A group of international researchers has identified a gene on the X chromosome that is duplicated in children who develop gigantism at a very young age, typically under 1 year old. They report their findings in a report published online December 3 in the New England Journal of Medicine.
The discovery may help shed light on how human growth is regulated and even one day enable the development of drugs to treat acromegaly and gigantism or, conversely, growth retardation, say the scientists.
"We have identified a new receptor that was not well known before, which seems to be very important in the regulation of growth hormone," one of the senior authors, Dr Albert Beckers (chief of the department of endocrinology, University of Liege, Belgium), told Medscape Medical News.
"It appears that the duplication of this gene can result in some of the tallest giants in the world," said Dr Beckers, who has devoted his whole career to researching acromegaly and pituitary-gland tumors.
This genetic condition likely affected the tallest man ever recorded, Robert Pershing Wadlow, also known as the Alton Giant/Giant of Illinois, who started growing abnormally as a young child and reached a height of 8 ft 11 in (2.72 m), said Dr Beckers, "although, as he died in 1940, we will never know for sure," he observed.
Duplication in Infant-Onset Gigantism
Most people with sporadic gigantism/acromegaly have a tumor in the pituitary gland that secretes extra growth hormone.
Those who develop this condition during childhood will grow abnormally tall and be affected by gigantism and may have delays in puberty. Those who are affected in adulthood generally develop large hands and feet instead, with other comorbidities.
Acromegaly is usually treated by surgically removing the tumor but can sometimes be treated with medication alone.
In this new research, lead authors Dr Giampaolo Trivellin (Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD], Bethesda, Maryland) and Dr Adrian Daly (University of Liege, Belgium) and an international consortium spearheaded by Dr Beckers and Dr Constantine Stratakis (scientific director, division of intramural research at NICHD) tracked down 43 giants from around the world, who were affected by a sporadic or inherited form that manifested during childhood or adolescence.
In some cases, three members of the same family were affected, and it was in these cases that they found the best clues.
Through genetic analysis, they narrowed down the likely cause to a locus on the X chromosome, and the duplication of four genes there.
"We found that the culprit was one of the four genes, GPR101, which was dramatically overexpressed, 1000-fold more than normal, in those family members affected by gigantism," Dr Beckers explained.
"We never found this duplication in anyone who started to grow abnormally at age 9 or 10. All those affected were born normal but started to grow excessively very early, before 1 year old or at least under 3, and then they grow and grow and never seem to stop," he told Medscape Medical News.
The GPR101 gene encodes an orphan G-protein–coupled receptor. There is 100% penetration in affected families, meaning the gene is dominant, he said.
Because of this and the fact it is linked to the X chromosome, 66% of those affected are female, Dr Beckers explained, "as a male (who has only one X chromosome) will never transmit this duplication to his son, but a woman (who has two X chromosomes) will transmit to both sons and daughters." The researchers propose the condition be called X-linked acrogigantism (X-LAG).
Mutation Causes Acromegaly; Could Deletion Cause Short Stature?
As well as causing this inherited disorder, the scientists also studied 248 individuals with sporadic acromegaly; although they didn't find the same duplication of GPR101, they did find that a mutation in this same gene was associated with about 4% of cases, Dr Beckers added.
The next step will be to discover the ligand for GPR101, and "thereafter we will understand better the regulation of the secretion of growth hormone."
"We also have to find out if deletion of this gene causes growth retardation — ie, is it responsible for some cases of short stature?" he added. This condition is currently treated by giving children growth hormone.
So in the future, this discovery "may allow the development of agonists or antagonists for this receptor that could help treat patients with growth disorders," he concluded.
Dr Stratakis agrees: "We believe GPR101 is a major regulator of growth," he says in a NICHD statement.
Dr Beckers has received an education grant from Pfizer Belgium in support of this work. Disclosures for the coauthors are listed in the article.
N Engl J Med. Published online December 3, 2014. Article
Medscape Medical News © 2014 WebMD, LLC
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Cite this: Gene Discovery in Giants Could Shed Light on Human Growth - Medscape - Dec 09, 2014.