synthesis, the hallmark of a defect in the s phase checkpoint, in patients with fa-d1 or fa-d2. such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of aml in these patients. fa proteins have cellular roles in autophagy and ribosome biogenesis in addition to dna repair. fancc, fanca, fancf, fancl, fancd2, brca1, and brca2 are required to clear damaged mitochondria from the cell (a process called mitophagy). brca1 (also known as fancs) interacts with the ribosomal dna (rdna) promoter and terminator in the nucleolus, the cellular location where ribosome biogenesis initiates, and is required for transcription of rdna. fanci functions in the production of the large ribosomal subunit by processing pre-ribosomal rna (pre-rrna), the transcription of pre-rrna by rnapi, maintaining levels of the mature 28s ribosomal rna (rrna), and the global cellular translation of proteins by ribosomes. in the nucleolus, fanci is predominantly in the deubiquitinated form. in addition, fanca is required to maintain normal nucleolar morphology, for transcription of pre-rrna, and global cellular translation. fancc, fancd2, fancg are also required to maintain normal nucleolar morphology and fancg is also required for global cellular translation. there may be a role for fa proteins outside the nucleolus in ribosome biogenesis or protein translation as fanci and fancd2 were the only fa proteins associated with polysomes. other inherited bone marrow failure syndromes also have defects in ribosome biogenesis or protein translation, including dyskeratosis congenita, diamond-blackfan anemia, and shwachman diamond syndrome, and like these other diseases, fa may also be a ribosomopathy. spermatogenesis in humans, infertility is one of the characteristics of individuals with mutational defects in the fanc genes. in mice, spermatogonia, preleptotene spermatocytes, and spermatocytes in the meiotic stages of leptotene, zygotene and early pachytene are enriched for fanc proteins. this finding suggests that recombinational repair processes mediated by the fanc proteins are active during germ cell development, particularly during meiosis, and that defects in this activity can lead to infertility. neural stem cell homeostasis microphthalmia and microcephaly are frequent congenital defects in fa patients. the loss of fanca and fancg in mice causes neural progenitor apoptosis both during early developmental neurogenesis and later during adult neurogenesis. this leads to depletion of the neural stem cell pool with aging. much of the fanconi anemia phenotype might be interpreted as a reflection of premature aging of stem cells. treatment the first line of therapy is androgens and hematopoietic growth factors, but only 50–75% of patients respond. a more permanent cure is hematopoietic stem cell transplantation. if no potential donors exist, a savior sibling can be conceived by preimplantation genetic diagnosis (pgd) to match the recipient's hla type. prognosis many patients eventually develop acute myelogenous leukemia (aml). older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. patients who have had a successful stem cell transplant and, thus, are cured of the blood problem associated with fa still must have regular examinations to watch for signs of cancer. many patients do not reach adulthood. the overarching medical challenge that fanconi patients face is a failure of their bone marrow to produce blood cells. in addition, fanconi patients normally are born with a variety of birth defects. a significant number of fanconi patients have kidney problems, trouble with their eyes, developmental delay and other serious defects, such as microcephaly (small head).