Fanconi Anemia: A Syndrome of Anemia and Skeletal Malformations Progressing to a Gene Network Involved in Genomic Stability and Malignant Disease

[摘要] In 1927, the Swiss pediatrician Guido Fanconi reported on three siblings with aplastic anemia and skeletal malformations (hypoplasia of the thumbs and radial hypoplasia) [Fanconi, 1927]. Initially, the hematologic disorder was described as “panmyelopathy,” and multiple genes were thought to cause the complexity of the symptoms in these children. Thus, possible polygenic causation would interfere with efforts to isolate “the gene” for Fanconi Anemia (FA). After several efforts had failed, not polygenic inheritance, but locus heterogeneity was considered. The latter was resolved by in vitro functional complementation assays. With this approach, the first FA gene, FANCC, was isolated [Strahdee et al., 1992]. In this way, an additional four FANC genes were subsequently isolated [Lo Ten Foe et al., 1996; de Winter et al., 1998; 2000a; 2000b]. Meanwhile, 22 FANC genes, spanning the alphabet from A to W, have been isolated and characterized [Niraj et al., 2019]. With the exception of the X chromosomal FANCB gene and an autosomal dominant variant in FANCR, biallelic mutations in any of these genes cause FA, and heterozygous variants in FANCD1 (BRCA2), FANCS (BRCA1), and FANCN (PALB2) result in elevated susceptibility to breast and ovarian cancer [Niraj et al., 2019]. In addition, the FANCN (PALB2; Partner and Localizer of Breast Cancer 2 [BRCA2]) gene appears to be mutated in gastric, pancreatic, and in head and neck cancer, mainly oral squamous cell carcinoma [Nepomuceno et al., 2017, Lott and Carvajal-Carmona, 2018; Amenábar et al., 2019]. Moreover, several FANC genes were previously identified in a different context (e.g., FANCG as XRCC9; FANCJ as BRIP1; FANCN as PALB2; FANCO as RAD51C; FANCP as SLX4; FANCQ as ERCC4/ XPF; FANCR as RAD51; FANCT as UBE2T; FANCU as XRCC2; FANCV as REV7/MAD2L2, and FANCW as RFWD3) [Knies et al., 2017]. This indicates that at the molecular genetic level, FA is related to disorders of DNA damage response. Finally, the phenotypes of FA show a great deal of functional overlap with Roberts (due to biallelic mutations in the acetyltransferase encoding ESCO2 gene) and Warsaw Breakage syndromes (due to biallelic mutations in the DNA helicase encoding DDX11/ChlR1 gene) [van der Lelij et al., 2010]. Several patients presenting with vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and a radial limb (VACTERL), and also including hydrocephalus (VACTERL-H) were initially diagnosed as cases of VACTERL association with hydrocephalus and BallerGerold syndrome [Rossbach et al., 1996]. This diagnosis was rescinded and changed to FA after the patients developed bone marrow failure. FA patients also show phenotypic overlap with Seckel syndrome, Nijmegen breakage syndrome, Dubowitz syndrome, Holt-Oram syndrome, thrombocytopenia absent radius syndrome, TownesBrocks syndrome, Saethre-Chotzen syndrome, velocardiofacial syndrome, Diamond-Blackfan anemia, and dyskeratosis congenita [Auerbach, 2009].

[学科分类] 基础医学