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Fanconi Anemia

Synonym: Fanconi Pancytopenia

, MD and , MD, MPH.

Author Information

Initial Posting: ; Last Update: June 3, 2021.

Estimated reading time: 48 minutes

Summary

Clinical characteristics.

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.

Diagnosis/testing.

The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) and/or one of the following identified on molecular genetic testing: biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA; a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA; or a hemizygous pathogenic variant in FANCB known to cause X-linked FA.

Management.

Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA; granulocyte colony-stimulating factor improves the neutrophil count in some individuals; hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, but the high risk for solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity. early detection and surgical removal remains the mainstay of therapy for solid tumors. Treatment of growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic manifestations as recommended by the subspecialty care provider. Hearing aids may be helpful for hearing loss as per otolaryngologist; supplemental feeding as needed by nasogastric tube or gastrostomy; vitamin D supplementation; early intervention for developmental delays; individualized education plan for school-age children; speech, occupational, and physical therapy as needed; liberal use of sunscreen and rash guards; social work and care coordination as needed.

Prevention of primary manifestations: Human papilloma virus (HPV) vaccination to reduce the risk for gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.

Prevention of secondary complications: T-cell depletion of the donor graft to minimize the risk of graft-vs-host disease; conditioning regimen without radiation prior to HSCT to reduce the subsequent risk of developing solid tumors.

Surveillance: Clinical assessment of growth, feeding, nutrition, spine, and ocular issues at each visit throughout childhood. Annual ophthalmology examination; annual evaluation with endocrinologist including TSH, free T4, 25-hydroxy vitamin D, two-hour glucose tolerance testing, and insulin levels; assessment of pubertal stage and hormone levels at puberty and every two years until puberty is complete; follow up hearing evaluation if exposed to ototoxic drugs; annual developmental assessment; blood counts every three to four months or as needed; bone marrow aspirate and biopsy to evaluate morphology and cellularity, FISH and cytogenetics to evaluate for emergence of a malignant clone at least annually after age two years; liver function tests every three to six months and liver ultrasound examination every six to twelve months in those receiving androgen therapy; gynecologic assessment for genital lesions annually beginning at age 13 years; vulvo-vaginal examinations and Pap smear annually beginning at age 18 years; oral examinations for tumors every six months beginning at age nine to ten years; annual nasolaryngoscopy beginning at age ten years; dermatology evaluation every six to 12 months; annual abdominal ultrasound and brain MRI in those with BRCA2-related FA. Additional cancer surveillance for individuals with BRCA1-, BRCA2-, PALB2-, BRIP1-, and RAD51C-related FA.

Agents/circumstances to avoid: Transfusions of red cells or platelets for persons who are candidates for HSCT; family members as blood donors if HSCT is being considered; blood products that are not filtered (leukodepleted) or irradiated; toxic agents that have been implicated in tumorigenesis; unsafe sex practices, which increase the risk of HPV-associated malignancy; excessive sun exposure. Radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications) should be minimized.

Evaluation of relatives at risk: DEB/MMC testing or molecular genetic testing (if the family-specific pathogenic variants are known) of all sibs of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers.

Genetic counseling.

Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).

Autosomal recessive FA: Each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants. Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous mutation of a subset of FA-related genes (e.g., BRCA1, BRCA2, PALB2, BRIP1, and RAD51C) is associated with an increased risk for breast and other cancers.

Autosomal dominant FA: Given that all affected individuals with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low.

X-linked FA: For carrier females the chance of transmitting the pathogenic variant in each pregnancy is 50%; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected.

Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.

Diagnosis

Recommendations for diagnosis were agreed upon at a 2013 consensus conference (see Fanconi Anemia Clinical Care Guidelines, 2020 edition).

Suggestive Findings

Fanconi anemia (FA) should be suspected in individuals with the following clinical and laboratory features.

Physical features (in ~75% of affected persons)

  • Prenatal and/or postnatal short stature
  • Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
  • Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
  • Microcephaly
  • Ophthalmic anomalies
  • Genitourinary tract anomalies

Laboratory findings

  • Macrocytosis
  • Increased fetal hemoglobin (often precedes anemia)
  • Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)

Pathology findings

  • Progressive bone marrow failure
  • Adult-onset aplastic anemia
  • Myelodysplastic syndrome (MDS)
  • Acute myelogenous leukemia (AML)
  • Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; liver tumors)
  • Inordinate toxicities from chemotherapy or radiation

Establishing the Diagnosis

The diagnosis of FA is established in a proband with either of the following:

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of FANCA can be performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes the genes in Table 1 and other genes of interest (see Differential Diagnosis) may be considered next if single-gene testing does not identify a FANCA pathogenic variant. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of Fanconi anemia. Such testing may provide or suggest a diagnosis not previously considered (e.g., pathogenic variant[s] in a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Fanconi Anemia

Gene 1, 2Comple-mentation Group 3% of FA Attributed to Pathogenic Variants in Gene 4Proportion of Pathogenic Variants 5 Detected by Method
Sequence analysis 6Gene-targeted deletion/duplication analysis 7
BRCA1 FA-S<1%>99%None reported
BRCA2 FA-D12%>99%None reported
BRIP1 FA-J2%>99%None reported
ERCC4 FA-Q<1%>99%None reported
FANCA FA-A60%-70%~60%~40%
FANCB FA-B2%~70%~30%
FANCC FA-C14%>90%<10%
FANCD2 FA-D23%<90%>10%
FANCE FA-E3%>99%None reported
FANCF FA-F2%~85%~15%
FANCG (XRCC9)FA-G10%>99%None reported
FANCI FA-I1%>95%<5%
FANCL FA-L<1%>90%<10%
FANCM FA-M<1%~75%1 reported
FAAP100 FA-Y1 individual 8>99%None reported
PALB2 FA-N<1%>95%1 reported
RAD51 FA-R2 reported>99%None reported
RAD51C FA-O<1%>99%None reported
REV7 (MAD2L2) FA-V1 reported>99%None reported
RFWD3 FA-W1 reported>99%None reported
SLX4 FA-P<1%>90%1 reported
UBE2T FA-T<1%<50%>50%
XRCC2 FA-U1 reported>99%None reported
UnknownNA<5%
1.

Genes are listed in alphabetic order.

2.
3.

Prior to identification of the genes, complementation groups were defined based on somatic cell-based methods. While complementation analysis testing has been supplanted by multigene panels; this terminology continues to be used in some contexts.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

See Molecular Genetics for information on pathogenic variants detected in these genes.

6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

Author, personal communication

Clinical Characteristics

Clinical Description

The primary clinical features of Fanconi anemia (FA) include physical features, progressive bone marrow failure manifest as pancytopenia, and cancer susceptibility; however, some individuals with FA have neither physical abnormalities nor bone marrow failure.

Physical Findings

Physical features occur in approximately 75% of individuals with FA.

  • Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
  • Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
  • Skeletal malformations of upper limbs, unilateral or bilateral (35%):
    • Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
    • Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
    • Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
    • Ulnae (1%). Dysplastic, short
  • Skeletal malformations of lower limbs (5%):
    • Syndactyly, abnormal toes, club feet
    • Congenital hip dislocation
  • Microcephaly (20%)
  • Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
  • Genitourinary tract anomalies:
    • Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
    • Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
    • Females (2%). Bicornuate or uterus malposition, small ovaries
      Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
  • Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [Petryk et al 2015]
  • Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
  • Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
  • Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
  • Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
  • Other:
    • Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
    • Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
    • Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline

Note: Percentages are calculated from 2,000 individuals reported in the literature from 1927 to 2014. Frequencies are approximate, since many reports did not mention physical descriptions.

Developmental Delay / Intellectual Disability

Developmental delay and/or intellectual disability is seen in 10%.

Bone Marrow Failure

The age of onset of bone marrow failure is highly variable, even among sibs. An analysis of 754 individuals with pathogenic variants in FANCA, FANCC, and FANCG identified an average age of onset of 7.6 years. Rarely, bone marrow failure can present in infants and small children [Shimamura & Alter 2010]. The risk of developing any hematologic abnormality is 90% by age 40 years [Kutler et al 2003].

  • Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
  • Pancytopenia generally worsens over time.
  • Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [Giulino et al 2011].
  • The severity of bone marrow failure can be classified by the degree of cytopenia(s) (Table 2). Importantly, to meet these criteria for marrow failure, the cytopenias must be persistent and unexplained by other causes.

Table 2.

Severity of Bone Marrow Failure in Fanconi Anemia

MildModerateSevere
Absolute neutrophil count (ANC) <1,500/mm3<1,000/mm3<500/mm3
Platelet count 150,000-50,000/mm3<50,000/mm3<30,000/mm3
Hemoglobin (Hb) level ≥8 g/dL<8 g/dL<8 g/dL

Cancer Susceptibility

Acute myelogenous leukemia(AML). The relative risk for AML is increased approximately 500-fold [Rosenberg et al 2008, Alter et al 2010, Tamary et al 2010]. In a competing risk analysis of the combined cohorts, the cumulative incidence of AML was 13% by age 50 years, with most individuals diagnosed between ages 15 and 35 years.

An increased risk of developing myelodysplastic syndrome (MDS)/AML is associated with monosomy 7 and most 7q deletions. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS/AML [Neitzel et al 2007, Mehta et al 2010].

Solid tumors may be the first manifestation of FA in individuals who have no birth defects and have not experienced bone marrow failure.

  • Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
    • Occur at an earlier age (20-40 years) than in the general population;
    • Most commonly occur in the oral cavity (e.g., tongue);
    • Present at an advanced stage;
    • Respond poorly to therapy.
  • Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [Morris et al 2011].
  • Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.

Phenotype Correlations by Gene

BRCA2. Biallelic pathogenic variants in BRCA2 are associated with early-onset acute leukemia and solid tumors [Hirsch et al 2004, Wagner et al 2004, Myers et al 2012]. The cumulative probability of any malignancy was 97% by age six years, including AML, medulloblastoma, and Wilms tumor [Alter et al 2007].

FANCB. More recently FANCB pathogenic variants are shown to predominantly cause early-onset bone marrow failure and severe congenital abnormalities. Biochemical and cell-based assays of causative variants reveal functional properties of FANCB that are associated with clinical severity [Jung et al 2020].

FANCG. Pathogenic variants in FANCG may be associated with severe marrow failure and a higher incidence of leukemia than FANCC [Faivre et al 2000].

PALB2. Solid tumors (e.g., medulloblastoma, Wilms tumor) are associated with PALB2 pathogenic variants [Reid et al 2007].

Genotype-Phenotype Correlations

The clinical spectrum of FA remains heterogenous. There are no clear-cut genotype-phenotype correlations. In general, null variants lead to a more severe phenotype (e.g., congenital anomalies, early-onset bone marrow failure, and MDS/AML) than hypomorphic variants. A literature review of genotype-phenotype associations in Fanconi anemia was recently published [Fiesco-Roa et al 2019].

BRCA2. All persons with an IVS7 pathogenic variant in BRCA2 developed AML by age three years; those with other BRCA2 pathogenic variants who developed AML did so by age six years [Alter 2006].

FANCA. Conflicting reports have associated [Faivre et al 2000] and refuted association [Castella et al 2011] of homozygous FANCA null pathogenic variants with earlier-onset anemia and higher incidence of leukemia than individuals with pathogenic variants that permit production of an abnormal FANCA protein. Other FANCA variants (p.His913Pro, p.Arg951Gln, p.Arg951Trp) have been associated with slower hematologic disease progression [Bottega et al 2018].

FANCB. Truncating variants often present with VACTERL-H [McCauley et al 2011].

FANCC

Prevalence

Fanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.

The ratio of males to females is 1.2:1 (p<0.001 vs expected 1.00).

Rosenberg et al [2011] showed higher carrier rates for FA than previously reported. Carrier frequency was 1:181 in North Americans and 1:93 in Israel. Specific populations have founder variants with increased carrier frequencies (<1:100), including Ashkenazi Jews (FANCC, BRCA2), northern Europeans (FANCC), Afrikaners (FANCA), sub-Saharan Blacks (FANCG), Spanish Gypsies (FANCA), and others.

Differential Diagnosis

Cells derived from individuals with other chromosome breakage syndromes may also exhibit high rates of spontaneous chromosome breakage; however, only cells derived from individuals with Fanconi anemia (FA) exhibit increased chromosome breakage in response to diepoxybutane (DEB). See Table 4 for selected examples of chromosome breakage syndromes and for other disorders to consider in the differential diagnosis of FA.

Table 4.

Genes and Disorders of Interest in the Differential Diagnosis of Fanconi Anemia

Gene(s)DisorderMOIChromosome BreakageClinical Characteristics
ATM Ataxia-telangiectasia (A-T)ARCells derived from persons w/A-T may exhibit high rates of spontaneous chromosome breakage.Progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, frequent infections, ↑ risk for malignancy, hypersensitivity to ionizing radiation
ATR
CENPJ
CEP152
CEP63
DNA2
NIN
NSMCE2
RBBP8
TRAIP
Seckel syndrome (OMIM PS210600)ARMay show ↑ chromosome breakage w/DNA cross-linking agents 1 (MMC, DEB)Growth deficiency, microcephaly w/ID, characteristic facial appearance; may be assoc w/pancytopenia &/or AML
BLM Bloom syndrome (BSyn)ARCells derived from persons w/BSyn may exhibit high rates of spontaneous chromosome breakage.Severe pre- & postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, high risk for many cancers that occur at an early age
NBN Nijmegen breakage syndrome ARMay manifest ↑ chromosome breakage w/MMCShort stature, progressive microcephaly w/loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, ↑ risk for cancer (esp lymphoma)
NF1 Neurofibromatosis 1 ADNot assoc w/↑ chromosome breakageMultiple café au lait spots, axillary & inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling
RBM8A 2 Thrombocytopenia absent radius syndrome ARNot assoc w/chromosome breakageBilateral absence of the radii w/presence of both thumbs & thrombocytopenia that is generally transient

AD = autosomal dominant; AR = autosomal recessive; DEB = diepoxybutane; FA = Fanconi anemia; ID = intellectual disability; MMC = mitomycin C; MOI = mode of inheritance

1.
2.

The diagnosis of thrombocytopenia absent radius syndrome is confirmed by identification of a null heterozygous allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1, but in some cases a heterozygous RBM8A pathogenic variant detected by molecular genetic testing) in trans with a heterozygous RBM8A hypomorphic allele.

VACTERL association (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial or renal dysplasia; OMIM 192350) can also be considered in the differential diagnosis. VACTERL association can be distinguished from FA by testing for chromosome breakage with DEB and MMC. The molecular cause of VACTERL association is unknown.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and management requirements in an individual diagnosed with Fanconi anemia (FA), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended (See also 2020 consensus guidelines [full text]).

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Fanconi Anemia

System/ConcernEvaluationComment
Growth Growth assessment; exam by endocrinologistAdditional studies (growth hormone levels, bone age radiographs) as recommended by endocrinologist
Musculoskeletal Clinical assessment for limb anomalies, hip dislocation, neck/spine anomalies & scoliosisReferral to orthopedic surgeon as indicated
Eyes Exam by ophthalmologist
Genitourinary Ultrasound exam of kidneys & urinary tractReferral to nephrologist, gynecologist &/or urologist as indicated
Endocrine Exam by endocrinologist; thyroid function tests; brain MRI for pituitary abnormalitiesAdditional studies (glucose tolerance testing, lipids, pituitary & gonadal function testing) as recommended by endocrinologist
Hearing Formal hearing evalReferral to otolaryngologist as indicated
Cardiac/
Vascular
Echocardiogram; brain MRI & angiography for moya moya syndromeReferral to cardiologist as indicated
Gastrointestinal
  • Urgent eval w/gastroenterologist & surgery for those w/obstructive GI malformations (e.g., esophageal atresia, duodenal atresia, or imperforate or bifurcated anus) &/or tracheoesophageal fistula, intestinal malrotation, or annular pancreas
  • Nutrition/feeding eval as needed
Referral to gastroenterologist, dietician, & surgeon as indicated
Development Developmental assessment (esp important for toddlers & school-age children)Referral to neuropsychologist or developmental/behavioral pediatrician as indicated
Hematology/
Oncology
Eval by hematologist incl complete blood count, fetal hemoglobin, full blood typing, blood chemistries (assessing liver, kidney, & iron status), & bone marrow aspirate for cell morphology, FISH & cytogenetics, & biopsy for cellularityThe bone marrow of those w/FA can exhibit signs of dysplasia, e.g., nuclear/cytoplasmic dys-synchrony, hypo-lobulated megakaryocytes, & bi-nucleated erythroid cells. These features must be distinguished from true forms of MDS by a hematopathologist experienced in eval of MDS in those w/FA.
HLA typing of the affected person, sibs, & parents for consideration of hematopoietic stem cell transplantation
Genetic
counseling
By genetics professionals 1To inform patients & families re nature, MOI, & implications of FA in order to facilitate medical & personal decision making
Family support
& resources
Assess:

FA = Fanconi anemia; GI = gastrointestinal; HLA = human leukocyte antigen; MOI = mode of inheritance; MDS = myelodysplastic syndrome

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Recommendations for treatment were agreed upon at a 2014 consensus conference and updated in 2020 (full text).

Table 6.

Treatment of Manifestations in Individuals with Fanconi Anemia

Manifestation/ConcernTreatmentConsiderations/Other
Growth deficiency Treatment per endocrinologist
Limb anomalies &
other orthopedic
manifestations
  • Mgmt per orthopedic surgeon
  • PT, OT
Ocular anomalies Mgmt per ophthalmologist
Renal malformations Mgmt per nephrologist &/or urologist
Genital anomalies Mgmt per gynecologist or urologist
Hypothyroidism Treatment per endocrinologist
Hearing loss Hearing aids may be helpful; per otolaryngologist.Community hearing services through early intervention or school district
Cardiac anomalies Treatment per cardiologist & surgery
Nutrition
  • Supplemental feeding as needed by nasogastric tube or gastrostomy
  • Vitamin D supplementation
Low threshold for clinical feeding eval if clinical signs or symptoms of dysphagia
Development Early intervention for DDs; individualized education plan for school-age children; therapies (speech, OT, PT) as needed
Dermatologic
manifestations
  • Liberal use of sunscreen & rash guards
  • Treatment per dermatologist
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

DD = developmental delay; OT = occupational therapy; PT = physical therapy

Androgens improve (at least transiently) the red cell and platelet counts in approximately 50% of individuals. Androgen therapy can be considered when the hemoglobin drops below 8 g/dL or the platelet count falls below 30,000/mm3 ("severe" – see Table 2). Oxymetholone therapy suppresses osteopontin transcription and induces hematopoietic stem cell cycling in Fanconi mice suggesting downregulation of osteopontin as an important potential mechanism for the drug's action [Zhang et al 2015]. Although only 10%-20% of individuals receiving continuous low-dose androgen therapy are long-term responders, this option can be particularly useful for individuals who do not have access to or are not ready for hematopoietic stem cell transplant (HSCT), or to individuals for whom of a suitable donor is not available.

  • Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
  • Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
  • Other synthetic androgens used in FA include stanozolol in Asia, and oxandrolone and danazol in North America.

Side effects of androgen administration include virilization and liver toxicity (e.g., elevated liver enzymes, cholestasis, peliosis hepatis [vascular lesion with multiple blood-filled cysts], and hepatic tumors). Individuals taking androgens should be monitored for liver tumors and undergo regular liver function tests (LFTs) for abnormalities. Blood tests for LFTs should be performed every three to six months; liver ultrasound should be performed every six to twelve months. If no response is seen after three to four months, androgens should be discontinued [Scheckenbach et al 2012, Rose et al 2014, Paustian et al 2016].

Granulocyte colony-stimulating factor(G-CSF) improves the neutrophil count in some individuals. G-CSF dose should be titrated to the lowest possible dose and frequency to keep ANC above 1,000/mm3. Note: (1) A bone marrow aspirate and biopsy should be performed prior to the initiation of G-CSF and monitored every six months throughout treatment, given the theoretic risk of stimulating the growth of a leukemic clone. (2) G-CSF should be administered in consultation with an FA expert.

HSCT is the only curative therapy for the hematologic manifestations, including aplastic anemia, myelodysplastic syndrome, and acute leukemia. Ideally, HSCT is performed prior to onset of MDS/AML and before multiple transfusions [Mehta et al 2010, Ebens et al 2017]. Individuals with FA are sensitive to chemotherapy and radiation, need special transplant regimens, and should be cared for and transplanted at centers with the most experience in HSCT in FA.

A multi-institutional study reported a one-year probability of overall survival of 80% in 45 individuals with FA transplanted for marrow failure and/or MDS, using alternative donors (including mismatched related and unrelated donors) and chemotherapy-only preparative regimen. Survival for individuals younger than age ten years transplanted for marrow failure was even better, at 91.3% (±5.9%) [Mehta et al 2017].

Fludarabine reduced the incidence of graft failure and allowed for removal of radiation from the preparative regimens in a matched sib donor setting [MacMillan et al 2015]. Transplant outcomes for recipients of alternative stem cell donors have achieved those of matched sib donors [Mehta et al 2017, Ebens et al 2018]. Newer approaches to graft manipulation, either in vivo or ex vivo, permit use of haploidentical donors without prohibitive rates of graft-vs-host disease (GVHD) [Bonfim et al 2017, Strocchio et al 2021, Zubicaray et al 2021].

MDS/AML treatment remains challenging. Options include chemotherapy, HSCT with or without prior induction chemotherapy, and investigational trials. Chemotherapy should be undertaken in coordination with centers experienced with FA, as it can cause severe, prolonged, or irreversible myelosuppression. Plans for HSCT should be in place prior to starting chemotherapy. Published reports of chemotherapy regimens for AML in individuals with FA are sparse and limited by the unclear benefit to the overall outcome due to the lack of longitudinal follow up [Mehta et al 2007, Talbot et al 2014, Mitchell et al 2014]. Recently published EBMT (European Society for Blood and Marrow Transplantation) experience suggests a survival benefit to achieving a complete remission prior to HSCT [Giardino et al 2020].

Solid tumors. Prompt, aggressive workup for any symptoms suggestive of a malignancy is indicated. Early detection and surgical removal remain the mainstay of therapy. Treatment is challenging due to the increased toxicity associated with chemotherapy and radiation in individuals with FA. Data is limited on use of chemotherapy at standard doses or reduced doses and schedules in individuals with FA, and there are reports of severe or fatal toxicities and poor treatment outcomes [Masserot et al 2008, Tan et al 2011, Spanier et al 2012, Kutler et al 2016]. Individuals diagnosed with a genital tract cancer should be referred to a gynecologic oncologist immediately, and care should be coordinated with FA experts.

Prevention of Primary Manifestations

Human papilloma virus (HPV) vaccination should be initiated at age nine years in order to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.

Prevention of Secondary Complications

Individuals with FA treated with HSCT who developed GVHD had a 28% incidence of head and neck cancers in the ten years following treatment (vs 0% in those without GVHD); this finding points to the importance of minimizing the risk of GVHD [Guardiola et al 2004]. Increased risk for GVHD observed in earlier studies was reduced significantly by T-cell depletion of the donor graft [Chaudhury et al 2008, MacMillan et al 2015].

Individuals successfully treated with HSCT are at increased risk for solid tumors, in addition to the baseline increased risk [Rosenberg et al 2005]. Due to the known contribution of radiation to the long-term complication of secondary solid tumors, most recent efforts have focused on using a conditioning regimen without radiation even in an unrelated donor setting. German, Brazilian, Turkish, and US groups now report excellent outcomes with alternative donors with a "chemotherapy-only" preparative regimen in single- and multi-center studies. The study from Germany showed 88% survival and normal hematopoiesis at a median follow up of 30 months. A prospective multi-institutional US study also showed similar excellent outcomes. One-year probabilities of overall and disease-free survival for the entire cohort, including individuals with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% and 77.7% respectively at a median follow-up of 41 months. All young children (age <10 years) undergoing HSCT for marrow failure using low-dose busulfan-containing regimen survived [Bonfim et al 2015, Chao et al 2015, Mehta et al 2017].

Surveillance

See 2020 consensus guidelines (full text).

Table 7.

Recommended Surveillance for Individuals with Fanconi Anemia

System/ConcernEvaluationFrequency
Growth Growth/feeding/nutrition assessmentAt each visit throughout childhood
Scoliosis Spine exam
Strabismus/
Cataracts
Exam by ophthalmologistAt each visit throughout childhood, then annually
Endocrine
manifestations 1
Endocrine eval incl:
  • TSH & free T4
  • 25-hydroxy vitamin D
  • 2-hr oral glucose tolerance test, insulin levels
Annually
Pubertal stage & hormone levelsAt puberty, then every 2 yrs until puberty complete
Hearing loss Formal hearing evalAt diagnosis & serially if exposed to ototoxic medications (e.g., chemotherapy agents)
Development Developmental assessmentAnnually throughout childhood
Pancytopenia Blood countsEvery 3-4 mos while stable & more often as needed 2, 3
Myelodysplasia
  • Bone marrow aspirate/biopsy to evaluate morphology & cellularity
  • FISH; & cytogenetics to evaluate for emergence of a malignant clone
  • At least annually (after age 2 yrs)
  • In persons on GCSF, bone marrow aspirate/biopsy every 6 mos, if possible
  • Prompt investigation for hematologic disease progression incl in those who develop Sweet syndrome
Liver dysfunction
due to androgen
therapy
Liver function testsEvery 3-6 mos in those receiving androgen therapy
Liver ultrasound exam for androgen-related changes, incl tumorsEvery 6-12 mos in those receiving androgen therapy
Genital tract
cancers
Gynecologic assessment for genital lesionsAnnually beginning at age 13
Thorough vulvo-vaginal exam & Pap smearAnnually beginning at age 18 or w/onset of sexual activity
Suspicious genital tract lesions should be biopsiedEvery 3-6 mos in those w/history of premalignant or malignant lesions
Oral, head, &
neck cancers
Exam by dentist, oral surgeon, or ENT familiar w/FA
  • Every 6 mos beginning by age 9-10 yrs
  • Every 2-3 mos in those w/history of premalignant or malignant lesions
NasolaryngoscopyAnnually beginning at age 10 yrs, or w/in first year after HSCT
Eval for esophageal cancer in those w/difficulty or pain w/swallowing
Skin cancers Eval by dermatologistEvery 6-12 mos
BRCA2-related
FA 4, 5
Abdominal ultrasound, brain MRIAnnually starting at diagnosis (incl newborns)
1.

For example, hypothyroidism, vitamin D deficiency

2.

Progressively changing blood counts without a potential cause (e.g., acute infection or suppression from medication) require immediate evaluation with a complete blood count and bone marrow examination with FISH and cytogenetics.

3.

It is important to recognize that rising blood counts can be due to either the development of MDS/AML or, rarely, reversion of a germline pathogenic variant in a stem cell, which repopulates the marrow with normal cells (somatic stem cell mosaicism). These individuals may require immediate HSCT (for MDS/AML) or continued close monitoring with complete blood counts at least every one to two months and a bone marrow examination with cytogenetics every six months.

4.

Neuroblastomas, brain tumors, kidney tumors

5.

These cancer surveillance recommendations may be considered for persons with PALB2-related Fanconi anemia in the absence of consensus guidelines.

Additional cancer surveillance for individuals with Fanconi anemia. Some of the genes associated with FA are known breast cancer susceptibility genes: BRCA1, BRCA2, BRIP1, PALB2, and RAD51C. Individuals who have FA due to pathogenic variants in one of these genes should follow the National Comprehensive Cancer Network (NCCN) screening guidelines that have been developed for individuals with a heterozygous pathogenic variant in one of these genes. This should be done under the care of a genetic health care professional. To date, the risk of breast cancer has not been established in individuals with FA due to biallelic pathogenic variants in these genes, and no additional recommendations have been determined for breast cancer screening.

Agents/Circumstances to Avoid

Blood transfusions. Blood products should be cytomegalovirus (CMV)-safe and irradiated. To reduce the chances of sensitization, family members must not act as blood donors. Once an individual requires transfusions, he/she should be referred for transplantation.

Toxic agents to avoid include smoking, second-hand smoke, and alcohol, which have been implicated in tumorigenesis.

Excessive sun exposure. Sunscreen and sun protective clothing should be used to limit UV exposure.

Unsafe sex practices increase the risk for HPV-associated malignancy.

Radiographic studies for the purpose of surveillance should be minimized in the absence of clinical indications. However, baseline skeletal surveys may be considered, in order to document bony anomalies that may lead to problems with age, such as anomalies of the wrist, hip, and vertebrae.

Evaluation of Relatives at Risk

It is appropriate to evaluate all sibs of an affected individual in order to identify as early as possible those who would benefit from appropriate monitoring for FA-related physical abnormalities, bone marrow failure, and related cancers. Evaluations include:

  • Molecular genetic testing if the pathogenic variant(s) in the family are known;
  • Cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) for detection of increased chromosome breakage and radial forms.

Breast cancer susceptibility. Some of the genes associated with FA are known breast cancer susceptibility genes (see Genetically Related Disorders). Family members found to have a pathogenic variant in a known breast cancer susceptibility gene should undergo cancer screening as recommended in the NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (no-fee registration and login required) and under the care of a genetic health care professional.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is possible in females with FA, whether or not they have undergone HSCT [Nabhan et al 2010, Tsui & Crismani 2019].

Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist.

Therapies Under Investigation

Gene therapy. Several early phase clinical trials of gene therapy targeting FANCA are underway using lentiviral vectors at sites across the world, including the University of Washington/Fred Hutchinson Cancer Research Center and Stanford University in the United States, as well as Hospital Universitari Vall d’Hebron Research Institute in Spain and Shenzhen Geno-Immune Medical Institute in China.

Separately, the United States National Heart, Lung, and Blood Institute completed a Phase I trial of retroviral vector transduction of autologous CD34+ stem cells in individuals with FANCC-FA (results pending).

While some trials aim to correct CD34+ stem cells obtained from bone marrow harvest, others are exploring peripheral blood mobilization with combination of G-CSF and plerixafor, shown advantageous in pre-clinical models [Río et al 2017].

HSCT. A multi-center study (Cincinnati Children’s Hospital Medical Center, Memorial Sloan Kettering Cancer Center, and Fred Hutchinson Cancer Research Center) is investigating risk-adjusted busulfan dosing in a chemotherapy-only conditioning regimen for HSCT in Fanconi anemia (including individuals with MDS and leukemia in addition to those with bone marrow failure as HSCT indication).

Ex vivo T cell receptor alpha/beta depletion of the stem cell product in HSCT is additionally under investigation at the University of Minnesota to reduce the risk of GVHD and allow avoidance of post-HSCT immune suppression.

A Phase I/II trial will incorporate an anti-cKIT antibody into HSCT conditioning to aid in myeloablation and reduce chemotherapy/radiation toxicity. This will be given in combination with T-cell receptor alpha/beta depletion of the stem cell product to individuals older than age two years with bone marrow failure as the HSCT indication (Jasper Therapeutics sponsored at Stanford University in California).

Hematopoiesis support. Phase I/II studies of the antioxidant quercetin, anti-hyperglycemic metformin and thrombopoietin mimetic eltrombopag are currently underway in the United States for marrow failure in children and adults with FA.

Squamous cell carcinoma (SCC). A Phase II study of the antioxidant quercetin for prevention of SCC in individuals with FA is also currently underway at Cincinnati Children’s Hospital Medical Center.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. The offspring of an individual with autosomal recessive FA are obligate heterozygotes for a pathogenic variant in an FA-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a pathogenic variant in an FA-related gene.

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the FA-related pathogenic variants in the family.

Individuals who are heterozygous for an autosomal recessive FA-related pathogenic variant cannot be detected by the DEB/MMC test.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • All probands with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with RAD51-related FA is presumed to have a 50% chance of inheriting the pathogenic variant; however, only one individual with RAD51-related FA has reached adulthood and no offspring have been reported.

Other family members. Given that all probands with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

Offspring of a male proband

  • Affected males transmit the FANCB pathogenic variant to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons.
  • To date, no male with FANCB-related FA has been old enough to have children; they may also be infertile, as are many males with FA. Further, FANCB has been demonstrated essential to regulation of spermatogenesis and affected mice are infertile [Kato et al 2015].

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the FANCB pathogenic variant and the aunt's offspring, depending on their gender, may be at risk of being heterozygotes or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose – information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Carrier testing for at-risk female relatives requires prior identification of the FANCB pathogenic variant in the family.

Individuals who are heterozygous for a FANCB pathogenic variant cannot be detected by the DEB/MMC test.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers) or who are at increased risk of being heterozygotes.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FA-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing (PGT) for FA are possible. PGT has successfully identified at-risk embryos as unaffected with FA and HLA-matched to affected sibs [Kahraman et al 2014, Rechitsky et al 2020].

Chromosome breakage. Prenatal testing is also possible for pregnancies at increased risk for FA by performing cytogenetic testing in the presence of DEB/MMC to evaluate for increased chromosome breakage in fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis [Auerbach et al 2003]; however, if the pathogenic variants are known in the family, molecular genetic testing is the method of choice for prenatal diagnosis.

Fetal ultrasound evaluation. Ultrasound examination can be used to evaluate for fetal anomalies consistent with FA. However, ultrasound examination is not a diagnostic test for FA. Many congenital anomalies characteristic of FA may not be detectable by ultrasound examination, and those that can be seen may be associated with diagnoses other than FA [Gandhi et al 2019].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Fanconi Anemia Cell Repository
    Department of Medical and Molecular Genetics
    3181 Southwest Sam Jackson Park Road L103
    Oregon Health & Science University
    Portland OR 97201
    Phone: 503-494-6888
  • Fanconi Anemia Research Fund, Inc. (FARF)
    1801 Williamette Street
    Suite 200
    Eugene OR 97401
    Phone: 888-326-2664 (Toll-free Family Support Line); 541-687-4658
    Fax: 541-687-0548
    Email: info@fanconi.org
  • International Fanconi Anemia Registry (IFAR)
    The Rockefeller University
    1230 York Avenue
    New York NY 10065
    Phone: 212-327-8862
    Fax: 212-327-8262
    Email: auerbac@rockefeller.edu
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
    Email: NCI.IBMFS@westat.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Fanconi Anemia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
BRCA1 17q21​.31 Breast cancer type 1 susceptibility protein BRCA1 homepage - LOVD
Database of BRCA1 and BRCA2 sequence variants that have been clinically reclassified by a quantitative integrated evaluation
Breast Cancer Information Core (BRCA1)
BRCA1 @ ZAC-GGM
BRCA1 BRCA1
BRCA2 13q13​.1 Breast cancer type 2 susceptibility protein BRCA2 homepage - LOVD
Database of BRCA1 and BRCA2 sequence variants that have been clinically reclassified using a quantitative integrated evaluation
Breast Cancer Information Core (BRCA2)
Fanconi Anaemia Mutation Database (FANCD1 - BRCA2)
BRCA2 @ ZAC-GGM
BRCA2 BRCA2
BRIP1 17q23​.2 Fanconi anemia group J protein BRIP1 @ LOVD
Fanconi Anaemia Mutation Database (FANCJ - BRIP1)
BRIP1 BRIP1
ERCC4 16p13​.12 DNA repair endonuclease XPF ERCC4 database ERCC4 ERCC4
FAAP100 17q25​.3 Fanconi anemia core complex-associated protein 100 FAAP100 FAAP100
FANCA 16q24​.3 Fanconi anemia group A protein Fanconi Anemia Mutation Database (FANCA) FANCA FANCA
FANCB Xp22​.2 Fanconi anemia group B protein FANCB @ LOVD
Fanconi Anaemia Mutation Database (FANCB)
FANCB FANCB
FANCC 9q22​.32 Fanconi anemia group C protein Fanconi Anemia Mutation Database (FANCC) FANCC FANCC
FANCD2 3p25​.3 Fanconi anemia group D2 protein Fanconi Anaemia Mutation Database (FANCD2) FANCD2 FANCD2
FANCE 6p21​.31 Fanconi anemia group E protein Fanconi Anaemia Mutation Database (FANCE) FANCE FANCE
FANCF 11p14​.3 Fanconi anemia group F protein Fanconi Anaemia Mutation Database (FANCF) FANCF FANCF
FANCG 9p13​.3 Fanconi anemia group G protein Fanconi Anaemia Mutation Database (FANCG) FANCG FANCG
FANCI 15q26​.1 Fanconi anemia group I protein Fanconi Anemia Mutation Database (FANCI) FANCI FANCI
FANCL 2p16​.1 E3 ubiquitin-protein ligase FANCL Fanconi Anaemia Mutation Database (FANCL) FANCL FANCL
FANCM 14q21​.2 Fanconi anemia group M protein Fanconi Anaemia Mutation Database (FANCM) FANCM FANCM
MAD2L2 1p36​.22 Mitotic spindle assembly checkpoint protein MAD2B MAD2L2 MAD2L2
PALB2 16p12​.2 Partner and localizer of BRCA2 PALB2 database PALB2 PALB2
RAD51 15q15​.1 DNA repair protein RAD51 homolog 1 RAD51 database RAD51 RAD51
RAD51C 17q22 DNA repair protein RAD51 homolog 3 RAD51C @ LOVD RAD51C RAD51C
RFWD3 16q23​.1 E3 ubiquitin-protein ligase RFWD3 RFWD3 RFWD3
SLX4 16p13​.3 Structure-specific endonuclease subunit SLX4 SLX4 @ LOVD SLX4 SLX4
UBE2T 1q32​.1 Ubiquitin-conjugating enzyme E2 T UBE2T UBE2T
XRCC2 7q36​.1 DNA repair protein XRCC2 XRCC2 @ LOVD XRCC2 XRCC2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Fanconi Anemia (View All in OMIM)

113705 BREAST CANCER 1 GENE; BRCA1
133520 EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4; ERCC4
179617 RAD51 RECOMBINASE; RAD51
227645 FANCONI ANEMIA, COMPLEMENTATION GROUP C; FANCC
227646 FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2
227650 FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA
300514 FANCONI ANEMIA, COMPLEMENTATION GROUP B; FANCB
300515 FANCB GENE; FANCB
600185 BRCA2 GENE; BRCA2
600375 X-RAY REPAIR CROSS COMPLEMENTING 2; XRCC2
600901 FANCONI ANEMIA, COMPLEMENTATION GROUP E; FANCE
602774 RAD51 PARALOG C; RAD51C
602956 FANCG GENE; FANCG
603467 FANCONI ANEMIA, COMPLEMENTATION GROUP F; FANCF
604094 MITOTIC ARREST-DEFICIENT 2 LIKE 2; MAD2L2
605724 FANCONI ANEMIA, COMPLEMENTATION GROUP D1; FANCD1
605882 BRCA1-INTERACTING PROTEIN 1; BRIP1
607139 FANCA GENE; FANCA
608111 FANCL GENE; FANCL
609053 FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI
609054 FANCONI ANEMIA, COMPLEMENTATION GROUP J; FANCJ
609644 FANCM GENE; FANCM
610355 PARTNER AND LOCALIZER OF BRCA2; PALB2
610538 UBIQUITIN-CONJUGATING ENZYME E2T; UBE2T
610832 FANCONI ANEMIA, COMPLEMENTATION GROUP N; FANCN
611301 FANCONI ANEMIA-ASSOCIATED PROTEIN, 100-KD SUBUNIT; FAAP100
611360 FANCI GENE; FANCI
613278 SLX4 STRUCTURE-SPECIFIC ENDONUELEASE SUBUNIT; SLX4
613390 FANCONI ANEMIA, COMPLEMENTATION GROUP O; FANCO
613897 FANCF GENE; FANCF
613899 FANCC GENE; FANCC
613951 FANCONI ANEMIA, COMPLEMENTATION GROUP P; FANCP
613976 FANCE GENE; FANCE
613984 FANCD2 GENE; FANCD2
614082 FANCONI ANEMIA, COMPLEMENTATION GROUP G; FANCG
614083 FANCONI ANEMIA, COMPLEMENTATION GROUP L; FANCL
614087 FANCONI ANEMIA, COMPLEMENTATION GROUP M; FANCM
614151 RING FINGER AND WD REPEAT DOMAINS-CONTAINING PROTEIN 3; RFWD3
615272 FANCONI ANEMIA, COMPLEMENTATION GROUP Q; FANCQ
616435 FANCONI ANEMIA, COMPLEMENTATION GROUP T; FANCT
617243 FANCONI ANEMIA, COMPLEMENTATION GROUP V; FANCV
617244 FANCONI ANEMIA, COMPLEMENTATION GROUP R; FANCR
617247 FANCONI ANEMIA, COMPLEMENTATION GROUP U; FANCU
617784 FANCONI ANEMIA, COMPLEMENTATION GROUP W; FANCW
617883 FANCONI ANEMIA, COMPLEMENTATION GROUP S; FANCS

See Table A for gene and protein names.

Molecular Pathogenesis

At least 23 genes that are involved in Fanconi anemia (FA) and also account for each of the phenotypic complementation groups have been identified. The proteins encoded by the FA-related genes are considered to work together in a common pathway/network called "the FA pathway" or "the FA-BRCA pathway/network," which regulates cellular resistance to DNA cross-linking agents [Taniguchi & D'Andrea 2006, D'Andrea 2010, Deans & West 2011, Kee & D'Andrea 2012]. Disruption of this pathway leads to the common cellular and clinical abnormalities observed in FA [D'Andrea 2010, Nakanishi et al 2011, Williams et al 2011, Crossan & Patel 2012, Kim & D'Andrea 2012].

Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with proteins FAAP24 [Ciccia et al 2007] and FAAP100 [Ling et al 2007] are assembled in a nuclear complex (FA core complex). This complex is a multisubunit ubiquitin ligase complex; monoubiquitination of two FA proteins (FANCD2 and FANCI) depends on the FA core complex [Garcia-Higuera et al 2001, Smogorzewska et al 2007]. In response to DNA damage or in S phase of the cell cycle, this FA core complex activates the monoubiquitination of the FANCD2 and FANCI proteins. Monoubiquitinated FANCD2 and monoubiquitinated FANCI are translocated to nuclear foci containing the proteins BRCA1, BRCA2, PALB2, and RAD51. FANCI shares sequence similarity with FANCD2; together they form a protein complex (ID complex) [Smogorzewska et al 2007]. Monoubiquitination of FANCD2 and FANCI is interdependent [Smogorzewska et al 2007]. A nuclease, FAN1, has been shown to bind to monoubiquitinated FANCD2, which directs its enzymatic activity [Huang & D'Andrea 2010]. A cell-free system has been used to recapitulate cross-link repair in vitro [Knipscheer et al 2009].

Furthermore, the FA core complex forms a larger complex with BLM, RPA, and topoisomerase IIIα, called BRAFT (BLM, RPA, FA, and topoisomerase IIIα) [Meetei et al 2003] in a further link to Bloom syndrome. FANCM is found in both separable complexes: the FA core complex as well as the BLM complex [Deans & West 2009].

BRCA2 (previously FANCD1) is a tumor suppressor that confers breast cancer susceptibility [Howlett et al 2002] and has a distinct clinical phenotype [Wagner et al 2004, Alter et al 2007, Myers et al 2012]. BRCA2 protein stability and localization is regulated by PALB2 (partner and localizer of BRCA2) [Xia et al 2006] encoded by PALB2 (previously FANCN), another breast cancer susceptibility gene [Reid et al 2007]. Another breast cancer susceptibility gene [Seal et al 2006], BRIP1 (previously BACH1 or FANCJ) [Cantor et al 2001], is also associated with FA [Levitus et al 2005, Levran et al 2005, Litman et al 2005]. BRCA2, PALB2, and BRIP1 are not required for FANCD2 protein monoubiquitination or FANCD2 nuclear foci formation, but are still required for cellular resistance to MMC or DEB. BRCA2 has been found to act in multiple subcomplexes of FA proteins, including FANCG and FANCD2 [Wilson et al 2010], suggesting that the notion of acting downstream of FANCD2 monoubiquitination may be too simplistic. Phosphorylation of FANCD2 by CHK1 has been shown to be necessary for interaction with BRCA2 [Zhi et al 2009]. BRIP1 and FANCD2 have also been shown to be functionally linked in foci formation [Zhang et al 2010].

Amelioration of FA pathology has been implicated in reports of downregulation of elements of the non-homologous end-joining pathway [Adamo et al 2010]. These data propose that much of FA pathophysiology results from the unfettered work of non-homologous end joining promoting inaccurate repair. On the other hand, FA involvement in homologous recombinatorial repair has been well established in interactions with BRCA1, BRCA2, and RAD51C. FANCD2 has also been shown to interact with PCNA and pol K, suggesting that translesion synthesis, a variant of homologous recombination, may be the most direct function of FA proteins in bypass of the lesion [Ho & Schärer 2010, Song et al 2010].

Mechanism of disease causation. Loss of function

Table 8.

Fanconi Anemia: Notable Pathogenic Variants by Gene

Gene 1Reference
Sequences
DNA Nucleotide Change (Alias 2)Predicted Protein
Change
Comment [Reference]
FANCA NM_000135​.4
NP_000126​.2
c.1115_1118delTTGGp.Val372AlafsTer42Common in northern Europeans
c.2738A>Cp.His913ProAssoc w/slower hematologic disease progression [Bottega et al 2018]
c.2852G>Ap.Arg951Gln
c.2851C>Tp.Arg951Trp
FANCC NM_000136​.3
NP_000127​.2
c.456+4A>T
(IVS4+4A>T)
Common in Ashkenazi Jewish; also reported in a Japanese cohort 3
c.37C>Tp.Gln13TerCommon in northern Europeans 3
c.67delG
(322delG)
p.Asp23IlefsTer23Common in northern Europeans & southern Italy 3
c.165+1G>TSee Genotype-Phenotype Correlations.
c.1642C>Tp.Arg548TerCommon in northern Europeans & southern Italy 3
c.1661T>Cp.Leu554ProSee Genotype-Phenotype Correlations.
FANCG NM_004629​.2
NP_004620​.1
c.307+1G>C
(IVS3+1G>C)
Common in Koreans & Japanese
c.925-2A>G
(IVS8-2A>G)
Common in Brazil & northern Europeans
c.1183_1192del10
(1184-1194del)
p.Glu395TrpfsTer5 Demuth et al [2000]
c.1480+1G>C
(IVS11+1G>C)
p.Trp599ProfsTer49Common in French Canadians & northern Europeans [Auerbach et al 2003]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Genes from Table 1 in alphabetic order

2.

Variant designation that does not conform to current naming conventions

3.

Chapter Notes

Author Notes

Comprehensive Center for Fanconi Anemia
Dana Farber Cancer Institute
Mayer 676
44 Binney Street
Boston, MA 02115
Phone: 617-632-6302

Author History

Blanche P Alter, MD, MPH, FAAP; National Cancer Institute (2011-2016)
Alan D'Andrea, MD; Dana Farber Cancer Institute (2002-2007)
Christen Ebens, MD, MPH (2021-present)
Gary Kupfer, MD; Yale University School of Medicine (2011-2016)
Parinda A Mehta, MD (2016-present)
Lisa Moreau, MS; Dana Farber Cancer Institute (2002-2007)
Akiko Shimamura, MD, PhD; Dana Farber Cancer Institute (2002-2007)
Toshiyasu Taniguchi, MD, PhD; Fred Hutchinson Cancer Research Center (2007-2011)
Jakub Tolar, MD, PhD; University of Minnesota (2016-2021)

Revision History

  • 3 June 2021 (sw) Comprehensive update posted live
  • 8 March 2018 (aa, pm) Revision: addition of one gene: RFWD3
  • 23 February 2017 (aa, pm) Revision: addition of two genes: MAD2L2 and XRCC2; edits to Prevention of Secondary Complications
  • 22 September 2016 (sw) Comprehensive update posted live
  • 7 February 2013 (cd) Revision: deletion/duplication analysis available clinically for FANCC
  • 6 September 2012 (cd) Revision: sequence analysis for mutations in RAD51C and SLX4 available clinically
  • 3 November 2011 (cd) Revision: deletion/duplication analysis available clinically for PALB2 deletions
  • 10 February 2011 (me) Comprehensive update posted live
  • 27 March 2008 (cd) Revision: sequence analysis and prenatal testing available clinically for FANCB-, FANCE-, FANCF- and FANCI-related Fanconi anemia
  • 29 January 2008 (cd) Revision: sequence analysis of entire coding region of FANCG and prenatal testing available
  • 7 November 2007 (cd) Revision: molecular genetic testing and prenatal diagnosis no longer available on a clinical basis for FANCF and FANCG
  • 22 June 2007 (me) Comprehensive update posted live
  • 1 March 2006 (cd) Revision: FANCB mutations: X-linked inheritance
  • 3 January 2006 (as) Revision: deletion/duplication testing clinically available
  • 13 September 2004 (me) Comprehensive update posted live
  • 14 February 2002 (me) Review posted live
  • 31 May 2001 (as) Original submission

References

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