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.

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:

• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC).
  Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See Fanconi Anemia Clinical Care Guidelines.
• Identification of biallelic pathogenic (or likely pathogenic) variants in one of the 21 genes known to cause autosomal recessive FA, or a heterozygous pathogenic (or likely pathogenic) variant in RAD51 known to cause autosomal dominant FA, or a hemizygous pathogenic (or likely pathogenic) variant in FANCB known to cause X-linked FA (see Table 1)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

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 missense, nonsense, and splice site variants and small intragenic deletions/insertions. 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 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.

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.

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

• c.456+4A>T, p.Arg548Ter, and p.Leu554Pro are associated with earlier onset of hematologic abnormalities and more severe congenital anomalies than other pathogenic variants, such as c.67delG [Faivre et al 2005]. However modifiers play a role as the c.456+4A>T variant in Japanese individuals results in a milder phenotype [Futaki et al 2000]
• c.67delG and p.Gln13Ter are associated with a lower risk for congenital anomalies and later progression to bone marrow failure [Yamashita et al 1996, Gillio et al 1997].
• c.165+1G>T founder variant in a Saudi population has been associated with a milder phenotype [Hartmann et al 2010].

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.

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]).

Treatment of Manifestations

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

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).

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, the individual 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 under way 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 under way 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 under way 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.

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

• The parents of a child with autosomal recessive FA are obligate heterozygotes (i.e., presumed to be carriers of one FA-related pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent of a child with autosomal recessive FA, the following possibilities should be considered:
  • A de novo pathogenic variant. One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulting in homozygosity for the pathogenic variant in the proband.
• 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 (see Genetically Related Disorders and BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer).

Sibs of a proband

• If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants.
• Heterozygotes are not at risk for 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 [Seal et al 2006, Berwick et al 2007, Reid et al 2007] (see Genetically Related Disorders and BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer).

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 evaluate their genetic status and inform recurrence risk assessment.
• 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:

• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the RAD51 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. (Parental germline mosaicism has not been described to date in RAD51-related FA.)

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

• The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the FANCB pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the FANCB pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a de novo FANCB pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/germline mosaicism.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

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

• If the mother of the proband has a FANCB pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%.
  • Male sibs who inherit the pathogenic variant will be affected;
  • Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [McCauley et al 2011].
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the FANCB pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

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 sex, 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, pathogenic mechanisms, 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 pathogenic mechanism unknown). For more information, see Huang et al [2022].

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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

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

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
• 22 September 2016 (sw) Comprehensive update posted live
• 10 February 2011 (me) Comprehensive update posted live
• 22 June 2007 (me) Comprehensive update posted live
• 13 September 2004 (me) Comprehensive update posted live
• 14 February 2002 (me) Review posted live
• 31 May 2001 (as) Original submission

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