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Endocrine Abstracts (2012) 29 S22.2

ICEECE2012 Symposia Pituitary tumorigenesis (3 abstracts)

Tracing back a Gene’s influence

M. Korbonits

Barts and the London School of Medicine, London, UK.

In the late 1700s, a 22 y patient suffering from pituitary gigantism died and his skeleton was deposited in a medical museum. A contemporary etching showed him standing alongside a set of giant twin brothers who were believed to be his cousins. The existence of such a rare disorder within closely related family members indicates to modern science a genetic dimension to their disease. In 1909 Cushing opened the skull and he found a greatly enlarged pituitary fossa. We identified a mutation in the AIP gene (aryl hydrocarbon receptor interacting protein, a gene known to predispose the young-onset pituitary adenomas) from a tooth of the patient indicating the genetic basis of his gigantism. In addition, several families, originating from the vicinity of the giant’s birthplace were also identified with familial isolated pituitary adenoma and exactly the same AIP mutation (c.901C>T/p.R304X). Whilst the geographical location of these families suggests a common ancestral origin, the possibility of a mutational hotspot also had to be considered, as this C>T change occurred at a CpG-site and such sites typically have higher mutation rates. The hotspot theory was supported by the fact that the same mutation has been identified in several patients from various countries around the world. Microsatellites demonstrated that the 18th-century giant and the families inherited this allele from a common ancestor, while other patients with the same mutation from elsewhere do not share this common ancestor. The age of this founder mutation and forward simulations allowed us to estimate the number of carriers alive today.

Genetic screening from this geographical area identified further carriers. Clinical screening of carriers provides earlier diagnosis with an anticipated improved clinical outcome. Our case study provides an interesting example of how medical history combined with molecular genetics has resulted in direct benefit to patients and their families.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.

Volume 29

15th International & 14th European Congress of Endocrinology

European Society of Endocrinology 

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