تسجيل الدخول

تسجيل

Bioinactive GH (Kowarski Syndrome, OMIM 262650)

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p1118

2026-09-22

52

The existence of defects in the GH molecule generating a bio logically inactive but immunoreactive GH was first proposed by Kowarski et al. in 1978. These authors evaluated two children with proportional short stature, normal GH secretion and very low somatomedin (IGF- 1) level. Contrary to what would be expected in a patient with GH insensitivity, these patients normalized their growth rate and IGF- 1 levels with exogenous GH treatment. Although the molecular basis in these first patients was not elucidated, Takahashi et al. published two other patients at the end of the 1990s with similar phenotypes associated with heterozygous pathogenic variants in the GH1 gene.

After these initial reports, a small number of other patients with bioinactive GH have been reported. These patients had a common phenotype characterized by severe short stature (usually height SDS < – 3), very low levels of IGF- 1/ IGFBP- 3 and normal or elevated GH levels (basal or after a stimulation test). Some patients presented with mild clinical characteristics observed in severe GHD (prominent forehead and saddle nose). All patients showed some improvement in growth rate and IGF- 1 concentrations with r- hGH treatment. In one patient, this improvement was suboptimal, possibly due to a marked dominant- negative effect of mutated GH. The majority of the cases had an autosomal dominant inheritance pattern, but an autosomal recessive inheritance was observed in one family.

The mutated GH molecules were capable of binding to the receptor with lower, similar, or even with higher affinity than wild- type GH, but all of them were unable to properly activate the signal transduction by GH receptor. Mutations associated with an autosomal dominant inheritance had a dominant- negative effect on wild- type GH action by competing for binding to the receptor and thus preventing the wild- type GH from activating the receptor. This is analogous to the mechanism of action of pegvisomant, a GH receptor (GHR) antagonist used in the treatment of conditions of GH excess.