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Fanconi Anemia Epidemiology and Pathophysiology

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Fanconi anemia is the most frequently reported rare inherited bone marrow failure syndromes (IBMFSs), around 2000 cases have been reported in the medical literature. It was first reported by Guido Fanconi in 1927. He observed 3 brothers with macrocytosis, pancytopenia, and physical abnormalities (Alter et al., 1993).


The total number of people suffering from FA has not been documented worldwide.Scientists estimate that the carrier frequency (people carrying a defect in one copy of a particular FA gene, while the other copy of that same FA gene is normal) for FA in the United States of America is 1 in 181. The incidence rate, or the chance of an offspring being born with FA, is about 1 in 131,000 in the U.S., with approximately 31 children born with FA each year. (Schroederet al., 1976; Swift et al.,1971). Fanconi anemia has been reported inall ethnic groups. However, due to founder effects, the heterozygote frequency is greater in South African Afrikaners, (Rosendorff et al.,1987) sub-Saharan blacks (Neil et al., 2005), and Spanish gypsies (Callen et al., 2005) than in the general world population. The expected birthrates in these ethnic groups are around 1 case per 40,000 births. The carrier frequency is about 1 case per 90 people for the Ashkenazi Jews in the United States(Rosenberg 2011). The male-to-female ratio is 1.2:1,though equal numbers are predicted in a disorder with over 99% autosomal recessive inheritance. Fanconi anemia has been diagnosed in patients from birth to 49 years, with a median age of 7 years. Individuals with birth defects are diagnosed at younger ages when compared to those without any birth defects (Tanguichi etal., 2006).


Sixteen FA complementation groups have been characterized so far (A, B, C, D1/BRCA2, D2, E, F, G, I, J/BACH1/BRIP1, L, M, N/PALB2, O/RAD51C, FANCP/SLX4 and FANCQ/ERCC4) (Crossanet al., 2012, Boglilo et al., 2013). All FA genes except FANCB are located on autosomes. FANCB is located on the X chromosome (Meetei et al., 2004). Table 1 depicts the chromosomal location of the 16 FANC genes. Individualswith mutations in any of these 16 FA genes share a distinctiveclinical and cellular phenotype, and these 16 gene products function in a common cellular pathway, called the Fanconi anemia pathway (Kee et al., 2010).

The basic FA pathway

DNA is replicated by DNA polymerase from multiple replication forks. Any lesions that disturb the structure of the chromatin, such as chemically induced DNA crosslinks, result in stalling of replication at the position of the lesion. The Fanconi Anemia pathway mainly acts in response to DNA damage that leads to the stalling of the DNA replication forks during S phase of the cell cycle. The activation of the FA core complex, that consists of at least 8 of the known FA proteins (A, B, C, E, F, G, L, and M) occurs through the recruitment of ATR (ataxia telangiectasia and Rad3 related) (Andreassen et al., 2004) to the single-stranded DNA at stalled replication fork (Zou and Elledge 2003). The activated FA core complex functions as an E3 ubiquitin ligase that mono-ubiquitinates FANCD2 (Fanconi anemia complementation group D2). FANCL is the putative catalytic element of the core complex complex. FANCL consists of a PHD domain and bears homology to other known E3 ubiquitin ligases (Meetei et al., 2003a). The monoubiquitination of FANCD2 results in its relocalization from the soluble nuclear compartment to the chromatin (Wang et al., 2004) and subsequently in its association with other repair proteins, such as BRCA1, RAD51, NBS1, and PCNA and with FANCD1/breast cancer 2, and early onset (FANCD1/BRCA2) in the chromatin (Wang et al., 2004; Garcia-Higuera et al., 2001; Tanguichi et al., 2002; Nakanishi et al., 2002; Hussain et al., 2004). During S phase of the normal cell cycle, the core complex, monoubiquitinates FANCD2 on Lys 561 and an induced monoubiquitination occurs when cells are exposed to DNA damaging substances such as MMC, IR and UV radiations (Garcia-Higuera et al., 2001; Gregory et al., 2003). Along with FANCD2, complex 1 also results in the monoubiquitination of FANCD1 (REF). DONE

Cells that cannot to form complex 1 or complex 2 are generally hypersensitive to cross-linking agentssuch as MMC and these cells exhibit the characteristic broken and radial chromosome forms of FA. Mutations in eight FA subtypes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) result in loss of FANCD2 and FANCI monoubiquitylation, which is the central regulatory step in the FA pathway. 90% of individuals with FA are reported to have mutations recorded in these eight FA genes (Table 1).

A close association has been established between the FA pathway and the BRCA proteins in the DNA repair mechanisms. BRCA2 was identified as an FA gene – FANCD1 (ref 27 ). FANCN/PALB2 is a known partner of BRCA2/FANCD1 and aids in its localization. (refs. 29, 30), FANCJ/BRIP1 (BRCA1-interacting helicase1) (refs. 31, 32), and, FANCO (RAD51C; an already known homologousrepair factor; refs. 33, 34) further strengthen the intricate associationof breast and ovarian susceptibility genes with FA.

There is clinical variability among FA patients, owing to the different FA subtypes.(1). FA patients of subtype A have milder disease and late onset of bone marrow failure. Patients of subtypes FANCC and FANCG generally have a more severe phenotype and require early intervention that includes bone marrow transplantation. While FA patients assigned to subtype FANCI have early onset and increased incidence of solid tumors and leukemia (35). In general, diagnosing the disease at an early stage and identifying the gene mutated is important for genetic counseling of parents with FA patients with regard to future pregnancies.


Individuals with FA exhibit numerous congenital defects, butapproximately 25%–40% of FA patients are physically normal (D’Andrea 2010)). Majority of children with FA have congenital skeletal anomalies of the thumb and forearm. The thumbs are usually smaller (hypoplastic), duplicated, or absent and the forearm radius is either reduced or absent (Giampietro et a., 1993). Fig represents the commonly observed deformities seen in FA patients. Several FA patients display endocrine abnormalities. More than half of FA individuals have short stature which has been attributed to insufficient growth hormone production and hyperthyroidism. There are also reports of FA patients with normal stature and no obviousdeficiency in growth hormone production. Abnormal glucose or insulin metabolism has also been associated with FA. While individuals with diabetes have reduced insulin levels, FA individuals generallyhave a higher level of serum insulin. Reports suggest that approximately 8% ofindividuals with FA are diabetic, while up to 72%have elevated serum insulin levels (Giri et al., 2007; Elder et al., 2008). In addition, osteoporosis has also been associatedwith FA (Wajnrajch et al., 2001; Rietscheli et al., 2001). Hematological abnormalities are the most predominant pathological manifestation of FA. 75%–90% of FA patientsdevelop bone marrow failure, aroundthe first decade of life (Butturini et al., 1994; Kutler et al., 2003).

In addition to bone marrow failure, most FA patientsdevelop varying degrees of blood disease, these include aplastic anemia,myelodysplastic syndrome (MDS), or acute myeloid leukemia(AML). The risk of AML occurrence in FA patients is approximately 800-foldhigher than that of the general population, with a median age ofonset of 14 years. Recent studies have revealed a common pattern ofchromosomal abnormalities in FA patients with MDSor AML (e.g., gain of 1q23-32, 3q26), suggesings that theseabnormalities can be worthwhile predictive markers (Soulier 2011; Quentin et al., 2011; Meyer et al., 2011; Meyer et al., 2007). The exact cause of these hematopoietic defects is uncertain, althoughincreasing evidence suggests an underlying hypersensitivity of FAhematopoietic cells to oxidative stress (Du et al., 2008).

Although FA is chiefly a pediatric disease, adult FA patientswho are older than 18 years, represent an increasing proportion of the entireFA patient population. This has been attributed to improved management of youngFA patients and a rigorous diagnostic testing in adults. One of themajor health threats faced by adult FA patients is the risk ofacquiring cancer (Taniguchi et al., 2006). In addition to hematologic cancers, solid tumors,predominantly squamous cell cancers (SCCs) of the head and neckand cervical/gynecological cancers, occur at evidently higherrates in FA patients (Kutler et al., 2003). Approximately one-third of FA patientsare reported to develop a solid tumor by their fourth decade of life (Rosenberg et al., 2003). In addition to the hematological abnormalities and increased cancer predisposition, FA individuals also exhibit other clinical problems,which includes hearing loss, ear anomalies as well as reduced fertility (Giampietro et al., 1993). Lowered sperm count is reported in male FApatients, and premature menopause is reported in female patients (Alter et al., 1991). The rate of successful pregnancy is approximately15% among non-transplanted FA patients (Alter et al., 1991), although improved fertility and successful pregnancy has been reported after HSC transplantation (Nabhan et al., 2010). Consistent with reports in FA patients, knock out mouse models of Fanca, Fancc, Fancg, and Fancd2 also exhibited pronounced hypogonadismand impaired fertility, with female offsprings more severely affected than males (Parmar et al., 2009; Koomen et al., 2002).

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