A clinical trial of high-dose growth hormone in a patient with a dominant-negative growth hormone receptor mutation

Nadia Merchant; Lisa Houchin; Kimberly Boucher; Andrew Dauber

doi:10.1530/ey.22.4.10

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 4.10 | DOI: 10.1530/ey.22.4.10

ESPEYB25 4. Growth and Growth Factors New Potential Indications for Growth Hormone Therapy (3 abstracts)

4.10. A clinical trial of high-dose growth hormone in a patient with a dominant-negative growth hormone receptor mutation

Nadia Merchant , Lisa Houchin , Kimberly Boucher & Andrew Dauber

J Clin Endocrinol Metab 2024 Oct 15;109(11):2937-2942.PMID: 38597155 doi: 10.1210/clinem/dgae244

Brief summary: This paper describes a precision medicine intervention for a patient with severe short stature and growth hormone (GH) resistance.

The patient had a heterozygous dominant-negative variant in the GHR gene (c.757del, p.Gln253Argfs*2). This specific variant results in the exclusive production of the extracellular domain of the GH receptor, leading to elevated levels of growth hormone binding protein (GHBP). The elevated GHBP acts as a "sponge", binding to circulating GH and preventing it from effectively reaching functional wild-type receptors on cells, causing GH resistance. The study tested whether extremely high-dose GH could overcome this resistance to normalize insulin-like growth factor (IGF)-1 levels and improve growth.

In this single-patient trial, daily subcutaneous GH was escalated to a maximum dose of 250 µg/kg/day. This high dose was required to achieve the target IGF-1 level (above the mean and below +2 SD for age, sex, and Tanner stage). The treatment resulted in significant improvement: the patient’s annualized height velocity was 8.7 cm/year, a notable increase of 3.4 cm/year from his baseline, leading to a 0.81 SD gain in height over 12 months. No adverse events were reported despite the high GH dose. The authors suggest the patient was protected because the underlying resistance meant his body was only exposed to a "normal" amount of GH signaling, as evidenced by his IGF-1 levels remaining within the normal range. This GH high-dose approach was preferred over recombinant IGF-1 treatment due to GH’s action through both IGF-1–dependent and IGF-1–independent pathways, fewer side effects, and direct addressing of the underlying pathophysiology.

In conclusion, this precision medicine trial successfully demonstrated that extremely high-dose GH can effectively overcome GH resistance caused by elevated GHBP levels, leading to significant growth improvement in this specific patient.