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.