Fanconi anemia: a master example of a rare disease

FA is a rare disease (1 case in 300,000 persons) that was first described nearly 100 years ago by Guido Fanconi (13). The clinical characteristics of FA are: (i) congenital malformations including absent radius, thumb hypoplasia, disturbed skin pigmentation, as well as inner organ abnormalities most frequently found in the renal and cardiac system as well as disturbed skin pigmentation (14), (ii) progressive bone marrow failure already at childhood age (15, 16), and (iii) dramatically increased risk of developing cancers, such as acute myeloid leukemia (17) and SCC, especially of the head and neck, in early adulthood (18). FA individuals have defects in the molecular machinery of detection and repair of interstrand crosslinks (ICLs) and DNA double-strand breaks (DSBs), which are mostly due to the biallelic inheritance of recessive pathogenic variants in a subset of at least 20 FANC genes (FANCA, FANCC, FANCD1 (BRACA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCO (RAD51C), FANCP (SLX4), FANC (ERCC4 ), FANCS (BRCA1), FANCT (UBE2T), FANCU (XRCC2), FANCV (MAD2L2), FANCW (RFWD3)) (19). Moreover, variants in the FANCB gene are inherited in an autosomal recessive X-linked manner, whereas the FANCR (RAD51 ) shows an autosomal dominant inheritance pattern and can also be spontaneously mutated (19-21). FANC genes encode for proteins that maintain genomic integrity during DNA replication, i.e., their inactivation leads to accumulation of DSBs and genomic instability (22). However, patients with identical variants, such as siblings, often show significant differences in their clinical presentation, i.e., there are more factors than the mutated FANC genes contributing to the disease (16, 23).
To date, hematopoietic stem cell transplantation is the only curative treatment option for the hematological complications of FA (24) and the main reason for improved life expectancy of young FA individuals (25). In addition, treatment with supra-pharmacological doses of testosterone analogs, such as Oxymetholone, Danazol, and others can stabilize declining blood counts and even improve them (26-29). Non-transplanted and, in particular, transplanted FA individuals have a several 100-fold increased risk for developing SCC, especially of their oral mucosa but also in their pharynx, larynx, esophagus, anus, and vulva (17), even without the main risk factors like alcohol and tobacco exposure. For adult FA individuals, developing SCC is the most life-threatening complication. Due to their dysregulated DNA repair machinery, FA patients cannot tolerate standard chemo-radiation therapies and treatment side effects are difficult to predict (30, 31). This makes non-surgical systemic therapeutical options very limited. Therefore, detecting SCC at an early stage and eliminating it surgically is effectively, at present, the best way to prolong the lives of FA individuals (32). Ultimately, prevention of disease progression should be the goal but is still far away from the clinical routine.
Based on its clinical and cellular phenotype, FA can also serve as a cellular model for the study of general molecular functions and physiological aspects, like aging, as well as other non-communicable diseases occurring in the general population. In that respect, the study of FA has had a major impact on the molecular understanding of breast/ovarian cancer (33). Moreover, FANC genes are frequently mutated or dysregulated in sporadic cancers (34), as well as in childhood cancers (35). Nevertheless, the enormous and quite specific cancer risk of SCC for FA individuals is poorly understood from a mechanistic standpoint.