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Clinical Trial
. 2024 Oct 15;109(11):2937-2942.
doi: 10.1210/clinem/dgae244.

A Clinical Trial of High-Dose Growth Hormone in a Patient With a Dominant-Negative Growth Hormone Receptor Mutation

Nadia Merchant  1 , Lisa Houchin  2 , Kimberly Boucher  1 , Andrew Dauber  1   3
Affiliations
Clinical Trial

A Clinical Trial of High-Dose Growth Hormone in a Patient With a Dominant-Negative Growth Hormone Receptor Mutation

Nadia Merchant et al. J Clin Endocrinol Metab. .

Abstract

Context: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention.

Objective: To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates.

Methods: Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment.

Results: A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height.

Conclusion: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.

Keywords: growth hormone; growth hormone receptor; growth hormone resistance; precision medicine.

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Figures

Figure 1.
Figure 1.
Mechanism of action of dominant-negative GHR mutations. Schematic of a cell with a dimer of GH receptors present in the cell membrane. Each GH receptor has an intracellular domain (blue) and an extracellular domain (red). The extracellular domain also serves at the GH binding protein (GHBP) when in circulation. The transmembrane domain is not shown. In circulation, the GH molecules (circles) are found either free or bound to GHBP. The free GH can bind to its receptor. (A) Normal GH signaling after GH binds its receptor. (B) A typical dominant-negative GHR mutation where there is a mutation in the intracellular domain of the receptor leading to a truncated intracellular domain. The truncated protein interacts with the wild-type copy leading to a dominant-negative effect. (C) Pathophysiology of the current patient with high GHBP levels preventing GH from binding to its receptor resulting in a lack of GH signaling. (D) The ability of high dose GH treatment to overcome this resistance.
Figure 2.
Figure 2.
IGF-1 Levels and growth hormone dosage throughout treatment.
Figure 3.
Figure 3.
Growth charts for weight and height. Arrow indicates initiation of growth hormone.
See this image and copyright information in PMC

References

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