Blocking the Growth Hormone-Releasing Peptide Could Treat a Rare Childhood Gigantism Syndrome | Research

The takeaway

Excess GHRH peptide drives the hormone overproduction in X-LAG syndrome, and a GHRH receptor antagonist successfully blocked growth hormone release from the patient's tumor cells in the lab.

GHRH antagonist blocked tumor GH release
A peptide that blocks the GHRH receptor stopped growth hormone overproduction in primary tumor cells from a child with X-LAG syndrome

What the researchers found

A young female patient with sporadic X-LAG syndrome showed consistently elevated circulating GHRH levels accompanied by marked GH and prolactin hypersecretion. In vitro, the GHRH receptor antagonist acetyl-(d-Arg2)-GHRH(1-29) amide blocked GHRH-induced GH stimulation and, importantly, also significantly reduced baseline GH release when used alone.

Pasireotide (a somatostatin analog) inhibited GH secretion, but octreotide did not. A ghrelin receptor agonist and inverse agonist produced modest but statistically significant changes in GH secretion. These data suggest hypothalamic GHRH dysregulation is part of X-LAG syndrome pathology and that GHRH blockade could be a therapeutic strategy.

Why it matters

X-LAG syndrome causes extreme childhood overgrowth that is challenging to manage surgically or medically. Identifying GHRH hypersecretion as a driver and showing that a peptide antagonist can block hormone release in vitro provides a new therapeutic target. This finding could lead to medical treatments that reduce the need for repeated pituitary surgeries in affected children.

How the study worked

Researchers performed serial hormonal profiles on a young female patient with sporadic X-LAG syndrome, including measurement of circulating GHRH, GH, and prolactin levels. After neurosurgical tumor resection, primary pituitary tumor cells were cultured and tested in vitro with GHRH, the GHRH receptor antagonist, pasireotide, octreotide, and ghrelin receptor modulators to assess their effects on hormone secretion.

What this study cannot tell us

This is a single-patient case study with in vitro experiments, severely limiting generalizability to other X-LAG patients. The in vitro results may not directly translate to in vivo therapeutic efficacy. The GHRH receptor antagonist used is a research tool, not a clinically available drug. The mechanisms connecting GPR101 gene duplication to hypothalamic GHRH dysregulation are still speculative. Long-term effects of GHRH blockade in growing children are unknown.

How to read the evidence

This is a single-patient case study with supporting in vitro experiments. While the case provides important mechanistic insight into a rare disease, the evidence level is low due to the single-patient design. The in vitro data supports the concept but clinical validation is needed.

When this study was published

Published in 2016, this is an early study characterizing X-LAG syndrome, which was only recently described. More recent studies may have expanded on these findings across additional patients.

The bigger picture

X-LAG syndrome was only recently described, and understanding its full pathophysiology is still evolving. This study expands the picture from a purely pituitary disorder to one involving hypothalamic peptide dysregulation — specifically GHRH. This has implications not just for X-LAG but for our broader understanding of how GHRH peptide signaling regulates growth and how its disruption causes disease.

Questions still open

Would chronic GHRH receptor antagonist therapy effectively control growth in X-LAG patients without affecting normal development?
Is GHRH hypersecretion a consistent finding across all X-LAG syndrome patients, or was this unique to this case?
Could GHRH receptor antagonists be developed as clinical drugs for pituitary conditions beyond X-LAG syndrome?

Common questions

What is X-LAG syndrome?

X-linked acrogigantism (X-LAG) syndrome is a very rare genetic condition caused by duplications of the GPR101 gene on the X chromosome. It causes a pituitary tumor or overgrowth that begins in early childhood, leading to extreme height and accelerated growth due to massive overproduction of growth hormone. This study found that excess GHRH peptide from the hypothalamus drives this hormone overproduction.

Could a peptide drug help children with this growth condition?

This study shows proof-of-concept that blocking the GHRH receptor can stop the growth hormone overproduction that drives X-LAG syndrome. While the specific antagonist used is only a research tool, the finding that pasireotide (an available drug) also works opens potential treatment options. However, any therapy for growing children requires careful evaluation of effects on normal development.

Read the original research

GHRH excess and blockade in X-LAG syndrome.

Endocrine-related cancer, 23(3), 161-70

View on PubMed ↗Publisher’s paper ↗

Citation

Daly, Adrian F; Lysy, Philippe A; Desfilles, Céline; Rostomyan, Liliya; Mohamed, Amira; Caberg, Jean-Hubert; Raverot, Veronique; Castermans, Emilie; Marbaix, Etienne; Maiter, Dominique; Brunelle, Chloe; Trivellin, Giampaolo; Stratakis, Constantine A; Bours, Vincent; Raftopoulos, Christian; Beauloye, Veronique; Barlier, Anne; Beckers, Albert. (2016). GHRH excess and blockade in X-LAG syndrome.. Endocrine-related cancer, 23(3), 161-70. https://doi.org/10.1530/ERC-15-0478