A number of inherited (constitutional/genetic) disorders are characterized by BM (Bone Marrow) failure usually in association with one or more somatic abnormality. The BM failure may involve all or a single lineage; in some cases it may be initially associated with a single peripheral cytopenia and then progress to pancytopenia. Scientifically, they constitute an exciting group of disorders and the two syndromes that are frequently associated with generalized BM failure; are FA (Fanconi’s Anemia, named for Swiss pediatrician, Guido Fanconi) and DC (Dyskeratosis Congenita) (Ref.1). FA is a rare autosomal recessive chromosome instability disorder clinically characterized by developmental defects, progressive BM failure, progressive AA (Aplastic Anemia), diverse congenital anomalies and an increased predisposition to malignancy, especially AML (Acute Myeloid Leukemia) and squamous cell carcinoma. Most, but not all, affected individuals also have one or more somatic abnormalities including skin, skeletal, genitourinary, gastrointestinal, cardiac and neurological anomalies (Ref.1 & 2). FA cells are hypersensitive to IR (Ionizing Radiation) and to the DNA crosslinking agents, such as MMC (Mitomycin-C) and DEB (Diepoxybutane), suggesting a cellular defect in DNA repair (Ref.3).
Eleven or more genetically distinct groups of FA have been described (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCG, FANCE, FANCF and FANCL), each caused by recessive mutations in a different gene (FANCA, FANCB, etc.) (Ref.4, 7 & 9). By far the largest fractions of FA cases fall within three of these groups: FA-A (65% of all FA cases), FA-C (15%) and FA-G (10%). BRCA2 mutations have been found in the FA-D1 group (and, possibly, in FA-B) and are therefore a rare cause of a rare syndrome, the overall incidence of which is in the order of 1 per 100,000 live births (Ref.4). The FA proteins, including a ubiquitin ligase (FANCL), a monoubiquitinated protein (FANCD2), a helicase (FANCJ/BACH1/BRIP1), and a breast/ovarian cancer susceptibility protein (FANCD1/BRCA2), cooperate in a pathway leading to the recognition and repair of damaged DNA. FANCE is an essential component of the nuclear FA core complex, which is required for monoubiquitination of the downstream target FANCD2, an important step in the FA pathway of DNA cross-link repair. FANCE is predominantly localized in the nucleus and acts as a molecular bridge between the FA core complex and FANCD2, through direct binding of both FANCC and FANCD2 (Ref.8). Six of the proteins (FANCA, FANCC, FANCE, FANCF, FANCG and FANCL) assemble in a multisubunit nuclear complex required for the activation of FANCD2 (FA subtype D2 protein) to a monoubiquitinated isoform (FANCD2-Ub), either in response to DNA damage or during S-Phase of the cell cycle, thereby targeting D2 to the FA protein complex and the cellular BASC (BRCA1-Associated Genome Surveillance Complex), which is important in recognizing and repairing DNA damage. BASC contains many tumor suppressors and DNA damage repair proteins including BLM (Bloom syndrome), the Rad50-MRE11-NBS1 complex, mismatch-repair proteins (Hereditary Nonpolyposis Colorectal Cancer), ATM (Ataxia-Telangiectasia) and ATR. ATM can phosphorylate both FANCD2 and BRCA1 (Ref.5 & 10). The ATM-dependent phosphorylation of FANCD2 occurs in response to DNA damage induced by IR, which is important in S-Phase checkpoint response (Ref.1 & 11). This puts FANCD2 in a central position in signaling DNA damage. Disruption of the FA pathway blocks FANCD2 ubiquitination and renders cells hypersensitive to DNA crosslinking agents. Double-strand DNA breaks caused by IR result in ATM-dependent phosphorylation of FANCD2, whereas interstrand DNA crosslinks caused by crosslinking agents (Cisplatin, Mitomycin-C, and Melphalan) produce monoubiquitination of FANCD2 via the FA nuclear complex (Ref.1). One of the defining characteristics of FA is hypersensitivity to the cytotoxic and clastogenic effects of DNA cross-linking agents, such as MMC, DEB, cisplatin, photo activated psoralens, etc. Thus, this feature can be used to good advantage to obtain a reliable and sensitive diagnosis of FA. FA cells have a well-known sensitivity to oxygen. FANCC (FA Group C Protein) regulates GSTP1 (Glutathione S-Transferase P1-1), a cytoplasmic enzyme involved in detoxifying ROS (Reactive Oxygen Species) and by-products of Oxidative Stress (Ref.6).
FA occurs equally in males and females. It is found in all ethnic groups. Though considered primarily a blood disease, it may affect all systems of the body. The most common are thumb and arm anomalies (misshapen, missing, bifid, or hypoplastic thumb, incompletely developed or missing radius in the forearm bones), skeletal anomalies (of the hips, spine, or ribs), kidney problems, including missing or horseshoe kidney, skin discoloration (that is, hypopigmentation or café au lait spots), small head or eyes, mental retardation or learning disabilities, low birth weight, gastrointestinal difficulties, small reproductive organs in males, defects in tissues separating chambers of the heart. Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. FA patients are usually smaller than average. FA usually reveals itself before children are 12 years old, but in rare cases no symptoms are present until adulthood. Patients may feel extreme fatigue and have frequent infections. Nosebleeds or easy bruising is the first sign. Sometimes myelodysplasia or AML is the first sign of FA. Many patients do not reach adulthood. Allogeneic BMT (Bone Marrow Transplantation) or umbilical cord-blood transplantations are the main effective treatments for FA but requires a dose reduction of alkylating agents used for conditioning because of the increased sensitivity of FA cells to DNA cross-linking agents (Ref.7).