Clinical manifestations and diagnosis of Fanconi anemia

INTRODUCTION — Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by pancytopenia, predisposition to malignancy, and characteristic physical abnormalities/congenital malformations. FA is caused by pathogenic variants (ie, mutations) in one of numerous genes involved with DNA repair. The diagnosis is usually made in childhood, but some individuals are not diagnosed until adulthood, due to variable disease manifestations and diagnostic delays.

It is important to define FA as the cause of bone marrow failure. Individuals with FA require increased surveillance for organ dysfunction and cancers, reduced doses of chemotherapy and/or radiation must be used for treating cancers or prior to hematopoietic cell transplantation, and FA must be excluded in sibling donors for hematopoietic cell transplantation (HCT) to avoid transplantation with a graft from an undetected, asymptomatic sibling with FA.

This topic discusses the clinical manifestations, diagnosis, and differential diagnosis of FA.

Management and prognosis of FA are discussed separately. (See "Management and prognosis of Fanconi anemia" and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)".)

PATHOPHYSIOLOGY — FA is an inherited disorder in which cells cannot properly repair DNA damage, which leads to genomic instability, disordered cell cycle regulation, and cell death.

FA is caused by an inability to properly repair DNA interstrand crosslinks (ICLs), an especially deleterious type of DNA damage in which opposing strands of DNA are abnormally joined. Disordered repair of ICLs leads to genomic instability, aberrant cell cycle regulation, and cell death. DNA damage can occur during fetal development, which can cause congenital anomalies, and during childhood and adulthood, which is associated with bone marrow failure (BMF), organ damage, and cancer. (See 'Genomic instability' below and 'Bone marrow failure' below.)

Genetics — FA can be caused by pathogenic variants (ie, mutations) in numerous genes that encode proteins involved in DNA repair. (See 'FA-associated genes' below.)

Inheritance — FA is caused by mutations in one of ≥22 different genes, which are described as FANCA to FANCW [1-15]. Most cases of FA are inherited in an autosomal recessive pattern, but other patterns of inheritance are seen with certain FA-associated genes.

The most commonly mutated genes are FANCA, FANCC, and FANCG; some FA-associated genes were previously recognized in other settings with different names (eg, FANCS was independently recognized as BRCA1). Pathogenic variants of FA genes include point mutations, large deletions, and gene duplications [16]. Genotype-phenotype correlations have been described for certain FA genes [15,17,18].

For most FA genes, inheritance follows an autosomal recessive pattern; thus, loss of normal function at both alleles is required to manifest disease, either with a homozygous pathogenic variant or compound heterozygous variants in an individual gene. Exceptions include FANCR, which is inherited with an autosomal dominant pattern and FANCB, which is X-linked recessive.

Individuals who are heterozygous for variants in FA genes other than FANCB and FANCR are considered unaffected carriers, although some of these individuals may have an increased susceptibility to cancer. (See 'Findings in heterozygotes' below.)

FA-associated genes — Mutations of FANCA, FANCC, and FANCG are the most common FA complementation groups (table 1); together, variants in these three genes account for 80 to 90 percent of cases of FA [19,20]. Mutations of FANCD1 are less common, but this complementation group has distinctive features, including earlier onset of malignancies.

●FANCA – Mutations in FANCA are responsible for most cases of FA (approximately 60 to 65 percent) [21,22].

More than 200 distinct pathogenic alleles of FANCA have been identified; thus, in most cases, FANCA alleles are unique to individual pedigrees [7]. Large intragenic deletions are common, though point mutations, smaller insertions/deletions, and splicing mutations are also frequent [23]. Genotype-phenotype correlations within the FANCA group show that, compared with individuals who have at least one hypomorphic mutation, patients with two mutations leading to null alleles have earlier onset of hematologic abnormalities, higher risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and shorter survival after diagnosis [1].

●FANCC – Mutations in FANCC account for 10 to 15 percent of cases of FA [1]. Compared with patients who have FANCA mutations, individuals with FANCC variants generally have a less severe hematologic course and lower incidences of congenital microcephaly and radial ray abnormalities [1].

The most common mutations of FANCC are 322delG in exon 1 and IVS4+4A>T in intron 4 [7]. The IVS4+4A>T variant is especially common in Ashkenazi Jews, and this variant along with Arg548Ter and Leu554Pro substitutions in exon 14 are associated with more congenital anomalies and earlier onset of hematologic abnormalities than the 322delG variant [24,25].

●FANCG – Mutations in FANCG (also called XRCC9) account for approximately 10 percent of cases of FA.

Compared with mutations in FANCA or FANCC, mutations of FANCG are associated with similar frequencies of non-hematologic anomalies but more severe cytopenias and higher rates of hematologic malignancies [1]. The 637-643delTACCGCC deletion in FANCG is thought to represent a founder mutation responsible for >80 percent of FA cases in the Black South African population [26]. The IVS3+1G>C and 1066C>T mutations in FANCG are common in Japanese and Korean populations, respectively [27,28].

●FANCD1 – FAND1 is identical to the gene that was independently identified as BRCA2; it accounts for approximately 3 percent of cases of FA [29].  

Numerous mutations of FANCD1 have been described. Patients have earlier onset of both AML and solid tumors and should undergo more aggressive screening protocols using magnetic resonance imaging (MRI) [29-32].

Updated information on FA gene mutations is available from an FA mutation database: www.rockefeller.edu/fanconi/

Genomic instability — FA proteins are needed to maintain genomic stability.

●Causes and results of genomic instability – Loss of FA gene function causes aberrant repair of DNA ICLs, which interferes with normal DNA replication and transcription by preventing strand separation, stalling replication forks, and compromising DNA integrity [33]. ICLs arise from endogenous aldehydes (eg, products of lipid peroxidation), exogenous aldehydes (eg, formed after alcohol consumption), and from exposure to radiation and DNA alkylating agents used as cancer chemotherapy. Aberrant repair of ICLs causes genomic instability, abnormal cell cycle regulation, and cell death. FA proteins also interact with other DNA damage response pathways and participate in stress response pathways (eg, oxidative stress).

●FA core complex – The FA core complex is a multicomponent complex that forms at the site of a DNA ICL and contains eight of the known FA proteins: FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM [34,35].

FANCL is an E3 ubiquitin ligase that serves as the catalytic component of the core complex. It interacts with FANCT (UBE2T) to monoubiquitinate the ID complex (a heterodimer of FANCD2 and FANCI), which is incorporated into nuclear foci, where it recruits an endonuclease complex (FANCP and FANCQ), which unhooks the aberrant crosslink and creates a DNA double strand break (DSB). FANCD1 (identical to BRCA2, the breast cancer susceptibility gene), FANCN, FANCJ, and FANCO then work via the DSB DNA repair pathway to restore DNA integrity, using nucleotide excision repair and homologous recombination during the S or G2 phases of the cell cycle [2,7,36-38].

FA proteins also interact with other DNA damage response pathways, including proteins encoded by the ataxia-telangiectasia genes (ATM and ATR) and the Nijmegen breakage syndrome (NBS) protein, nibrin (encoded by NBN) [2,39-43]. FA proteins also participate in oxidative stress response [20,44].

Bone marrow failure — BMF in FA refers to a deficiency or impairment of hematopoietic stem cells (HSCs) that causes bone marrow hypoplasia leading to single or multiple cytopenias and eventual aplasia with pancytopenia.

BMF is caused by premature, selective attrition of CD34+ HSCs, which can be observed prior to the onset of cytopenias. The precise mechanisms of stem cell loss are uncertain, but they include defective DNA repair leading to increased DNA damage and cell cycle arrest, increased levels of reactive oxygen species (ROS) and circulating inflammatory cytokines, and excessive damage from reactive aldehydes in the absence of intact FA repair pathways [45-48]. Chronic stress-induced HSC activation caused by dysregulated oxidative stress and inflammatory cytokine exposure in the bone marrow microenvironment also contributes to BMF [45].

Endogenous aldehydes appear to affect HSCs during development [49]. To illustrate the importance of endogenous aldehydes in this process, accelerated progression of BMF was reported in a series of 64 patients with FA who were deficient in acetaldehyde dehydrogenase 2 [50]. Other mechanisms that have been implicated in HSC attrition include an increase in the level of inflammatory cytokines, reduced redox signaling, a diminished heat shock protein response, and abnormal telomere shortening [51-59].

EPIDEMIOLOGY — While rare, FA is the most common inherited bone marrow failure syndrome (IBMFS). The incidence has been estimated to be 1 in 300,000 live births and the prevalence of 1 to 9 per million, but the carrier frequency varies according to the population studied [60]. FA has been described in nearly all races and ethnic groups.

Most individuals are diagnosed with FA between six and nine years of age (concurrent with the onset of bone marrow failure), but recognition of the variable clinical manifestations and increased disease awareness are leading to earlier diagnoses [61]. As many as 9 percent of individuals are diagnosed after age 16 years, typically, when they present with a malignancy [62,63].

Specific founder mutations account for a higher incidence of FA in certain populations. As examples, the FANCA c.295C>T mutation is found in Spanish Romani populations, the FANCC IVS4 + 4A>T mutation in Ashkenazi Jews, exon 15 deletions in patients of North African and Middle Eastern descent, a large intragenic deletion in the South African Afrikaner population, and others [27,64-71]. The carrier frequency varies according to the populations studied. In the general population, the carrier frequency is 1 in ~190, but it is 1 in 100 in the Afrikaans population in South Africa, 1 in 100 in Ashkenazi Jews, and up to 1 in 64 in Spanish Romani populations [64,65,69,70]. Founder mutations have also been identified in people from Tunisia, Japan, Korea, and Brazil [27,66,71].

CLINICAL FEATURES — FA is typically associated with cytopenias, predisposition to malignancy, and congenital and developmental abnormalities. Some individuals have only modest or isolated cytopenias (eg, macrocytic anemia, thrombocytopenia) for years before they are recognized as having FA.

Congenital anomalies — Congenital malformations are the most common presenting features of FA (table 2), but an absence of such findings does not eliminate the possibility of FA.

Malformations have been reported in 60 to 75 percent of individuals with FA, but this is likely an underestimate, as many patients do not manifest classical physical findings [72]. The <5 percent of cases that are diagnosed in the first year of life are usually due to recognition of classic congenital anomalies. Increasingly, gene sequencing panels identify individuals with non-classical or subtle findings.

In a series of 419 patients in the International FA Registry, one-third lacked an obvious congenital abnormality, even though most had short stature, skin pigmentation abnormalities, or microphthalmia [73]. In a series of 20 patients with FA who underwent brain magnetic resonance imaging (MRI), 90 percent had at least one abnormality, such as a small pituitary gland or an abnormality of the posterior fossa or corpus callosum [74]. Ophthalmologic abnormalities such as microcornea, microphthalmia, and visual processing defects may also be underreported [75,76]. In the US National Institutes of Health (NIH) experience, 75 percent of patients had hearing loss or structural ear abnormalities, while 90 percent had an ophthalmologic abnormality [72]. Small series have also reported dental anomalies, conductive hearing loss, and skull base/posterior fossa abnormalities [77-80].

The most common developmental abnormalities in 370 patients enrolled in the International FA Registry and from a review of >2000 patients reported in the literature (1927 to 2009) included [72,81]:

●Skin (approximately 40 to 60 percent), including hyper- or hypopigmentation or café-au-lait spots

●Short stature (40 to 60 percent)

●Thumb or other radial ray abnormalities (50 percent):

•Thumbs absent or hypoplastic, bifid/duplicated, rudimentary, triphalangeal (35 percent)

•Radii absent or hypoplastic (7 percent)

•Other features, such as flat thenar eminence, clinodactyly, polydactyly, missing first metacarpal, dysplastic ulnae (6 percent)

●Axial skeleton (25 percent), especially microcephaly, triangular facies, short/webbed neck, vertebral anomalies

●Eyes (20 to 40 percent), including strabismus and hypo/hypertelorism

●Kidney/urinary tract (approximately 20 to 30 percent), including horseshoe, ectopic, dysplastic, or absent kidney; hydronephrosis; hydroureter

●Gonadal/genital

•In males, hypospadias, micropenis, undescended/absent testes, infertility (25 percent)

•In females, uterus malformation, small ovaries, hypogenitalia (<5 percent)

●Ear abnormalities (10 to 20 percent) with conductive hearing loss due to middle ear anomalies or atretic ear canal

●Congenital heart disease (approximately 5 percent), such as patent ductus arteriosus, ventricular septal defect, aortic coarctation, truncus arteriosus

●Gastrointestinal (approximately 5 percent), such as tracheoesophageal fistula, esophageal atresia, intestinal atresia, imperforate anus

●Central nervous system (CNS) (<5 percent) involving the pituitary gland (eg, small, interrupted pituitary stalk syndrome), hydrocephalus, cerebellar hypoplasia, or absent corpus callosum

FA is also associated with VACTERL-H, a syndrome in which individuals have ≥3 of the following: vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb anomalies, and hydrocephalus. One-third of 54 patients with FA met criteria for VACTERL-H in an NIH study, although previous literature reviews had suggested only 5 percent had VACTERL-H [82]. VACTERL-H is more common in patients with mutations of FANCI, FANCL, and possibly FANCB, while it is less common in patients with FANCD1 mutations [29,83,84]. (See 'VACTERL-H' below.)

Cytopenias/bone marrow failure — Hematologic manifestations of FA include thrombocytopenia, macrocytic anemia, or pancytopenia. Bone marrow failure (BMF) eventually occurs in most patients with FA, but the time to onset can be quite variable. Progression to pancytopenia can occur soon after initial cytopenias are noted, but it may take months or years to develop in other individuals; rarely, BMF does not develop at all.

●Cytopenias – BMF is described as mild, moderate, or severe, according to the degree of cytopenias (table 3). Severe neutropenia and thrombocytopenia are especially problematic and can cause life-threatening infections and bleeding.

Cytopenias may be mild initially or they may first present later in the disease course, especially if the diagnosis was made based on congenital anomalies. In some cases, only a single cell line (typically thrombocytopenia) will be involved, particularly early in life. Severe neutropenia (absolute neutrophil count [ANC] <500/microL) and thrombocytopenia (platelet count <30,000/microL) can cause infections and bleeding. Anemia is often the last severe cytopenia to develop; it is typically macrocytic and some individuals have macrocytosis without anemia.  

●Bone marrow failure – One study reported BMF in 80 percent of 754 patients at the time of enrollment in a FA registry; the cumulative incidence was 90 percent by age 40 years [17].

Specific genetic factors may protect certain patients from developing BMF. It arises less often in patients with biallelic FANCD1/BRCA2 mutations, but this may reflect the high rate and early onset of malignancies, coupled with the short lifespan in this population. In addition, up to one-quarter of patients with FA may develop acquired somatic mosaicism through gene conversion events (in compound heterozygous patients), back mutation, or compensatory deletions/insertions, which lead to correction of the chromosomal breakage sensitivity phenotype [85-88]. While many patients may have somatic mosaicism detectable only in lymphocytes, patients with mosaicism in hematopoietic stem/progenitor cell compartments have less BMF, although they remain at risk for hematologic malignancies and non-hematologic complications.

Bone marrow findings with FA may be indistinguishable from those seen with other causes of BMF, such as aplastic anemia or myelodysplastic syndromes (MDS). For patients diagnosed in infancy due to congenital anomalies, screening bone marrow biopsies are often normocellular. However, by the onset of cytopenias, the marrow may reveal severe hypocellularity that is out of proportion to the degree of cytopenias. Bone marrow may reveal erythroid dysplasia (eg, hyperplastic erythroblast islands, megaloblastic features), but it should not be interpreted as MDS unless other features of MDS are also seen (eg, increased blasts or cytogenetic abnormalities). Conversely, dysplasia in the myeloid series, increased myeloblasts, or dysmegakaryopoiesis should be considered to be evidence for clonal abnormalities consistent with MDS [20,89].

MDS/leukemia — MDS and leukemia are common with FA. In some cases, MDS or acute myeloid leukemia (AML) is the presenting finding. Lymphoid malignancies also occur, but they are much less common in most FA subtypes.

●MDS/AML prevalence – Compared with the general population, the risk for MDS in patients with FA has been estimated to be increased 6000-fold, while the risk for AML was increased 700-fold; the lower prevalence of leukemia (3.1 percent) was presumably due to the early use of hematopoietic cell transplantation (HCT) in patients who developed MDS [90]. A US National Cancer Institute (NCI) registry reported MDS in 16 percent of 163 patients after 15 year follow-up; the cumulative incidence of MDS was 80 percent by age 60 for patients who did not receive HCT [91].

Leukemia risk is especially high in patients with biallelic mutations in FANCD1/BRCA2; these individuals have an 80 percent cumulative incidence of leukemia by age 10 [29]. Most of these patients develop AML, although some may develop T cell acute lymphoblastic leukemia (ALL). Patients with FANCD1/BRCA2 mutations involving the IVS7 site have particularly early risk of leukemia, with most developing AML by three years of age.

Karyotypic abnormalities are common in patients with FA who develop MDS or AML, including translocations of chromosome 1p, monosomy 7, and gain of chromosome 3q [20]. A literature review of 46 cases of AML in patients with FA found the most common cytogenetic abnormalities to be chromosomal gains of 1q, 3q, or 13q, along with loss of chromosome 7q [92]. In contrast, cytogenetic lesions that are more common in de novo AML, including t(8;21), trisomy 8, and inv(16), were not seen in any of the patients with FA. In a study of 53 patients, 18 had 3q amplification, which was associated with shorter survival and increased risk for development of AML [93].

Patients with FA who have any cytogenetic abnormality require close monitoring of the bone marrow and blood counts. Some cytogenetic abnormalities may remain stable or become undetectable over time, whereas loss of part or all of chromosome 7 is more likely to herald malignant progression.

Management of patients with FA and cytogenetic abnormalities is discussed separately. (See "Management and prognosis of Fanconi anemia", section on 'Hematologic neoplasms'.)

●Lymphoid malignancies, including ALL and Burkitt lymphoma are also seen in patients with FA, but they are much less common than myeloid malignancies [17].

Solid tumors — Solid tumor types occur at increased frequency in individuals with FA and these tumors present at younger ages, compared with tumors in unaffected individuals. All patients with FA should undergo screening for cancers, as described separately. (See "Management and prognosis of Fanconi anemia", section on 'Surveillance and prevention'.)

The most common tumors are squamous cell cancers (SCC) of skin and head/neck/tongue, skin basal cell carcinoma, and anogenital cancers. A malignancy is the presenting finding in many cases of FA that are not diagnosed until adulthood. Solid tumors are uncommon in children with FA (with the exception of patients with mutations of FANCD1/BRCA2), but the annual risk increases with age, particularly in those >30 years. Solid tumors are increasing as individuals with FA live longer, due in part, to more widespread use of HCT to cure BMF and increased long-term malignancy risk associated with HCT.

●Incidence of solid tumors – Solid tumors were seen in 20 percent of individuals with FA by age 60 in the US NCI registry; the most common tumors were SCC of skin and head/neck/tongue, skin basal cell carcinoma, and anogenital cancers [91]. In a study that followed 754 patients for >20 years, 28 percent developed a solid tumor by age 40 [17]. SCC of the head, neck, esophagus, anus, and urogenital region were the most common solid tumors (49 percent); others included liver tumors (23 percent), kidney (8 percent), brain tumors (6 percent), breast (4 percent), and others (eg, germ cell tumors, sarcomas). Similar findings have been reported in other cohorts [61,94].

●Association with age and HCT – The risk for developing a solid tumor increases in association with age in individuals with FA; this pattern differs from that with AML, for which the risk plateaus between age 30 to 40 [17,61,90,94,95]. A study of 1300 individuals with FA estimated the median age of cancer development to be 16 years, compared with 68 years in the general population [96].

In patients who undergo HCT, exposure to DNA-damaging agents or radiation in the conditioning regimen and development of graft-versus-host disease (GVHD) further increase the risk of solid tumors. A study reported that, compared 145 patients with FA who did not undergo HCT, 117 individuals with FA who underwent HCT had a 4.4-fold higher age-specific hazard of SCC and the tumors occurred at a younger age (median age, 18 versus 33 years) [97]. In another series of 37 individuals with FA who underwent HCT, the 15-year incidence of head and neck cancers was 53 percent [98].

Patients with biallelic FANCD1/BRCA2 mutations have especially high rates of cancer development. In one report, there was >97 percent likelihood of developing a malignancy by age seven [99]. By age five, brain tumors developed in more than one-half of patients with FANCD1, but new onset brain tumors were rare beyond this age [90]. Wilms tumor is also common in patients with biallelic FANCD1 mutations; other solid tumors of childhood are seen less often, including rhabdomyosarcoma and neuroblastoma [99].

The role of human papilloma virus (HPV) infection in patients with FA who develop SCC is unclear. A 2003 report from a United States cohort suggested that the high incidence of SCC of the head/neck and anal/urogenital regions in patients with FA was due to genomic instability produced by HPV, as >80 percent of these tumors were HPV-positive [100]. However, two subsequent reports contradicted these findings, demonstrating HPV DNA in only 2 of 21 and 1 of 9 patients (many of these tumors had mutated TP53) [101,102].

The role of HPV vaccination in patients with FA is discussed separately. (See "Management and prognosis of Fanconi anemia", section on 'Solid tumors'.)

Endocrine — Individuals with FA have a range of endocrine disorders, including thyroid, adrenal, and gonadal dysfunction; diabetes; and dyslipidemias.

In many cases, endocrine abnormalities are caused by anatomical disruption of the hypothalamic-pituitary axis during development (eg, pituitary stalk interruption syndrome, septo-optic dysplasia) [103]. In other cases, endocrine abnormalities may be intrinsic to FA or develop in association with the HCT conditioning regimen or treatment of GVHD.

●Short stature is seen in most individuals with FA, but some patients have normal or even above-average height regardless of genotype [104]. Short stature may be intrinsic to FA, but in many cases, short stature is driven by growth hormone deficiency.

●Primary hypothyroidism is seen in over 60 percent of patients with FA, usually due to central hypothalamic or intrinsic thyroid dysfunction rather than autoimmunity.

●Adrenal dysfunction occurs in a subset of patients due to low ACTH secretion, although these patients will generally have a normal response to exogenous ACTH stimulation [104].

●Diabetes – Altered glucose metabolism, including diabetes mellitus and impaired glucose tolerance, occurs in nearly 50 percent of patients with FA due to dysfunction of pancreatic islet cells [105].

●Dyslipidemia/metabolic syndrome – Patients with FA are also at increased risk for dyslipidemia and other aspects of metabolic syndrome.

●Gonadal – Infertility and delayed or abnormal progression of puberty are also very frequent in FA. In males, infertility may result from gonadal dysfunction and/or developmental defects in genital tract formation. In females, fertility is possible; however, premature ovarian failure occurs in over 75 percent of patients [106].

Patients with these abnormalities require evaluation by an endocrinologist with expertise in FA. (See "Management and prognosis of Fanconi anemia", section on 'Identification and management of organ dysfunction'.)

Findings in heterozygotes — Individuals who are heterozygous for FA mutations do not develop BMF and are considered asymptomatic carriers, with the following exceptions:

●FANCB (X-linked recessive) and FANCR (autosomal dominant) are phenotypically manifest with mutations in a single allele.

●Monoallelic FANCS and FANCD1 mutations (also known as BRCA1 and BRCA2, respectively) predispose to breast, ovarian, and other cancers; heterozygous mutations in FANCN (PALB2) and FANCJ (BRIP1) have also been identified as low to moderate penetrance breast and/or ovarian cancer susceptibility genes [107-109].

The association between FA carrier status and increased cancer risk is less certain for other FA subtypes, but congenital anomalies are seen occasionally. Individuals who are heterozygous for mutations in ≥2 distinct FA genes do not develop classic FA features. However, a family with familial childhood ALL was found to have potentially pathogenic germline variants in both FANCP and FANCA [110]. Large scale genomic studies are needed to determine if co-inheritance of ≥2 deleterious germline heterozygous mutations in distinct FA genes increases cancer susceptibility.

The International FA Registry compared a cohort of 404 FA carriers with 329 non-carriers (relatives of individuals in the registry) and with the Surveillance, Epidemiology, and End Results (SEER) and Connecticut tumor registries [111]. There was no increase of overall cancer incidence (standardized incidence ratio [SIR] relative to the United States population, 1.0 [95% CI 0.8-1.3]); however, there was a slightly higher risk of breast cancer in carrier grandmothers of individuals with FA (SIR 1.7 [95% CI 1.1-2.7]).

EVALUATION — Evaluation includes a history and physical examination, screening tests for defective DNA repair, and genetic testing to identify the specific genetic disorder. Clinical features associated with FA are described above. (See 'Clinical features' above.)

Diagnostic delays are common, especially in individuals who do not develop bone marrow failure (BMF) early in their course. Early diagnosis is important because FA is associated with cancer predisposition and sometimes subtle congenital anomalies. Diagnosis is also important so that siblings can be tested to avoid hematopoietic cell transplantation (HCT) using a stem cell donor with the same genetic abnormality. Family planning with conception and preimplantation genetic screening of additional children can also be performed [112].

Indications for screening — Screening for FA with chromosome breakage testing is needed urgently in any child or young adult with:

●Persistent moderate to severe cytopenias – Individuals with >2 weeks of moderate or severe cytopenias in ≥2 lineages in the context of severely hypocellular bone marrow (<25 percent of normal cellularity), in the absence of malignancy, cytotoxic therapy, active severe infection, or other known cause. (See 'Cytopenias/bone marrow failure' above.)

●Characteristic physical findings – Findings that satisfy criteria for VACTERL-H (ie, ≥3 of the following: vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb anomalies, and hydrocephalus) or multiple malformations, such as short stature, café-au-lait spots, thumb/radial ray abnormalities, or hypospadias that are strongly associated with FA. (See 'Congenital anomalies' above.)

●Relative with FA diagnosis – Close relatives of a patient known to have FA; this is particularly important for relatives who are being evaluated as potential donors for HCT. (See "Management and prognosis of Fanconi anemia", section on 'Testing of siblings and management of heterozygotes'.)

●Others – Screening should also be considered in a child or adult with unexplained cytopenias (which may be mild, single lineage, or macrocytic) associated with characteristic congenital abnormalities; individuals ≤40 years with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or certain cytogenetic abnormalities (eg, partial or complete loss of chromosome 7; gain of 1q, 3q, or 13q); development of squamous cell cancer (SCC) of the head, neck, or anorectal region with no known attributable exposure; and patients who had severe toxicity with chemotherapy or radiation therapy [20,113].

Chromosome breakage testing — The hallmark of FA is defective DNA repair that causes extreme sensitivity to DNA interstrand crosslinking agents. Screening for FA involves exposure of cells to diepoxybutane (DEB) or mitomycin C (MMC) followed by assessment for chromosomal breakage [62,114]. This screening should be performed with peripheral blood rather than bone marrow; in some cases (described below), chromosome breakage testing should use skin fibroblasts.

Clinical and laboratory findings that suggest FA are described above. (See 'Indications for screening' above.)

Screening tests are quite sensitive for FA, but not entirely specific, as a positive test can also be seen with other inherited disorders associated with chromosomal instability [115]. Qualitative assessments of the patterns of abnormal breakage can help distinguish FA from other chromosome instability syndromes. With FA, there are increased rates of spontaneous breakage and increased breakage in response to both DEB and MMC; by contrast, increased breakage to MMC alone is more common in other chromosomal breakage syndromes and atypical features (eg, railroad figures, premature centromere separation) are seen exclusively in cohesinopathies [116]. (See 'Differential diagnosis' below.)

Screening of peripheral blood is preferred to screening of bone marrow because testing is performed on T lymphocytes. In vitro expansion of cultured cells enables testing even in patients with severe leukopenia. For individuals with a high pre-test probability of FA and negative screening for chromosomal breakage with lymphocytes, we repeat the testing on skin fibroblasts, as T cells may show normal DNA repair due to somatic mosaicism or revertant mutations. Skin fibroblast testing is also needed for patients who have already undergone HCT [18].

Some experts proceed directly to genetic diagnosis without first performing screening tests. (See 'Genetic testing' below.)

Genetic testing — Next-generation sequencing (NGS) is required to confirm the diagnosis of FA and to identify the specific molecular defect. NGS testing should be performed for all individuals with a positive chromosomal breakage test. (See 'Chromosome breakage testing' above.)

NGS testing is essential for:

●Identifying the particular genetic abnormality, personalizing care according to genotype/phenotype correlations (eg, cancer screening in heterozygotes for mutations with increased risk of solid tumors), and excluding other chromosomal breakage disorders.

●Rapidly evaluating family members as potential transplant donors and to provide proper management for affected relatives.

●Prenatal testing and genetic counseling, given that heterozygous carriers will not have abnormal chromosomal breakage testing [18].

NGS or whole-exome sequencing testing is now available to evaluate all genes associated with FA and can be performed through a number of laboratories, such as those listed on the Genetic Testing Registry website.

Testing for mutations in individual genes can be performed instead of NGS testing for family members of an individual with a known FA mutation.

For most patients, DNA sequencing has replaced complementation group testing, which involves somatic cell fusions of patient cells with index cells for specific complementation groups. Complementation testing can also involve gene transfer of complementary DNA (cDNA) for known FA genes into patient cells and assessment for correction of an FA cellular phenotype. Although it is no longer performed routinely, it can be useful to define the functional subtype (ie, complementation group) of FA in situations where either no variants in FA genes are identified by NGS, if a variant of uncertain significance is detected in an FA gene, or if variants are seen in several distinct FA genes; in such cases, complementation analysis can be useful for attributing causality to a specific gene variant.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FA includes other acquired and inherited causes of bone marrow failure (BMF) (table 4).

Drug- or infection-associated cytopenias — Medications, chemicals, certain viral infections, sepsis, or other severe bacterial infections can cause transient pancytopenia and bone marrow hypoplasia. These conditions are generally associated with transient and reversible cytopenias, patients lack congenital anomalies, and they can be conclusively distinguished from FA with a negative chromosomal breakage test.

Immune cytopenias — Isolated cytopenias (eg, thrombocytopenia, anemia) caused by FA may be erroneously assumed to be caused by an immune mechanism. As an example, FA-associated thrombocytopenia is often initially considered to be due to immune thrombocytopenia (ITP). The presence of characteristic physical findings and the lack of response to immune-modulating therapies can help to distinguish immune cytopenias from FA.

Acquired aplastic anemia (AA) — AA is an acquired BMF syndrome caused by autoreactive T cell destruction of bone marrow stem and progenitor cells [117]. AA often arises after exposure to environmental triggers in susceptible individuals, such as individuals with autoimmune thyroid disease or other autoimmune manifestations. Like FA, patients with AA often present between 5 to 15 years of age with multilineage cytopenias and bone marrow aplasia, but individuals with AA typically have a more rapid onset and progression of cytopenias, normal chromosomal breakage screening/DNA sequencing, lack characteristic FA-associated congenital anomalies and endocrine features, and respond to immunosuppressive therapy. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Treatment of acquired aplastic anemia in children and adolescents".)

Paroxysmal nocturnal hemoglobinuria (PNH) — PNH typically develops concurrent with or after the onset of immune-mediated AA and is associated with chronic hemolytic anemia and a high risk of thrombosis. In PNH, acquired mutations in the PIGA gene cause dominance of hematopoiesis by a clone of cells that lack glycosylphosphatidylinositol (GPI) anchors. PNH clones are never seen in patients with FA and detection of a CD55-negative or CD59-negative clone of cells is 100 percent specific for acquired BMF [118]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

Other IBMFS — Other inherited bone marrow failure syndromes (IBMFS) can be associated with BMF. Some of these conditions may be suspected based on characteristic findings with chromosome breakage testing, as described above. (See 'Chromosome breakage testing' above.)

Other IBMFS that should be distinguished from FA include:

●Dyskeratosis congenita (DC) – DC is an IBMFS associated with a characteristic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; predisposition to cancers, certain congenital anomalies, and liver or lung fibrosis. Individuals with DC have abnormal screening for chromosome breakage, but unlike FA, they have very short telomeres on telomere length analysis of peripheral blood lymphocytes. (See "Dyskeratosis congenita and other telomere biology disorders".)

●Reticular dysgenesis (RD) – RD is a severe combined immunodeficiency caused by mutations in the AK2 gene in which bone marrow aplasia develops in infancy in association with sensorineural hearing loss and severe adaptive immune dysfunction. (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'Reticular dysgenesis'.)

●Other IBMFS – Shwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia (CAMT), and Diamond-Blackfan anemia (DBA) can also be associated with multilineage cytopenias and bone marrow hypoplasia. As with FA, DBA can overlap with VACTERL-H, but pancytopenia in these IBMFS typically develops after an extended period of isolated neutropenia (SDS), thrombocytopenia (CAMT), or anemia (DBA). Individuals with these conditions have a negative chromosomal breakage test and, instead, have other mutations in specific genes. (See "Shwachman-Diamond syndrome" and "Diamond-Blackfan anemia" and "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

VACTERL-H — Some cases of FA overlap with VACTERL-H (vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, hydrocephalus) or PHENOS (pigmentation, small head, small eyes, central nervous system abnormalities other than hydrocephalus, otology, and short stature) syndromes [82,91]. VACTERL-H can be seen in association with FA or other conditions (eg, DBA).

Myelodysplastic syndromes (MDS) — These clonal bone marrow neoplasms are characterized by cytopenias, morphologic dysplasia, and ineffective hematopoiesis [119]. MDS can cause BMF with variable levels of cytopenias, multilineage dysplasia, cytogenetic abnormalities, and increased blasts. While MDS can develop in patients with FA, it can also arise from age-related clonal hematopoiesis or from other acquired/inherited BMF syndromes.  

Importantly, individuals with MDS in whom FA is being considered should have chromosomal breakage tests performed on skin fibroblasts rather than hematopoietic cells, because bone marrow cytogenetic abnormalities associated with MDS clones may skew chromosomal breakage results performed on lymphocytes. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Chromosome breakage syndromes — Certain chromosomal instability syndromes are associated with sensitivity to ionizing radiation and variable sensitivity to DNA crosslinking agents used in chromosomal breakage testing. These rare disorders are associated with multiple congenital anomalies (eg, microcephaly, short stature) and predisposition to cancers, but they typically do not exhibit BMF (except in the setting of evolving malignancy). They can be distinguished from FA by DNA sequence analysis. These conditions (and the associated genes) include:

●Nijmegen breakage syndrome (NBS) – (See "Nijmegen breakage syndrome".)

●Bloom syndrome (BLM) – (See "Bloom syndrome".)

●Ataxia telangiectasia (ATM) – (See "Ataxia-telangiectasia".)

●LIG4 syndrome (LIG4) – (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'XRCC4 and DNA ligase IV'.)

●NHEJ1 deficiency (NHEJ1) – (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Nonhomologous DNA end joining (recombination and DNA repair)'.)

●Seckel syndrome (ATR)

●Cohesinopathies (eg, Roberts syndrome [ESCO2], Cornelia de Lange syndrome [NIPBL, SMC1, or SMC3], Warsaw breakage syndrome [DDX11])

Unlike FA, patients with NBS do not typically exhibit BMF, except in the setting of evolving malignancy. Also compared with FA, these conditions show subtle differences in the associated congenital anomalies, the spectrum of associated malignancies, and the specific abnormalities seen with chromosomal breakage testing (eg, increased chromosome 7 and 14 abnormalities in NBS, railroading figures in cohesinopathies). Nevertheless, gene sequencing distinguishes FA from NBS and other rare chromosomal breakage syndromes.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

●Fanconi anemia (FA) – FA is an inherited bone marrow failure syndrome (IBMFS) in which cells cannot properly repair interstrand crosslinks (ICLs) in DNA. This results in increased sensitivity to cytotoxic therapies, predisposition to malignancies, characteristic congenital abnormalities, and bone marrow failure (BMF).

●Genetics – FA can be caused by pathogenic variants (ie, mutations) in at least 22 distinct genes that are involved with DNA repair (table 1). FANCA, FANCC, and FANCG are the most common categories (complementation groups). Most cases of FA exhibit autosomal recessive inheritance, but some FA-associated genes are inherited with other patterns; with few exceptions, individuals who are heterozygous for an FA mutation are considered asymptomatic carriers. (See 'Genetics' above.)

●Epidemiology – FA is rare, but it is the most common IBMFS. Certain populations have a higher prevalence (eg, Spanish Romani populations, Ashkenazi Jews). (See 'Epidemiology' above.)

●Clinical features – FA can present with characteristic congenital malformations (table 2) and/or findings associated with cytopenias/BMF; myelodysplastic syndromes (MDS), leukemia, or solid tumors (especially squamous cell cancers) may also be found. (See 'Clinical features' above.)

●Evaluation for FA – The hallmark of FA is defective DNA repair that results in extreme sensitivity to DNA ICL agents (eg, diepoxybutane or mitomycin C). Chromosome breakage testing is indicated for a child or young adult with persistent cytopenias (eg, ≥2 weeks), characteristic physical abnormalities (eg, short stature, microcephaly, developmental delay, café-au-lait skin lesions), and other clinical findings. (See 'Indications for screening' above and 'Chromosome breakage testing' above.)

●Diagnosis – The diagnosis of FA requires DNA sequencing to identify a pathogenic variant in an FA-associated gene. (See 'Genetic testing' above.)

First-degree relatives of identified patients should be tested for proper management and to avoid affected individuals as potential transplant donors.

●Differential diagnosis – Other conditions that should be distinguished from FA include other causes of pancytopenia (eg, infections, medications), immune cytopenias, acquired aplastic anemia, paroxysmal nocturnal hemoglobinuria, MDS, and rare IBMFS or chromosomal breakage syndromes (table 4). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — UpToDate acknowledges Akiko Shimamura, MD, PhD; and Alison Bertuch, MD, PhD, who contributed to earlier versions of this topic review.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.