Chromosome X microduplications implicated in infancy-onset gigantism

By Eleanor McDermid, Senior medwireNews Reporter

Researchers report that heritable microduplications on chromosome Xq26.3 may underlie a “striking” form of gigantism with onset in late infancy, and reveal a candidate culprit gene.

Patients with these microduplications were of normal size at birth, but by the time of diagnosis at a median age of 36 months they had a median height standard deviation score of +3.8. Excess linear growth was associated with increased levels of growth hormone (GH) and insulin-like growth factor-1.

As reported in The New England Journal of Medicine, Constantine Stratakis (National Institutes of Health, Bethesda, Maryland, USA) and colleagues studied 43 patients who had gigantism with excessive GH levels and evidence of an anterior pituitary adenoma on magnetic resonance imaging. They found the patients fell into two distinct phenotypes, based on whether or not they had microduplications.

Thirteen patients had definite chromosome Xq26.3 microduplications, and one was a probable carrier. These patients were aged a median of 1 year at the onset of abnormally rapid growth and 71% were female. By contrast, patients without microduplications were aged a median of 16 years at onset, with none presenting before the age of 5 years, and just 24% were female.

Commenting on the study for medwireNews, Martin Savage, Emeritus Professor of Paediatric Endocrinology from Barts and the London School of Medicine & Dentistry, UK, stressed how rare GH-secreting pituitary adenomas causing gigantism are.

“The key word to emerge clearly from this article is ‘collaboration’,” he said. “Results such as these can only be achieved through collaboration between centres, collaboration between clinicians and molecular scientists and collaboration between paediatric and adult endocrinologists. This article is the classic example of the rewards of such an approach.”

The researchers identified a single gene – GPR101 – that they believe to be responsible for gigantism in the patients with microduplications. The genomic regions affected by microduplications varied among the patients, but all involved four genes. However, the other three genes – CD40LG, ARHGEF6 and RBMX – were either not upregulated or not expressed at all in the patients’ pituitary tumours.

By contrast, GPR101 was upregulated by as much as 1000-fold in patients’ tumours. This gene encodes an orphan G-protein–coupled receptor that is reported to be highly expressed in the hypothalamus of rodents.

The team studied DNA from 248 patients with sporadic acromegaly, and identified 11 who had a mutation (c.924G to C substitution; p.E308D) in GPR101. When they overexpressed GPR101 with this mutation in cultured rat pituitary cells, it resulted in increased secretion of GH and cell proliferation, whereas nonmutated GPR101 did not have this effect.

Savage described this result as “impressive”, saying that it “strongly suggests a causative link to the human phenotype.”

Stratakis et al say it is not clear how GPR101 overexpression could result in GH hypersecretion; however, they note that deletions in genomic regions involving this gene have been reported in several patients with short stature, adding weight to their theory that GPR101 has a role in growth.

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