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354 Part IV Disorders of Hematopoietic Cell Development

Pathophysiology Decreased colony numbers in these studies can be interpreted as the
result of an absolute decrease in progenitors and/or progenitors that
Wild-type FA proteins are part of a cluster of survival signaling have faulty proliferative properties and cannot form colonies in vitro.
molecules that protect against genotoxic insult and suppress apoptosis Additional factors are operative in FA BM failure. Telomeres,
signaling. With inactivation of any of the known FA genes, the the nonencoding DNA at each end of chromosomes, shorten with
prosurvival benefit is lost. This underlies the phenotype of clinical each round of cell division in normal human somatic cells. Their
FA but does not explain or unify the relationship among congenital length is a reflection of the mitotic history of the cell. Telomerase,
anomalies, BM failure, the predisposition to cancer, and chromosome a ribonucleoprotein reverse transcriptase that can restore telomere
fragility. length, is variably present in hematopoietic progenitors. Leukocyte
Two theories of the pathophysiology of FA relate to either (1) a telomere length is significantly shortened in patients with FA but
heightened sensitivity to oxygen, resulting in cell damage; or (2) there is increased telomerase activity, suggesting an abnormally
defective DNA repair. The oxygen sensitivity phenotype of FA cells high proliferative rate of progenitors that ultimately leads to their
is characterized by overproduction of oxygen radicals, a deficient premature senescence. In parallel, increased BM cell apoptosis has
oxygen radical defense, a deficiency in superoxide dismutase, and been demonstrated in patients with FA and in knock-out mouse
poor cell growth at ambient oxygen, all producing shortened cell models and is mediated by Fas, a membrane glycoprotein receptor
survival. A cardinal phenotype of FA cells is an abnormality in cell containing an integral death domain. FA cells exposed to TNF-α,
cycle distribution with an increased number of cells with 4N DNA INF-γ, MIP-1α, Fas ligand, and double-stranded RNA undergo
content arising from a delay in the G 2/M or late S phase of the cell exaggerated apoptotic responses.
cycle. The strongest evidence supporting an oxygen metabolism Studies of cytokines in patients with FA have shown varied
deficiency in FA is a reduction of FA cells with 4N DNA content abnormalities. Although FA fibroblasts showed no deficiencies in
when grown at low oxygen levels and the unexpected appearance of SCF or macrophage colony-stimulating factor (M-CSF) production,
4N DNA content when normal cells are grown at high oxygen levels. variability ranging from diminished production to augmentation
Of note, some wild-type FA proteins play a role in redox-related of production of IL-6, GM-CSF, and G-CSF (granulocyte colony-
functions. FANCC associates with NADPH (nicotinamide adenine stimulating factor) has been observed in different patients. A consis-
dinucleotide phosphate), cytochrome P-450 reductase, and glutathi- tent finding that may relate directly to pathogenesis is diminished
one S-transferase, proteins with redox functions. FANCA and IL-6 production in patients with FA and markedly increased TNF-α
FANCG are redox-sensitive proteins that multimerize after H 2 O 2 generation.
treatment, prompting the notion that the FA pathway may function Initial attempts to generate induced pluripotent stem cells (iPSCs)
in oxidative stress management. from patients with FA have been difficult since reprogramming causes
The best evidence supporting the theory that the primary defect increased DNA double-stranded break and the FA pathway needs to
is in DNA repair relates to the critical role of wild-type FANC pro- be activated. This barrier can be bypassed by either correcting the
teins in the DNA damage response pathway. Whereas clastogenic genetic defect before reprogramming or performing the reprogram-
bifunctional cross-linker agents such as MMC and DEB induce ming under hypoxic conditions. Successful reprogramming resulted
chromosomal breakage in FA cells, monofunctional chemical agents in cells that recapitulate the hematopoietic defect and identify the
do not, indicating that FA cells cannot repair interstrand cross-links. early pathogenetic defect at the stage of hemoangiogenic progenitors.
There were also experiments in the 1980s in which the frequency of
mutations induced by 8-methoxypsoralen plus near-ultraviolet radia-
tion at the HPRT locus was lower in FA cells than in control partici- Clinical Features
pants. These results indicated that FA cells cannot repair cross-links
through the normal pathway involving mismatch repair, recombina- History and Physical Examination
tional repair after bypass of the lesion, or both. Additional evidence
for defective DNA repair in FA cells includes an accumulation of The diagnosis of FA can readily be made based on signs and symp-
DNA adducts, a failure to arrest DNA synthesis in response to DNA toms related to aplastic anemia and the presence of characteristic
damage, increased homologous recombination, defective nonhomolo- congenital physical anomalies. However, a study from the Interna-
gous end joining, abnormal induction of p53, and increased tional Fanconi Anemia Registry (IFAR, Rockefeller University),
apoptosis. which used confirmatory chromosomal breakage studies, showed that
The two theories for the pathophysiology of FA can be reconciled only 39% of patients with FA have both aplastic anemia and anoma-
theoretically. It is possible that loss of any FA protein causes a transient lies. The rest of the patients had aplastic anemia but no anomalies
increase of oxidative damage to which the repair machinery is par- (30%), anomalies but not aplastic anemia (24%), or neither (7%).
ticularly sensitive. Table 29.2 lists the characteristic physical abnormalities and their
approximate frequency based on more than 2000 published case
Hematopoietic Dysfunction reports. The two most common anomalies are skin hyperpigmentation
Hematologic abnormalities in FA are evident at the hematopoietic and short stature, each with a frequency of 40% of cases. Characteristi-
progenitor cell level in BM and peripheral blood. The frequencies cally, the hyperpigmentation is a generalized brown melanin-like
of CFU-E (colony-forming unit-erythroid), BFU-E (burst-forming splattering that is most prominent on the trunk, neck, and intertrigi-
unit-erythroid), and CFU-GM (colony-forming unit-granulocyte nous areas and that becomes more obvious with age. Café-au-lait
macrophage) colony-forming cells are reduced fairly consistently in spots are common alone or in combination with the generalized
almost all patients after aplastic anemia ensues as well as in a few hyperpigmentation and sometimes with vitiligo or hypopigmenta-
patients before the onset of aplastic anemia. Although FA BM cells tion. The skin pigmentation should not be confused with
show normal transcripts for the α and β chains of the GM-CSF hemosiderosis-induced bronzing in transfusion-dependent patients
(granulocyte macrophage colony-stimulating factor)/interleukin-3 who have not been adequately iron chelated. In those with short
(IL-3) receptor and for c-kit protein, there is a deficient prolif- stature, most are less than the third percentile for height. In some
erative response of CFU-GEMM (colony-forming unit granulocyte, patients, growth failure is associated with endocrine abnormalities.
erythrocyte, macrophage, megakaryocyte), BFU-E, and CFU-GM In one report, spontaneous overnight growth hormone secretion was
progenitors to GM-CSF plus stem cell factor (SCF) (c-kit ligand) abnormal in all patients tested, and 44% had a subnormal response
or to IL-3 plus SCF. Because all hematopoietic lineages are affected, to growth hormone stimulation. Approximately 40% of patients also
the basic defect is presumed to be at the HSC level. Cure of FA have overt or compensated hypothyroidism, sometimes in combina-
BM failure by HSC transplantation (HSCT) supports this view. tion with growth hormone deficiency.
Confirmatory data for defective stem cells in FA using long-term BM Malformations involving the upper limbs are common, especially
cultures were reported by one group but not confirmed by another. hypoplastic, supernumerary, bifid, or absent thumbs. Hypoplastic or