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Fanconi Anemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Since the cloning of the first Fanconi anemia-related gene (FANCC) in 1992, a total of 22 genes (i.e., FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR/RAD51, FANCS, FANCT, FANCU, FANCV, and FANCW) have been isolated and characterized by using complementation analysis of cell lines from affected patients, positional cloning, biochemical purification, and sequencing analysis (Table 73.1). These genes encode components of the FA (or FA/BRCA) pathway that work in coordination to repair DNA damage and ensure genome stability [5]. Homozygous or compound heterozygous mutations in 20 of these genes (except for FANCB and FANCR/RAD51), or heterozygous mutations in FANCR/RAD51, or hemizygous mutations in X-chromosome-linked FANCB result in nonfunctional proteins that cause disruption in the FA pathway, compromise DNA damage repair, and induce various chromosome breaks (Figure 73.1) [6–9].
Hematological problems in the neonate
Published in Prem Puri, Newborn Surgery, 2017
Andrea M. Malone, Owen P. Smith
FA is a chromosomal instability disorder caused by genetic defects in DNA repair. Bone marrow failure is rarely present in infancy. It is characterized by physical abnormalities (commonly short stature, skin hyper- or hypopigmentation, upper limb and thumb abnormalities), bone marrow failure, and an increased risk of malignancy. Progressive bone marrow failure with pancytopenia typically presents in the first decade. Thrombocytopenia is usually the first cytopenia to appear but rarely in the neonatal period. The diagnosis of FA rests upon the detection of increased chromosomal breakage in lymphocytes after exposure to DNA cross-linking agents such as di-epoxybutane or mitomycin C. Recent advances in genomic technology, including next-generation sequencing and whole exome analysis, have accelerated gene discovery efforts. Whereas the first genetic mutation causing FA was discovered more than 20 years ago, there are currently 16 known genes that cause FA. Abnormalities of FA genes are inherited in an autosomal recessive manner except for pathogenic variants in FANCB, which are inherited in an X-linked manner.15 A multidisciplinary team approach is required in the management of infants with FA. HSCT is the only curative treatment for the hematological manifestations of FA.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: a genetically heterogeneous disorder, 13 genes have been identified to date, which define the respective FA complementation groups: FANCA (includes the previously designated FANCH), FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG (XRCC9), FANCI (KIAA1794), FANCJ (BRIP1), FANCL (PHF9), FANCM, FANCN ( PALB2), and FANCO ( RAD51C). All the FA subtypes are autosomal recessive disorders, except for FANCB which is X-linked. The products of the genes FANC- A, C, E, F, G, L are part of a nuclear complex which regulate the monoubiquitination of FANCD2 during the S phase of the cell cycle or after DNA damage by crosslinking agents (e.g. mitomycin C, diepoxybutane (DEB), cisplatin), which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. The FA/BRCA pathway (FANCD1-BRCA2, FANCJ-BRIP1, FANCN-PALB2) is implicated in the repair of DNA damage. The diagnosis first relies on the finding of increased chromosomal breakage or rearrangements when a patient’s cell culture is exposed to diepoxybutane (DEB) or radial figures when exposed to mitomycin C (MMC).
Germ line predisposition to myeloid malignancies appearing in adulthood
Published in Expert Review of Hematology, 2018
Martina Crysandt, Kira Brings, Fabian Beier, Christian Thiede, Tim H Brümmendorf, Edgar Jost
Fanconi anemia (FA) is inherited in an autosomal recessive fashion for all genes except for FA complementation group B (FANCB), which is X linked. Furthermore, 90% of patients affected by the disease will develop bone marrow failure before the age of 40 [53]. About 70% of individuals affected by FA show growth retardation, organ malformation (cardio-pulmonary, kidneys, eyes, ears), skin pigmentation abnormalities as well as radial ray defects and these findings often contribute to the diagnosis of FA. However, about one-third of patients with FA will not present these typically associated abnormalities and as a consequence, the diagnosis of FA in this subcohort will often only be made in adulthood and/or in association with a malignant disorder. MDS and AML are the most frequent neoplasms found in patients affected by FA who have a 600–800-fold increased risk (Table 5) [54].
Clinical Presentations and Diagnostic Imaging of VACTERL Association
Published in Fetal and Pediatric Pathology, 2023
Gabriele Tonni, Çağla Koçak, Gianpaolo Grisolia, Giuseppe Rizzo, Edward Araujo Júnior, Heron Werner, Rodrigo Ruano, Waldo Sepulveda, Maria Paola Bonasoni, Mario Lituania
Fanconi anemia (FA) is an recessive disorder with at least 22 responsible genes, including FANCA, FANCB, FANCC, and FANCD1 [68]. Congenital anomalies in FA patients are multisystemic and variable. In patients diagnosed with FA, progressive bone marrow failure, leukemia, café-au-lait spots, and other congenital abnormalities such as short stature and thumb defects can be seen [68–71]. In FA, limb, gastrointestinal, and tracheoesophageal defects are seen more commonly than costovertebral, cardiac, and renal anomalies [70]. The frequency of VACTERL among those with FA has been reported to be around 5%. In a cohort study conducted by Alter et al. [71], fifty-four children with FA were evaluated and 18 (33%) had at least three VACTERL association features.
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
The first defect is famous as Fanconi anemia (FA). 22 genes have a contribution to the pathogenesis of FA and all genes of this defect, except the FANCB gene, inherit as an autosomal recessive form. Studies have identified that some genes of FA are associated with the first thrombocytopenia sign included FANCA and FANC2. Given that, these patients may experience acute thrombocytopenia for para/post-infection reasons and retrieve by themselves [58, 233]. However, endomitosis reduction during megakaryopoiesis has been reported in mice study upon Fanca deficiency [234].