Elixirgen Pharmaceuticals [Telomere biology
disorders]. All of the relevant financial relationships listed have been mitigated. Peter Newburger,
MD Consultant/Advisory Boards: X4 Pharmaceuticals [neutropenia therapy]. All of the relevant financial
relationships listed have been mitigated. Alan G Rosmarin, MD No relevant financial relationship(s) with
ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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20/11/23, 15:07 Management and prognosis of Fanconi anemia - UpToDate

Official reprint from UpToDate®

Literature review current through: Oct 2023.

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by

Management of patients with FA is challenging because hematopoietic stem cell transplantation

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 1/23

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

OVERVIEW OF MAJOR MANAGEMENT ISSUES

Major issues in managing FA include the following:

● Coordinating subspecialty follow-up for complications related to congenital anomalies,

BONE MARROW FAILURE

If there is a cytogenetic abnormality known to be associated with poor-risk MDS in the

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 3/23

Potential donor sources include:

incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 5/23

• Haploidentical HCT using a parent or other related donor is under investigation at

● Choice of androgen – Danazol is our preferred androgen for use in FA [15-18].

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 6/23

reported overall, 21 were hepatocellular carcinomas and 13 were adenomas. In the

A retrospective series of 70 patients treated with an androgen (mostly oxymetholone) from

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 7/23

However, increasing evidence supports a judicious approach, as extensive transfusions may be

● Platelets – Platelet transfusion is indicated in patients with platelet counts <10,000/microL

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 8/23

Therapies under development

● Metformin – In a mouse model of FA (FANCD2 gene knockout), metformin produced

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&us… 9/23

● Patients with morphologic features concerning for hematologic neoplasm, including

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● Breast cancer – Breast self-examination should be performed monthly beginning in the

IDENTIFICATION AND MANAGEMENT OF ORGAN DYSFUNCTION

We perform the following evaluations for all patients with FA:

● An oral cavity examination by a dental health professional for leukoplakia or other

● An endocrine evaluation that includes the following:

• Regular screening for thyroid function.

• Pituitary magnetic resonance imaging (MRI; recommended in patients with evidence of

Involvement of a consulting endocrinologist with experience in managing patients with FA

● Hearing test and/or formal audiogram. If screening is abnormal, assessment by an

TESTING OF SIBLINGS AND MANAGEMENT OF HETEROZYGOTES

Testing of family members should be accompanied by counseling with a genetic counselor or

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&u… 14/23

● Individuals who are heterozygous for a mutation in FANCD1/BRCA2 or FANCS/BRCA1 have a

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

increased risk for malignancies.

● Transplantation – Allogeneic hematopoietic cell transplantation (HCT) is the only curative

Additional information about HCT in children with FA is presented separately. (See

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

• Surveillance/prevention – Individuals with FA are at increased risk for developing solid

• Management – Dose reductions or alternative regimens of chemotherapy and/or

Use of UpToDate is subject to the Terms of Use.

https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&u… 17/23

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https://www.uptodate.com/contents/management-and-prognosis-of-fanconi-anemia/print?search=anemia de fanconi&source=search_result&selectedTitle=2~79&u… 20/23

Severity of bone marrow failure in patients with Fanconi anemia

Absolute neutrophil Hemoglobin

Mild ≥1000 ≥50,000 ≥10

Moderate 500 to 1000 30,000 to <50,000 8 to 10