Fanconi Anemia

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 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, gastrointestinal tract, 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). The diagnosis is confirmed by identification of one of the following:

• Biallelic pathogenic variants in one of the 19 genes known to cause autosomal recessive FA
• A heterozygous pathogenic variant in RAD51, known to cause autosomal dominant FA
• 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; administration of G-CSF improves the neutrophil count in some; 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.

Prevention of primary manifestations: Human papilloma virus (HPV) vaccination to reduce the risk of 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 risk of subsequent solid tumors.

Surveillance: Annual evaluation with a multidisciplinary team including an endocrinologist; monitoring for evidence of bone marrow failure (regular blood counts; at least annual bone marrow aspirate/biopsy to evaluate morphology, cellularity, and cytogenetics); for those receiving androgen therapy, monitoring liver function tests and regular ultrasound examination of the liver; monitoring for solid tumors (oropharyngeal and gynecologic examinations).

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; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications).

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 carrier, and a 25% chance of inheriting both normal alleles and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic.

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; and liver tumors)
• Inordinate toxicities from chemotherapy or radiation

Establishing the Diagnosis

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

• 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: Guidelines for Diagnosis and Management.
• Identification of biallelic pathogenic variants in one of the 18 genes known to cause autosomal recessive FA, or 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 (see Table 1)

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, followed by gene-targeted FANCA deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes the genes in Table 1a and Table 1b 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 serial 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., mutation of 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.

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.
• Endocrine: hypothyroidism, glucose/insulin abnormalities
• Hearing loss, usually conductive secondary to middle ear bony anomalies; abnormal ear shape: dysplastic, narrow ear canal, abnormal pinna (10%)
• 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, 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 2009. Frequencies are approximate, since many reports did not mention physical descriptions.

Developmental delay and/or intellectual disability (10%)

Bone marrow failure. The age of onset 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 out 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 3). Importantly, to meet these criteria for marrow failure, the cytopenias must be persistent and unexplained by other causes.

Cancer susceptibility. The relative risk for acute myelogenous leukemia (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 compared to HNSCCs seen in the general population. HNSCCs:
  • Occur at an earlier age (20-40 years) than in the general population;
  • Are most commonly in the 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 in the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCC 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].

FANCG. Pathogenic variants in FANCG may be associated with severe marrow failure and a higher incidence of leukemia compared to 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 clearcut genotype-phenotype correlations [Neveling et al 2009]. 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.

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. Individuals who are homozygous for null pathogenic variants in FANCA may have earlier onset of anemia and higher incidence of leukemia than individuals with pathogenic variants that permit production of an abnormal FANCA protein [Faivre et al 2000].

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 del22G [Faivre et al 2005].
• p.Asp23IlefsTer23 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.456+4A>T results in a milder phenotype in Japanese individuals than in Ashkenazi Jewish individuals [Futaki et al 2000].

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 following evaluations are recommended:

• Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, full blood typing, blood chemistries (assessing liver, kidney, and iron status), and bone marrow aspirate for cell morphology, FISH and cytogenetics, as well as biopsy for cellularity
  Note: The bone marrow of individuals with FA can exhibit signs of dysplasia, such as nuclear/cytoplasmic dys-synchrony, hypo-lobulated megakaryocytes, and bi-nucleated erythroid cells. These features must be distinguished from true forms of MDS by a hematopathologist experienced in the evaluation of MDS in individuals with FA.
• HLA typing of the affected individual, sibs, and parents for consideration of hematopoietic stem cell transplantation
• Examination by an ophthalmologist
• Ultrasound examination of the kidneys and urinary tract
• Formal hearing evaluation
• Echocardiogram
• Referral to an endocrinologist
• Developmental assessment (particularly important for toddlers and school-age children)
• Referrals as indicated to an otolaryngologist, hand surgeon, gastroenterologist, gynecologist, and urologist
• Evaluation by a clinical geneticist and genetic counseling

Treatment of Manifestations

Recommendations for treatment were agreed upon at a 2014 consensus conference (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). 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 stanazolol in Asia, and oxandrolone and danazol in North America.

Side effects of androgen administration include virilization and liver toxicity such as 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 (LFT) for abnormalities. Blood tests for LFTs should be performed every three to six months; liver ultrasound should be performed every six to 12 months. If no response is seen after three to four months, androgens should be discontinued [Scheckenbach et al 2012, Rose et al 2014].

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