Two-tier protection against endogenous aldehydes and consequences of its failure. (A) Hematopoietic stem and progenitor cells are protected against endogenous aldehydes through high expression of ALDH2 (detoxifies formaldehyde and acetaldehyde) and ADH5 (detoxifies formaldehyde) (tier 1 protection). Any aldehyde-induced DNA damage is repaired by the FA DNA repair pathway (tier 2 protection). (B) In humans, the loss of tier 1 protection through the combined genetic deficiency of ALDH2 and ADH5 leads to ADDS, whereas loss of tier 2 protection through deficiency of the FA pathway (or combined loss of tier 1 and tier 2) results in the eponymous FA syndrome. Both conditions share common clinical features that stem from overwhelming formaldehyde genotoxicity, in particular, aplastic anemia and predisposition to acute leukemia. Beyond the hematopoietic defect, both conditions also exhibit microcephaly, short stature, skin pigmentation such as café-au-lait spots, and skeletal malformations.