Until now, it has been possible to explain 35% of gigantism cases: an explanation still needed to be found for the remaining 65% of cases. This has now been achieved for the most spectacular cases among this remaining group following an international study which gathered data on 200 giants throughout the world. Professor Albert Beckers who is a professor at the University of Liege and Head of the Department of Endocrinology at the University Hospital of Liege has, together with his colleagues, succeeded in identifying the gene responsible for the tallest giants known to mankind. They found that individuals affected by the condition known as the X-LAG syndrome, carry a microduplication of 4 genes including the GPR101 gene on the X chromosome.

“Where do giants live”? How would you answer a child if they asked you this question? You would probably answer “in fairytales” or “in fantasy films” in order to reassure the child or simply because you are unaware of the fact that there are giants living in our midst…The tallest man ever recorded up to the present day was an American called Robert Wadlow (1918-1940). He measured 2m72. The tallest man alive today is Sultan Kösen; he was born in Turkey and measures 2m51. Closer to home, Julius Koch (alias Constantin the giant) lived in Mons from 1872 to 1902 and measured 2m59 while a man currently living in France has grown to a height of 2m48.

Gigantism is characterised by excessive growth. There are different syndromes which are directly related to excessive production of growth hormone. “When this overproduction occurs before the individual has finished growing, this may result in gigantism. On the other hand, when this excessive production of growth hormone occurs in the adult, acromegaly occurs, that is to say an abnormal increase in the size of hands, feet, the nose and the soft tissues in general”, explains Professor Albert Beckers, Head of the Endocrinology Department at the Liege University Hospital Center (CHU). “Once growth has finished, growth hormone can no longer act on the size of bones except the lower jaw but it also acts on the soft tissues”.

Hypophyseal adenomas, benign tumors with collateral damage

The cause of this hyperproduction of growth hormone is situated in the pituitary gland, the part of the brain where a large range of hormones are produced. In most cases of gigantism or acromegaly, a pituitary adenoma is the cause of this hormonal imbalance. It is a benign tumor affecting this gland which results in collateral damage such as the overproduction of hormones or the compression of adjoining brain structures once the tumor has reached a significant size.

For more than 30 years Albert Beckers has been fascinated by giants and has studied the causes of gigantism. He also discovered a new familial form of pituitary adenoma: FIPA (Familial Isolated Pituitary Adenomas). The results of that study were published in 2006 in the Journal of Clinical Endocrinology and Metabolism (JCEM) (1) (see article:  Hypophyseal tumors, the search for the genes has begun!). “At the same time, we also demonstrated the involvement of the AIP gene in this pathology because 15% of patients suffering from this disease presented with mutations on this gene”, continues the scientist (2). In-depth research has also enabled Albert Beckers and his colleagues to establish that pituitary adenomas in patients presenting with a mutation on the AIP gene (patients AIP +) was a lot more aggressive and early than in patients who did not have a mutation on this gene (patients AIP -) (3). “AIP + patients have pituitary adenomas before the age of 20 that are twice as big as those affecting AIP patients who tend to develop tumors at around the age of forty”, says Albert Beckers.

The genetic data of 200 giants under the microscope

Given the fact that giants develop following an imbalance in the production of the growth hormone during childhood/adolescence and that AIP + patients develop hypophyseal adenomas at a younger age, it is not surprising that researchers have observed a large number of giants among AIP+ patients. “This is where we got the idea to begin a large international study on giants in 2011”, indicates the endocrinology specialist. “This study has made it possible to gather clinical and genetic data on 200 giants around the world. Up to that point we could explain 35% of gigantism cases; we therefore wanted to discover the genetic causes for the remaining 65% of cases”. Among the research centers that participated in this international study is the National Institute of Health (NIH) in the USA. “A colleague and friend of mine who works there had been trying to find a genetic explanation for a form of gigantism but without success. We therefore decided to collaborate in order to try to solve this mystery”, explains Albert Beckers.  “His research team had identified the duplication of 11 genes on the X chromosome but none of these genes was well-known or linked to the production of growth hormone. In addition, they were working on a small which was not sufficient to demonstrate the existence of a new syndrome or to confirm the involvement of these duplications in gigantism”, the scientist continues. The researchers at NIH therefore pointed out the location of the region of the X chromosome where the duplication of the 11 genes was observed to the researchers in Liege. “Using our gigantism database, three months later, the problem was solved”! Albert Beckers explains.

(1) Clinical Characterization of Familial Isolated Pituitary Adenomas. The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3316-3323
(2) Aryl Hydrocarbon Receptor Interacting Protein Gene Mutations in Familial Isolated. Pituitary Adenomas : Analysis in 73 families. J. Clin. Endocrinol. Metab, 92(5):1891-1896, 2007. Doi : 10.1210/ jc.2006-2513. 

(3) Clinical Characteristics and Therapeutic Responses in Patients with Germ-Line AIP Mutations and Pituitary Adenomas: An International Collaborative Study. The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 11 E373-E383.