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Duplication Error May Make Giants

— Novel mutation may underlie some cases of gigantism.

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A duplication in a short stretch of the X chromosome may be responsible for a specific type of gigantism seen in children, researchers reported.

These patients with early-onset gigantism had a microduplication on chromosome Xq26.3 in which four genes were duplicated -- one of them being GPR101, which probably drives the condition, , of the National Institutes of Child Health and Human Development, and colleagues

They called it a "striking phenotype of gigantism that has an onset in early childhood and that is caused by an excess of growth hormone," and proposed that the syndrome be called X-linked acrogigantism (X-LAG).

The research began when a mother who had been treated for gigantism brought her two sons who were also growing rapidly to the NIH for treatment in the 1990s, followed by a second Australian patient with gigantism who came to the institute. All of these patients had the duplication on chromosome Xq26.3, according to a press release from the NIH.

Stratakis then collaborated with , of the University of Liege in Belgium, who had been following patients with gigantism and acromegaly for most of his career. The two groups pooled their research efforts in order to study 43 patients with gigantism -- 13 of whom had microduplication on chromosome Xq26.3.

They noted that, among those with gigantism who didn't carry the duplication, none had disease onset before age 5.

In this duplicated stretch of DNA, the researchers found four genes. One of them, GPR101, encodes an orphan G-protein coupled receptor and is probably the sequence that creates the phenotype in young children, they reported.

Stratakis and colleagues then looked at genetic samples from 248 patients with acromegaly, finding that none of the patients had the duplication -- but 11 of them did have a mutation in GPR101, suggesting that the gene may play a role in acromegaly as well.

"Finding the gene responsible for childhood overgrowth would be very helpful, but the much wider question is what regulates growth," Stratakis . "As pediatricians and endocrinologists, we look at growth as one of the hallmarks of childhood. Understanding how children grow is extraordinarily important, as an indicator of their general health and their future well-being."

Stratakis said a next step is to understand exactly how the protein derived from GPR101 works, with the ultimate goal of developing new treatments for children with gigantism.

Disclosures

The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Primary Source

New England Journal of Medicine

Trivellin G, et al "Gigantism and acromegaly due to Xq26 microduplications and GRP101 mutation" N Engl J Med 2014; DOI: 10.1056/NEJMoa1408028.