From time to time those of us with kids (excluding me) have to deal with them being sick. One of the first things that a parent with a sick kid does is strap their child into their car seat and take them on down to go see the pediatrician. Usually the consult goes along the lines of, "Hey doc, the munchkin isn’t feeling so great and they have XYZ going on. What’s wrong with them?" Thanks to modern medicine and well-trained clinicians, these pediatricians can quickly diagnose most problems and determine a suitable remedy.

But this wasn’t always the case back in 1927. Imagine the difficulty of Swiss pediatrician Guido Fanconi trying to determine the root cause of three brothers who shared physical defects and presented with what was thought to be pernicious anemia. Ultimately, the three boys did not survive and died shortly thereafter. Fanconi personally conducted the autopsy of the boys and authored a case study on their condition. The 23-page paper, more than half of which is spent describing the symptoms of his patients, serves as a record of Fanconi’s meticulous notes.

Left: Guido Fanconi. Credit: Ze'ev Aleksandrowicz

This paper laid the groundwork for Dr. Guido Fanconi to spend 40 years studying what would eventually be called Fanconi Anemia (FA). In 1964 Fanconi proffered the hypothesis that this disease was caused by a chromosomal translocation, based upon the fact that Fanconi Anemia patients had the appropriate number of chromosomes. Shortly thereafter, multiple groups showed that patients afflicted with FA suffered from chromosomal instability that was spontaneous but also exaggerated by treatment with DNA-crosslinking substances. This disease, despite Fanconi’s doubts, is passed down to the next generation in an autosomal recessive fashion.

Time will only tell…

As time went by and years changed on the calendar the scientific community came to understand more about the symptoms and molecular basis of this disease. Many FA patients suffer from bone marrow failure and eventually develop acute myelogenous leukemia before the age of 40. Those that do live on to adulthood have increased susceptibility to multiple types of cancer. Evidence of FA can sometimes be observed at birth, with affected children displaying thumb or arm anomalies, kidney dysfunction, café-au-lait skin discoloration on regions of the body, and mental retardation. Typically FA will present in early childhood but some FA patients are symptom-free well into adulthood.

Right: Radiological image of a thumb abnormality seen in an FA patient. Credit:

The conclusive test for Fanconi Anemia is to take blood from the suspected patient and treat with mitomycin C, an agent that causes DNA interstrand crosslinks (ICL), and measure chromosomal breakage. Unaffected patients are able to tolerate and repair most of the damage caused by these agents whereas FA patients have a heightened level of chromosomal breakage. Typically, the most conservative treatment for FA is the therapeutic use of androgens to stimulate red blood cell production and hematopoietic growth factors to increase white blood cell counts, but more extreme cases may require bone marrow transplantation.

Linking the past to the present?

To understand the basis of Fanconi Anemia, researchers focused in on the sensitivity of FA patients to DNA-interstrand crosslinking agents. Upon exposure to an interstrand crosslinking agent, both strands of the duplex DNA become covalently linked, forming the ICL.

Left: When treated with ICL agents, the two strands of DNA become “chained” to one another. Credit: Author

ICLs are notoriously toxic to cells and can occur endogenously, for example through lipid peroxidation or through exposure to exogenous agents. The ICL acts like a thick gauge chain that functions as a sort of roadblock for vital cellular process such as DNA replication and transcription. During DNA replication, the crosslink prevents progression of the DNA polymerase along the template DNA, causing a stalled replication fork. If a stalled replication fork persists for too long, they can collapse and lead to the chromosomal instability that is cytological hallmark of FA.

Right: Chromosomal breaks, notated by arrows, are evident in the cells of FA patients. Credit: Wikimedia Commons

Diving deeper into the genetics of FA, we see that there are 13 complementation groups whose mutations cause FA. The groups are as follows: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN. Remember how I was telling you that FA was an autosomal recessive disorder, well that’s not completely true for FA patients in the FANCB complementation group, the gene responsible for which lies on the X chromosome. Also of note is that the gene involved in the FANCD1 complementation group is BRCA2, a tumor suppressor gene involved in DNA repair and often mutated in breast cancer.

Breaking the chains that bind us

Much of the specifics regarding the mechanism of ICL repair is still being fleshed out and is also dependent upon what stage of the cell cycle that the cell is in during repair of these cytotoxic lesions. What is known is that any defects in the genes that encode the FANC proteins seriously compromises the repair of ICLs. If you would like to learn more about the repair of ICLs see (Moldovan 2009). Study of ICL repair and FA is important to cancer because many of today’s front line therapeutics for cancer (cisplatin, carboplatin, mitomycin c, nitrogen mustard) are ICL-inducing agents. By understanding more about ICL repair, we can find new ways to target this process and thus increase the efficacy of cancer therapeutics and further better patient outcomes.

So gang, as we close in on hotel-motel time, I’ll leave you with a quote from Winston Churchill, "We shall draw from the heart of suffering itself the means of inspiration and survival."

If you would like to learn more about FA, I encourage you to visit the Fanconi Anemia Research Fund.


D'Andrea, A. D. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362, 1909-1919 (2010)

Lobitz, S. & Velleuer, E. Guido Fanconi (1892-1979): a jack of all trades. Nat Rev Cancer 6, 893-898 (2006)

Moldovan, G. L. & D'Andrea, A. D. How the fanconi anemia pathway guards the genome. Annu Rev Genet 43, 223-249 (2009)

Wiedemann, H. R. Guido Fanconi (1892-1979) in memoriam. Eur J Pediatr 132, 131-132 (1979)

About the Author: The Genomic Repairman is a graduate student in biomedical sciences, who focuses on using genetics and biochemistry to elucidate DNA repair in cells. He also maintains a blog, Tales of the Genomic Repairman, at Scientopia.

The views expressed are those of the author and are not necessarily those of Scientific American.