INTRODUCTION — Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by pancytopenia, predisposition to malignancy, and physical abnormalities including short stature, microcephaly, developmental delay, café-au-lait skin lesions, and malformations belonging to the VACTERL-H association. Diagnosis is usually made in childhood, although diagnostic delays and variable disease manifestations are common and some individuals may not be diagnosed with FA until adulthood.

Determining whether FA is the cause of bone marrow failure has important implications for management because individuals with FA require increased surveillance for hematologic and non-hematologic malignancies and other organ dysfunction, and dramatically reduced doses of chemotherapy for treating malignancies and in the preparative regimen for hematopoietic cell transplantation (HCT). Additionally, the presence of FA must be confirmed or excluded when evaluating siblings as HCT donors, so that the patient does not receive hematopoietic stem cells from a sibling with FA.

This topic review discusses the clinical manifestations, diagnosis, and differential diagnosis of FA. The management and prognosis of FA is discussed in detail separately. (See "Management and prognosis of Fanconi anemia".)

Separate topic reviews also present a general overview of the evaluation of bone marrow failure in children and adults, and discuss the diagnosis and management of other specific inherited and acquired causes of bone marrow failure:

●General approach (child) – (See "Treatment of acquired aplastic anemia in children and adolescents".)

●General approach (adult) – (See "Approach to the adult with pancytopenia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

●Dyskeratosis congenita (DC) – (See "Dyskeratosis congenita and other telomere biology disorders" and "Inherited aplastic anemia in children and adolescents".)

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

●Paroxysmal nocturnal hemoglobinuria (PNH) – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

●Myelodysplastic syndromes (MDS) – (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

PATHOPHYSIOLOGY — FA is an inherited disorder in which cells cannot properly repair a particularly deleterious type of DNA damage known as interstrand crosslinks (ICLs). This defect in DNA repair results in genomic instability, which in turn leads to increased sensitivity to cytotoxic therapies and a predisposition to certain malignancies. This defect also causes loss of hematopoietic stem cells by a poorly understood mechanism, which in turn can result in bone marrow failure. (See 'Genomic instability' below and 'Etiology of bone marrow failure' below.)

Genetics — FA is caused by mutations in one of at least 17 different FA genes (FANCA to FANCQ), although pathogenicity of mutations in FANCM has been called into question [1-6]. Additional genetic subtypes may be added, including those affecting RAD51 (FANCR), BRCA1 (FANCS), UBE2T (FANCT), XRCC2 (FANCU) [6-13].

In most cases, FA is inherited in an autosomal recessive manner through homozygous or compound heterozygous mutations affecting an individual FA gene. For the majority of FA genes, loss of normal function at both alleles of the gene is required to manifest disease. Two exceptions are the rare FA subtypes associated with mutation in FANCB, which is X-linked recessive, and FANCR (RAD51), which is autosomal dominant [14,15]. Heterozygotes for mutations in FA genes other than FANCB and FANCR are considered to be unaffected carriers, although some of these individuals may have an increased susceptibility to cancer. (See "Management and prognosis of Fanconi anemia", section on 'Testing of siblings and management of heterozygotes'.)

A number of different types of pathogenic alleles have been reported for FA genes, including point mutations, large deletions, and duplications [16]. Genotype-phenotype correlations have been described for certain FA genes [17-19]. However, the presence of congenital malformations in one sibling does not necessarily mean that all affected siblings will have similar congenital malformations [20]. Updated information on FA gene mutations is available from an FA mutation database (www.rockefeller.edu/fanconi/).

Prior to the identification of FA-specific gene mutations and rapid panel-based sequencing methods, subtypes of FA were defined through assignment of complementation groups, a process that historically involved somatic cell fusion studies of patient cells with known index cells for given complementation groups, but now involves gene transfer of complementary DNA (cDNA) for known FA genes into patient cells and assessment for correction of an FA cellular phenotype.

Subsequently, subtype identification for clinical diagnosis has been replaced with next-generation sequencing (NGS) panels (see "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Whole genome, exome, or gene panel'), with the interpretation of the significance of specific mutations supplemented by the expanding literature detailing specific sites of mutations in FA genes associated with disease. Complementation group testing is primarily reserved for clinical scenarios in which chromosomal stress testing is abnormal and either a mutation in known FA genes is not identified or previously undescribed variant(s) are identified and pathogenicity of the variant needs to be determined. (See 'Diagnostic evaluation' below.)

The most commonly mutated genes in patients with FA are FANCA, FANCC, and FANCG, accounting for 80 to 90 percent of FA cases [21,22]:

●FANCA – Mutations in FANCA are responsible for the majority of cases of FA (approximately 60 to 65 percent) [23,24]. A large number (>200) of distinct pathogenic FANCA alleles have been identified, suggesting that in the majority of cases, the 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 [25] . Founder mutations have been described for specific populations. As an example, a large intragenic deletion is seen in the South African Afrikaner population, consistent with a founder effect [26]. The C295T mutation is seen in Spanish Romani populations, who have the highest carrier frequency of FA in the world [27]. Exon 15 deletions, as well as several other specific mutations, are frequent in patients of North African and Middle Eastern descent [28,29] . Genotype-phenotype correlations within the FANCA group show that patients with two mutations leading to null alleles have an earlier onset of hematologic abnormalities, a higher risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and shorter survival after diagnosis than patients with at least one hypomorphic mutation [1].

●FANCC – Mutations in FANCC account for approximately 10 to 15 percent of cases of FA, and have overall been associated with a less severe hematologic course compared with FANCA mutations, with lower incidences of congenital microcephaly and radial ray abnormalities [1]. The most common mutations 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 [30,31].

●FANCG – Mutations in FANCG (also called XRCC9) account for approximately 10 percent of cases of FA. Compared with mutations in FANCA or FANCC, FANCG mutations are associated with similar frequencies of non-hematologic anomalies, but more severe cytopenias and higher rates of MDS and AML [1]. The 637-643delTACCGCC deletion in FANCG is thought to represent a founder mutation responsible for over 80 percent of FA cases in the black South African population [32]. The IVS3+1G>C and 1066C>T mutations in FANCG are common in Japanese and Korean populations, respectively [33,34].

In addition to true FA disorders, defects in non-FA genes (eg, ATR) occasionally have been reported to cause an FA-like syndrome [35-37] . (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2".)

Genomic instability — The major function of FA proteins is to maintain genomic stability, mainly through the repair of DNA interstrand crosslinks (ICLs), DNA lesions in which opposing strands of DNA are abnormally joined together [14,38,39]. ICLs form following exposure to radiation and DNA alkylating agents used as cancer chemotherapy, and from interactions with endogenous aldehydes formed as products of lipid peroxidation or exogenously derived aldehydes formed following alcohol consumption [40]. They interfere with normal DNA replication and transcription by preventing strand separation, stalling replication forks, and compromising DNA integrity. (See "Management and prognosis of Fanconi anemia", section on 'Solid tumors'.)

The formation of ICLs leads to assembly of a multicomponent complex at the site of the ICL called the FA core complex. This complex contains eight of the known FA proteins: FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM. Within this complex, FANCL acts as the catalytic component, functioning as an E3 ubiquitin ligase. The core complex interacts with FANCT (UBE2T) to monoubiquitinate (add a single ubiquitin chain to) the heterodimeric complex of FANCD2 and FANCI. This monoubiquitinated FANCD2/FANCI complex, known as the ID complex, is then incorporated into nuclear foci, where it recruits an endonuclease complex that includes FANCP and FANCQ, which unhooks the aberrant crosslink and creates a DNA double strand break (DSB). Downstream FA proteins encoded by FANCD1 (identical to BRCA2, the breast cancer susceptibility gene), FANCN, FANCJ, and FANCO then work via the well-described DSB DNA repair pathway to restore DNA integrity via nucleotide excision repair and through homologous recombination during the S or G2 phases of the cell cycle [2,7,39,41,42].

In addition to their role in repair of ICLs, increasing evidence suggests that FA proteins participate in other stress response pathways, especially those involving oxidative stress [22,43]. In addition, 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 the NBN gene [2,14,44-47].

In patients with FA, loss of FA gene function leads to disruption of this normal repair process, genomic instability, aberrant cell cycle regulation, and cell death. These cellular effects occur both during development, leading to congenital anomalies, as well as during childhood and into adulthood, leading to increased risk of bone marrow failure, organ susceptibility to toxic exposures, and cancer. (See 'Clinical features' below.)

Etiology of bone marrow failure — The term bone marrow failure refers to a deficiency or impairment of hematopoietic stem cells (HSCs), resulting in bone marrow aplasia and peripheral pancytopenia. Bone marrow failure in FA is thought to occur due to premature, selective attrition of CD34⁺ HSCs, which can be identified even prior to the onset of cytopenias. Many factors have been shown to result in premature HSC loss in individuals with FA, including defective DNA repair leading to increased DNA damage and cell cycle arrest; increased levels of reactive oxygen species and circulating inflammatory cytokines; and excessive damage caused by reactive aldehydes in the absence of intact FA repair pathways, although the exact mechanism of stem cell loss remains unclear [48-51].

The inability to repair DNA damage within HSCs was initially thought to be the major mechanism responsible for HSC attrition. However, subsequent evidence has suggested that in FA the bone marrow microenvironment, which is disrupted because of dysregulated oxidative stress and inflammatory cytokine exposure, may contribute to bone marrow failure via chronic stress-induced HSC activation [48]. In particular, endogenous aldehydes may affect HSCs during development [52]. Evidence to support this theory comes from a series of 64 Japanese patients with FA, in which those who were deficient in acetaldehyde dehydrogenase 2 had accelerated progression of bone marrow failure [53].

Other mechanisms contributing to stem cell attrition have been demonstrated in vitro and in animal models, including an increase in the level of inflammatory cytokines, reduced redox signaling, a diminished heat shock protein response, and abnormal telomere shortening [54-62].

EPIDEMIOLOGY — FA is rare overall, but it is one of the most common inherited bone marrow failure syndromes. The incidence is approximately 1 in 100,000 to 250,000 births [63].

FA has been described in nearly all races and ethnic groups [64]. Ethnic groups with a higher-than-average prevalence of FA include Ashkenazi Jews, Spanish Romani populations, and Black and Afrikaner populations from South Africa [26,65]. These increased prevalences are due to specific founder mutations. Other populations/countries in which founder mutations have been identified include Tunisia, Japan, Korea, and Brazil [28,33,66].

FA is also relatively more prevalent in parts of the world such as specific regions in the Middle East where tribal and/or local customs with respect to marriage make consanguinity, and thus likelihood of inheriting an autosomal recessive disease, more common. In one series, 30 percent of families had two affected children, and consanguinity was noted in 10 percent [64]. The first description of FA was by Guido Fanconi in 1927, in which he described a family with three boys with birth defects and anemia [67].

Historically, the heterozygote frequency for pathogenic FA mutations has been estimated to be 1:300 in the United States and Europe and 1:100 in Ashkenazi Jews and South African Afrikaners. A 2011 study using demographic data from the Fanconi Anemia Research Fund estimated a higher carrier frequency in the United States (within the range of 1:156 to 1:209) and in Israel (within the range of 1:66 to 1:128) [65].

CLINICAL FEATURES

Congenital anomalies — Congenital malformations are the most common presenting features of FA (table 1). Malformations have been reported to occur in 60 to 75 percent of patients, but many in the field believe this represents an underestimate, as many patients with FA do not manifest classical physical findings [68]. Young adults with more subtle clinical findings increasingly may be identified from genomic sequencing. Despite the high frequency of malformations, only a small percentage of patients with FA (<5 percent) are diagnosed within the first year of life based on classic congenital anomalies. Thus, while the presence of these findings provides an important clue to the diagnosis, their absence does not eliminate the possibility of FA.

In a series of 370 patients enrolled in the International FA Registry and a review of over 2000 patients reported in the literature from 1927 to 2009, the most common developmental abnormalities included the following [20,68]:

●Skin findings (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)

•Hands/other such as flat thenar eminence, clinodactyly, polydactyly, missing first metacarpal, dysplastic ulnae (6 percent)

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

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

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

●Gonadal/Genital malformations

•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 anomalies (approximately 5 percent) such as tracheoesophageal fistula, esophageal atresia, intestinal atresia, imperforate anus

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

As noted above, many experts believe that the frequency of congenital anomalies in FA may be underreported, because the above features (in addition to other findings) may be subtle. In a 1997 series of 419 patients in the International FA Registry, one-third lacked an obvious congenital abnormality; however, most of these individuals had short stature, skin pigmentation abnormalities, or microphthalmia [69]. In a 2015 series involving 20 patients with FA who underwent brain magnetic resonance imaging (MRI), 18 (90 percent) had at least one abnormality, the most common being small pituitary gland or an abnormality of the posterior fossa or corpus callosum [70]. Ophthalmologic abnormalities such as microcornea, microphthalmia, and visual processing defects may also be underreported [71,72]. In a 2010 report of the United States National Institutes of Health (NIH) experience, 75 percent of patients were found to have hearing loss or structural ear abnormalities; 90 percent had an ophthalmologic abnormality [68]. Other small series have reported increased incidence of dental anomalies, conductive hearing loss, and skull base/posterior fossa abnormalities [73-76].

An increasing emphasis has been placed on the connection between FA and the VACTERL-H association (defined as three or more of the following: vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb anomalies, and hydrocephalus) for underlying FA. A 2016 study in which a panel of experts in FA examined 54 patients with FA from the NIH inherited bone marrow failure registry (including examinations and imaging studies) found that 18 (33 percent) met criteria for VACTERL-H, a much higher proportion than the 5 percent suggested by earlier studies involving literature reviews [77]. VACTERL-H association is particular strong for patients with mutations in FANCI, FANCL, and possibly FANCB, and may be less common in patients with FANCD1/BRCA2 mutations [78-80].

Cytopenias/bone marrow failure — Cytopenias in FA include thrombocytopenia, macrocytic anemia, or pancytopenia. Bone marrow failure eventually occurs in the majority of patients, though the time to onset can be quite variable. Progression to pancytopenia may occur rapidly after initial cytopenias are noted or may take months or years to develop, or (rarely) may not develop at all.

●Cytopenias – Cytopenias may only be mild upon presentation or may develop later in the disease course if the FA diagnosis is made based on congenital anomalies. In some cases only a single cell line will be involved (typically thrombocytopenia), particularly early in life. Mild to moderate thrombocytopenia may be misdiagnosed as immune thrombocytopenia (ITP). The anemia is typically macrocytic, and some individuals may have macrocytosis without anemia. The degree of cytopenia may be used to characterize the degree of bone marrow failure as mild, moderate, or severe (table 2). Most patients eventually develop symptomatic anemia, although contrary to the name Fanconi "anemia," symptomatic anemia is often the last severe cytopenia to develop. Severe neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet count <30,000/microL) are often more problematic, as they can lead to potentially life-threatening infections and bleeding. Definitions of disease severity based on the bone marrow cellularity and blood counts is discussed in more detail separately. (See "Treatment of acquired aplastic anemia in children and adolescents".)

●Bone marrow failure – In a 2003 report from the International FA Registry that included 754 patients, 601 (80 percent) had bone marrow failure at the time of enrollment; the cumulative incidence was 90 percent by age 40 [18]. In the small percentage of patients in whom bone marrow failure does not develop, specific genetic factors may protect from bone marrow aplasia. Patients with biallelic FANCD2/BRCA2 mutations appear less likely to develop bone marrow failure, though the high rate and early onset of malignancies, coupled with the short lifespan in this population may contribute to this perceived effect. In addition, up to 25 percent of patients with FA may develop acquired somatic mosaicism through gene conversion events (in compound heterozygous patients), back mutation, or even compensatory deletions/insertions, which lead to correction of the chromosomal breakage sensitivity phenotype [81-84]. While many patients may have somatic mosaicism detectable only in lymphocytes, patients with mosaicism in hematopoietic stem cells (HSCs) or progenitor cells have been shown to have an ameliorated bone marrow phenotype. However, these individuals remain at risk for hematologic malignancy and other non-hematologic complications.

Findings on bone marrow examination may be indistinguishable from findings seen in other causes of bone marrow failure such as aplastic anemia or myelodysplastic syndrome (MDS). For patients diagnosed with FA in infancy due to congenital anomalies, screening bone marrow biopsies are often normocellular. By the onset of cytopenias, the marrow may reveal severe hypocellularity out of proportion to the degree of cytopenias. Erythroid dysplasia, including hyperplastic erythroblast islands and megaloblastic features, is commonly seen in many, but not all, bone marrow aspirates from patients with FA, and should not be interpreted in isolation as MDS in the absence of other dysplastic features, increased blasts, or cytogenetic changes. On the other hand, dysplasia in the myeloid series, increased myeloblasts, and with somewhat less specificity dysmegakaryopoiesis, should be considered to be concerning evidence for onset of clonal abnormalities consistent with MDS [22,85].

MDS/Leukemia — MDS and leukemia are common in patients with FA; in many cases, MDS or acute myeloid leukemia (AML) is the presenting finding. Patients with FA have been estimated to have a 6000-fold and 700-fold greater risk than the general population for developing MDS and AML, respectively [86]. By age 50, up to 40 percent of patients with FA will develop MDS and up to 15 percent will develop AML. Lymphoid malignancies including acute lymphoblastic leukemia (ALL) and Burkitt lymphoma are also seen, although they are much less common [18]. A period of bone marrow hypoplasia precedes the development of hematologic malignancies in some but not all cases [22].

Leukemia risk is even higher in patients with biallelic mutations in FANCD1/BRCA2. These individuals have a cumulative incidence of leukemia of 80 percent by age 10 [80]. Most develop AML, although some may develop T cell ALL. Patients with mutations in BRCA2 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 gains of chromosome 3q [22]. In one study of 53 patients, 18 had 3q amplification, which was associated with shorter survival and increased risk for development of AML [87]. A 2012 literature review identified 46 cases of AML in patients with FA in whom cytogenetics were available and found the most common cytogenetic abnormalities to be chromosomal gains of 1q, 3q, or 13q, along with loss of chromosome 7 (or more specifically, 7q) [88]. In contrast, cytogenetic lesions common in de novo AML including t(8;21), trisomy 8, and inv(16) were not seen in any of the patients with FA.

Cytogenetic clones should be interpreted within the context of the bone marrow morphology. Some cytogenetic clones of unclear clinical significance may remain stable or become undetectable over time, whereas loss of part or all of chromosome 7 necessitates consideration of hematopoietic cell transplant (HCT) prior to leukemia progression. With any cytogenetic abnormality, close monitoring of the bone marrow and the blood counts is warranted. (See "Management and prognosis of Fanconi anemia", section on 'Hematologic neoplasms'.)

Solid tumors — A number of solid tumor types have been reported to occur at increased frequency in individuals with FA, and these appear at a much younger age than the age at which these tumors are seen in unaffected individuals. As an example, a 2003 study involving a cohort of 1300 individuals with FA estimated the median age of cancer development to be approximately 16 years, compared with 68 years in the general population [89]. In many late-onset cases of FA, malignancy is the presenting finding.

The cumulative incidence of solid tumors is increasing as individuals with FA are living longer, due to cure of bone marrow failure by HCT. In addition, HCT may increase the risk of solid tumors in some individuals with FA, likely due to a combination of factors including exposure to DNA damaging agents or radiation in the conditioning regimen and the development of graft-versus-host disease (GVHD). This trend was demonstrated in a study that compared the rates of cancer between 117 individuals with FA who underwent HCT with 145 who did not [90]. The age-specific hazard of squamous cell cancer was 4.4-fold higher in individuals who had a transplant, and the tumors occurred at a younger age (median age, 18 versus 33 years). In another series of 37 individuals with FA who underwent HCT, the 15-year incidence of head and neck cancers was 53 percent [91].

Unlike for AML, where risk in patients with FA reaches a plateau between 30 to 40 years of age, the annual risk of developing a solid tumor continues to increase significantly with age, particularly in FA patients greater than age 30 [18,86,92-94]. A 2003 study from the International FA Registry estimated the cumulative incidence of solid tumors by the age of 40 years at 28 percent [18]. This study followed 754 patients for over 20 years and identified 79 solid tumors. The most common were squamous cell cancers (SCCs) of the head, neck, esophagus, anus, and urogenital region; these accounted for 39 of the solid tumors (49 percent). There were also 18 liver tumors, accounting for 23 percent of tumors; as well as six renal tumors, five brain tumors, three breast cancers, and other tumor types including germ cell tumors and sarcomas. Similar findings have been reported in other cohorts [92,93].

Despite this high incidence of malignancy, solid tumors are rare in childhood, with the exception of those harboring biallelic FANCD1/BRCA2 mutations, in whom the likelihood of at least one malignancy is greater than 97 percent by seven years of age [95]. For patients with FANCD1/BRCA2 mutations, brain tumors occur in over 50 percent by five years of age (second only to leukemia in frequency), although new onset brain tumors are rare beyond this age [86]. Wilms tumor is also common in patients with biallelic FANCD1/BRCA2 mutations, and less frequently other solid tumors of childhood are seen, including rhabdomyosarcoma and neuroblastoma [95].

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 were due to increased susceptibility to genomic instability produced by HPV, as >80 percent of these tumors were HPV-positive [96]. However, subsequent reports contradicted these findings, demonstrating HPV DNA in only two of 21 and one of nine patients in the two reports [97,98]. Many of the tumors in the European cohort demonstrated p53 mutations [98]. Thus, whether patients with FA have increased indication to receive vaccination to HPV compared to the general public remains unknown. We give the HPV vaccine to all patients with FA since uncertainty remains regarding this issue. (See "Virology of human papillomavirus infections and the link to cancer" and "Epidemiology and risk factors for head and neck cancer" and "Management and prognosis of Fanconi anemia", section on 'Solid tumors'.)

Endocrine manifestations — Individuals with FA may have a range of endocrine disorders. In many cases, endocrine abnormalities result from anatomical disruption of the hypothalamic-pituitary axis during development, including common abnormalities such as pituitary stalk interruption syndrome and septo-optic dysplasia [99]. In other cases, specific organ dysfunction, either intrinsic to the disease or as a consequence of HCT-associated therapies (eg, conditioning regimen, therapy for GVHD) leads to endocrine abnormalities.

●Short stature is seen in the majority of patients, but some patients have normal or even above-average height regardless of genotype [100]. 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 [100].

●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 [101].

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

●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 [102].

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 individual FA mutations have long been considered to be asymptomatic carriers, with the exception of monoallelic FANCS/BRCA1 and FANCD1/BRCA2 mutations, which are well-known to predispose to breast and ovarian cancer; FANCB, which is X-linked recessive; and FANCR (RAD51), which is autosomal dominant. Individuals who are heterozygous for FA mutations other than FANCB and FANCR do not develop bone marrow failure, although these individuals are occasionally noted to have FA-associated congenital anomalies.

Concerns that carriers of other heterozygous FA mutations might have an increased risk of cancer was addressed in a cohort of 404 carriers and 329 non-carriers of an FA mutation (relatives of individuals in the International FA Registry), in whom cancer rates were compared with population cancer rates from the Surveillance, Epidemiology, and End Results (SEER) and Connecticut tumor registries [103]. This study found no suggestion of an increased overall cancer incidence (standardized incidence ratio [SIR] relative to the US 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). Since this study was published in 2007, however, heterozygous mutations in several FA genes, including FANCN (PALB2) and FANCJ (BRIP1), have been identified as low to moderate penetrance breast and/or ovarian cancer susceptibility genes [104-106].

Individuals who are heterozygous for mutations in two or more distinct FA genes also are not reported to develop classic FA features, as long as these mutations occur exclusively in distinct FA genes (ie, as long as they are not compound heterozygous mutations in the same FA gene). The possibility of an increased cancer risk in individuals who are heterozygous for two distinct FA mutations was raised in a report of a family with familial childhood acute lymphoblastic leukemia (ALL), in which potentially pathogenic germline variants in both FANCP and FANCA were identified [107]. This finding raises the possibility that co-inheritance of two or more deleterious germline heterozygous mutations in distinct FA genes may synergistically increase cancer susceptibility. However, this hypothesized effect has yet to be proven in large scale genomic studies.

DIAGNOSTIC EVALUATION

Indications for testing — Diagnostic delays are common in FA, especially in individuals who do not develop bone marrow failure early in their course [20]. Most children are diagnosed between six and nine years of age, concurrent with the onset of bone marrow failure. Registry series have reported a typical age at diagnosis of approximately seven years (6.5 years for boys and 8 years for girls), although the time to diagnosis appears to be shortening with increased disease awareness [20,63,93]. As many as 9 percent are diagnosed after 16 years of age, when they present with a malignancy [63,108].

Early diagnosis is important because it allows time for additional evaluation of the patient (eg, for congenital anomalies) and the siblings (as potential hematopoietic cell transplantation [HCT] donors). Family planning with conception and preimplantation genetic screening of additional children who may be potential HCT donors has been performed, although success rates to date with this approach have been quite low [20,109].

Testing for FA is absolutely and urgently indicated in any child or young adult meeting any of the following criteria:

●Two or more moderate to severe cytopenias (absolute neutrophil count [ANC] <1000/microL, platelet count <50,000/microL, hemoglobin <10 g/dL with absolute reticulocyte count <40,000/microL), persistent for more than two weeks, and a hypocellular bone marrow (<25 percent of normal cellularity) in the absence of malignancy, cytotoxic therapy, or other known cause. (See 'Cytopenias/bone marrow failure' above.)

●Findings that satisfy criteria for the VACTERL-H association or multiple other malformations such as short stature, café-au-lait spots, or hypospadias, which are strongly associated with FA. (See 'Congenital anomalies' above.)

●Relative of a known patient with FA who is being evaluated as a potential donor for HCT. (See "Management and prognosis of Fanconi anemia", section on 'Testing of siblings and management of heterozygotes'.)

Testing for FA is also recommended (although less urgently) in the following scenarios, with the rationale that the diagnosis of FA should be established (or eliminated) prior to administration of cytotoxic chemotherapy for cancer or HCT; and if FA is present, related family members should be tested before being considered as HCT donors:

●Any patient with single-lineage or multi-lineage cytopenias without known cause who also has one or more congenital malformations strongly associated with FA.

●Any patient less than 40 years of age diagnosed with myelodysplastic syndrome (MDS) not attributable to other known genetic cause or to prior cytotoxic radiation or chemotherapy.

●Any patient less than 40 years of age with de novo acute myeloid leukemia (AML) not caused by another known germline predisposition and associated with the following cytogenetics: monosomy 7, deletion 7q, complex, gain of 1q, 3q, or 13q. The rationale is that doses of chemotherapy and/or cytotoxic agents given as part of the HCT conditioning regimen would be dramatically reduced in a patient with FA.

●Any patient with unexplained severe toxicity to cytotoxic agents indicative of increased sensitivity without other known cause [22,110].

●Any child or young adult who develops head/neck or anorectal squamous cell carcinoma with no known attributable exposures.

●Family members of known FA patients who request genetic testing.

As noted above, while the presence of congenital anomalies is helpful in identifying affected individuals, the absence of these features does not eliminate the possibility of FA. (See 'Congenital anomalies' above.)

Diagnostic testing — The hallmark of FA is defective DNA repair that results in extreme sensitivity to DNA interstrand crosslinking agents. The screening laboratory test for this defect involves assessment of chromosomal breakage upon exposure of cells to diepoxybutane (DEB) or mitomycin C (MMC) [63,111]. This testing is performed on T lymphocytes; thus, peripheral blood is preferred as a test source over bone marrow. In settings of severe leukopenia, the testing can still be performed, provided that the testing lab is able to adequately expand cells in culture. Due to the nature of this assay, the turnaround time for this testing is generally in the range of two to four weeks.

If chromosomal breakage testing of lymphocytes is negative in the setting of a high pre-test probability of FA based on characteristic physical features, we repeat the testing on skin fibroblasts. Skin fibroblast testing is also needed for patients who have already undergone HCT [19].

While chromosomal breakage testing is quite sensitive for FA, it is not entirely specific, as there are several other rare genetic conditions associated with chromosomal instability (see 'Differential diagnosis' below) that can yield a positive test [112]. Qualitative assessments of the patterns of abnormal breakage can help distinguish FA from other chromosome instability syndromes, including rates of spontaneous breakage, increased breakage in response to both DEB and MMC (most common in FA) versus increased breakage to MMC alone (more common in other chromosomal breakage syndromes), and the presence of atypical features such as railroad figures and premature centromere separation, which is seen exclusively in the cohesinopathies [113].

An alternative to traditional chromosomal breakage testing is cell cycle analysis by flow cytometry following DNA crosslinking agent exposure. In this test, FA cells that are unable to repair DNA damage undergo cell cycle arrest in G2, leading to a much higher percentage of cells in G2 in MMC-exposed blood cells from FA versus non-FA patients. However, because this test yields similar information as the more widely used chromosomal breakage testing and does not differentiate FA from other breakage syndromes, its use in routine testing remains limited [113]. Immunoblotting for FANCD2 ubiquitination as a clinical test has the advantage of enabling rapid diagnosis but the disadvantage of missing patients with FA mutations downstream of FANCD2 [114]. Thus, this test also is not routinely used.

FA gene sequencing is recommended for all patients with a positive result from chromosomal breakage testing. The reasons for this recommendation are several-fold:

●Identification of the genetic defect definitively confirms the diagnosis and eliminates other chromosomal breakage disorders as the cause of the abnormal screening test.

●Sequencing enables screening of family members for the purposes of identifying HCT donors, performing prenatal testing, and genetic counseling, given that heterozygous carriers will not have abnormal chromosomal breakage testing [19].

●Sequencing enables precision medicine application of genotype/phenotype correlations (see 'Genetics' above) to the care of individual patients (eg, cancer screening in heterozygotes for mutations with increased risk of solid tumors).

When sequencing is done, in most cases the initial test should consist of single gene sequencing of FANCA, which is most likely to be affected, with reflex to sequencing the remaining FA-associated genes via multiplex next-generation sequencing (NGS) panel testing if the FANCA gene is normal. NGS panel testing is available clinically through a number of laboratories, many of which are listed on the Genetic Testing Registry website. In individual circumstances however, this algorithm may be adjusted. For instance, patients from Ashkenazi Jewish backgrounds may be screened first for the founder IVS4 +4A>T mutation in FANCC before proceeding to NGS testing, and family members of an individual with a known mutation should be tested for that mutation.

As discussed above (see 'Genetics' above), complementation group testing, once a standard part of the assessment and subtype assignment for patients with FA, has largely been replaced by sequencing for most patients. However, complementation group testing may still be used to define the functional subtype of FA in situations where either no variants in FA genes are identified by NGS, or several variants in distinct FA genes are identified. In these cases, attributing causality to a specific mutation can be accomplished through complementation analysis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FA includes other inherited and acquired causes of bone marrow failure (table 3).

●Acquired aplastic anemia (aAA) – aAA is an acquired bone marrow failure syndrome caused by autoreactive T cell destruction of hematopoietic stem cells (HSC) and bone marrow progenitor cells [115]. aAA develops following poorly understood environmental triggers in susceptible individuals who often have other manifestations of autoimmunity, including autoimmune thyroid disease. Like FA, patients with aAA often present between 5 to 15 years of age with multilineage cytopenias and bone marrow aplasia, and hematopoietic cell transplantation (HCT) is an effective curative modality. Unlike FA, individuals with aAA have normal chromosomal breakage testing; absence of pathogenic mutations in FA genes; lack of congenital anomalies and endocrine features characteristic of FA; typically a more rapid onset and progression of cytopenias; and a response 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 is an acquired bone marrow failure syndrome typically developing concurrent to or following the onset of aAA, in which acquired mutations in the PIGA gene result in the dominance of a hematopoietic progenitor cell clone lacking glycosylphosphatidylinositol (GPI) anchors. Like FA, PNH is associated with bone marrow failure. Unlike FA, individuals with PNH have chronic intra- and extravascular hemolytic anemia and a high risk of thrombosis, and they do not have abnormal chromosomal breakage testing or FA-associated congenital anomalies. The presence of a PNH clone, regardless of size, is increasingly used as evidence that bone marrow failure is due to acquired autoimmunity rather than an inherited condition such as FA. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

●Other inherited bone marrow failure syndromes – The other inherited bone marrow failure syndrome that is frequently associated with bone marrow aplasia is dyskeratosis congenita (DC) (see "Dyskeratosis congenita and other telomere biology disorders"). Unlike FA, patients with DC will have very short telomeres on telomere length analysis of peripheral blood lymphocytes. Reticular dysgenesis (RD) is a type of severe combined immunodeficiency caused by mutations in the AK2 gene that may also be associated with bone marrow aplasia. However, unlike FA, patients with RD develop bone marrow aplasia in infancy associated with sensorineural hearing loss and severe adaptive immune dysfunction. Shwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia (CAMT), and Diamond-Blackfan anemia (DBA) also may be associated with trilineage aplasia in the bone marrow, but typically this develops after an extended period of isolated neutropenia (SDS), thrombocytopenia (CAMT), or anemia (DBA). DBA in particular is often difficult to distinguish on clinical features from FA due to the overlap in VACTERL-H association in both DBA and FA. Unlike FA, patients with these other conditions have other gene mutations and a negative chromosomal breakage test.

●Drug-induced or infection-associated pancytopenia – Transient pancytopenia and bone marrow hypoplasia may be caused by a number of exposures including medications, chemicals, certain viral infections, and sepsis or other severe bacterial infections. Like FA, these conditions typically present in childhood with bone marrow failure. Unlike FA, patients with these causes of pancytopenia lack congenital anomalies and in most cases pancytopenia is transient and reversible, although in rare cases, bone marrow aplasia caused by drugs can be permanent. These conditions also are associated with a negative chromosomal breakage test. (See "Treatment of acquired aplastic anemia in children and adolescents".)

●Rare chromosomal breakage syndromes – A number of non-FA chromosomal instability syndromes associated with sensitivity to ionizing radiation and variable sensitivity to DNA crosslinking agents used in chromosomal breakage testing have been characterized. These disorders and the genes in which causal mutations have been found include Nijmegen breakage syndrome (NBS), Bloom syndrome (BLM), ataxia telangiectasia (ATM), LIG4 syndrome (LIG4), NHEJ1 deficiency (NHEJ1), Seckel syndrome (ATR), and the cohesinopathies Roberts syndrome (ESCO2) and Warsaw breakage syndrome (DDX11).

Like FA, these rare chromosomal instability syndromes are associated with multiple congenital anomalies, often including microcephaly, short stature, and increased risk of malignancy. Also like FA, these syndromes will often cause an abnormal chromosomal breakage test.

Unlike FA, patients with NBS do not typically exhibit bone marrow failure except in the setting of evolving malignancy. Also compared to FA, these conditions show subtle differences in the associated congenital anomalies, the spectrum of associated malignancies, and the specific abnormalities seen within chromosomal breakage testing (eg, increased chromosome 7 and 14 abnormalities in NBS, railroading figures in cohesinopathies). However, in particularly difficult cases, genomic sequencing studies are especially helpful in distinguishing FA from NBS and other rare chromosomal breakage syndromes. (See "Nijmegen breakage syndrome".)

●De novo myelodysplastic syndrome (MDS) – MDS is defined in the World Health Organization (WHO) 2016 guidelines as a group of clonal bone marrow neoplasms characterized by ineffective hematopoiesis and manifested by morphologic dysplasia and peripheral cytopenias [116]. MDS can arise de novo or secondary to another bone marrow disorder; many patients with FA develop secondary MDS in childhood or young adulthood. Like FA and FA with secondary MDS, de novo MDS can cause bone marrow failure with variable cytopenias, multilineage dysplasia, cytogenetic abnormalities, and increased blasts. Unlike FA or FA with secondary MDS, de novo MDS is not associated with congenital anomalies, an abnormal chromosome breakage test, or FA mutations. 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".)

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) is an inherited bone marrow failure syndrome in which cells cannot properly repair a particularly deleterious type of DNA damage known as interstrand crosslinks (ICLs). This results in increased sensitivity to cytotoxic therapies, predisposition to certain malignancies, and bone marrow failure. In most cases, inheritance is autosomal recessive. A large number of genes are involved; the most commonly mutated are FANCA, FANCC, and FANCG. (See 'Pathophysiology' above.)

●FA is rare overall, but it is one of the most common inherited bone marrow failure syndromes, with an incidence of approximately 1 in 100,000 to 250,000 births. Groups with a higher prevalence of FA include Ashkenazi Jews, Spanish Romani populations, and Black and Afrikaner populations from South Africa. (See 'Epidemiology' above.)

●The most common presenting features of FA are congenital malformations (table 1). Cytopenias are also common, and many patients eventually develop bone marrow failure. Common malignancies include myelodysplastic syndrome (MDS), leukemia, and solid tumors, especially squamous cell cancers (SCC). With some exceptions noted above, heterozygotes for FA mutations are considered to be asymptomatic carriers. (See 'Clinical features' above.)

●Diagnostic delays are common in FA. Testing for FA is absolutely and urgently indicated in any child or young adult with two or more severe cytopenias (table 2) and reduced bone marrow cellularity in the absence of a known cause; patients who satisfy criteria for the VACTERL-H association or have other typical FA malformations; and first degree siblings of affected individuals who are being considered as hematopoietic cell transplant (HCT) donors. Testing for FA is also recommended in other patient groups listed above. (See 'Indications for testing' above.)

●Diagnostic testing for FA is done by assessment of chromosomal breakage upon exposure of peripheral blood lymphocytes or skin fibroblasts to diepoxybutane (DEB) or mitomycin C (MMC). FA gene sequencing is recommended for all patients with a positive result from chromosomal breakage testing. (See 'Diagnostic testing' above.)

●The differential diagnosis of FA includes acquired aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), other inherited bone marrow failure syndromes, other causes of pancytopenia, other chromosomal breakage syndromes, and de novo MDS (table 3). (See 'Differential diagnosis' above.)

●The management and prognosis of FA is discussed in detail separately. (See "Management and prognosis of Fanconi anemia".)

●The general evaluation of a child or adult with unexplained pancytopenia or bone marrow failure is also discussed separately. (See "Treatment of acquired aplastic anemia in children and adolescents" and "Approach to the adult with pancytopenia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

ACKNOWLEDGMENTS — UpToDate would like to acknowledge 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.