ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This single-patient intervention study showed the efficacy of high-dose rhGH treatment in overcoming GH resistance in a child harboring a dominant-negative GH receptor (GHR) mutation.

GH insensitivity includes a broad spectrum of defects (1). Laron syndrome is the best-known GH insensitivity syndrome, characterized by recessive mutations in GHR and good response to IGF-I treatment (2). Dominant-negative variants of GHR are extremely rare and affect different domains of the receptor. Usually, the extracellular binding domain of GHR can be cleaved into GH binding protein (GHBP) which acts as carrier protein for circulating GH. Mutations affecting the extracellular domain may thus influence GHBP levels as well as GH signaling.

In this case report, rhGH was administered to a boy carrying a heterozygous variant of GHR, located in the extracellular domain. The patient had high GHBP levels, consistent with higher degree of truncated protein caused by the mutation. The patient had severe short stature (-3.18 SDS at the age of 9 years and 9 months) and biochemical features consistent with GH resistance (high GH peak under stimulation test and reduced IGF-I levels). The patient’s father, who had the same mutation and severe short stature, had been unsuccessfully treated with GH at normal dosage. In this trial high rhGH doses were used to overcome GH resistance. To achieve an IGF-1 serum concentration above the mean but below +2 SDS, a dose escalation phase was employed, whereby the GH dosage was progressively increased from 50 μg/kg/day to the maximum dose of 250 μg/kg/day over a period of 2.5 months. This was followed by a dose-stable phase, resulting in a total treatment period of 12 months. Height velocity increased from 5.3 cm/year to 8.7 cm/year, leading to a height gain of 0.81 SDS (-3.18 to -2.37 SDS). Notably, no significant advancement of bone age or adverse effects were reported. An extension of the therapeutic phase is still ongoing and will provide further data on long-term safety and efficacy.

References: 1. Mastromauro C, Giannini C, Chiarelli F. Short stature related to Growth Hormone Insensitivity (GHI) in childhood. Front Endocrinol (Lausanne). 2023 15:14:1141039.2. Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol. 2010;6(9):515-25.