Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action

Abstract

GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature and dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical, and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical, and genetic characteristics. The objective of this review is to clarify the definition, identification, and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.

Figure 1.

Growth charts of patients carrying heterozygous GHR variants. Ranges of short stature phenotypes and responses to therapy are shown in the growth charts of four patients with dominant negative heterozygous GHR mutations (52). Patients carrying heterozygous GHR variants are (a) P1, c.964dupG; (b) P2, c.920_921ins14; (c) P3, c.945+2T>C; and (d) P4, c.899dupC (67). The time frame of rhIGF-1, rhGH, and rhIGF-1 plus IGFBP-3 treatments are indicated on the growth curves. CDC, Centers for Disease Control and Prevention. [Reproduced from Vairamani K, Merjaneh L, Casano-Sancho P, et al. Novel dominant-negative GH receptor mutations expands the spectrum of GHI and IGF-I deficiency. J Endocr Soc 2017;1:345–358.]

Figure 2.

The role of STAT5B in the GHR intracellular signaling pathways. Following recruitment to activated receptors, the latent cytosolic STAT5B protein is phosphorylated on a single tyrosine at position 699 by kinases, including JAK2, which serves to facilitate subsequent homodimerization. The dimeric STAT5B is then mobilized into the nucleus where binding to DNA response elements regulate transcriptional activities. AKT, v-akt murine thymoma viral oncogene homolog, also known as protein kinase B; PI3K, phosphatidylinositol 3-kinase; P, phosphorylated residue; Y, tyrosine.

Figure 3.

Pathophysiological STAT5B mutations. Schematic of the STAT5B gene showing the discrete functional protein domains. L, linker; ND, N-terminal domain.

Figure 4.

Heights of dominant negative STAT5B patients are comparable to dominant negative GHR patients. Height SDS values of GHIS patients with GHR mutations (black) were compared with height SDS values of STAT5B mutational carriers (blue). GHR defects: AR, autosomal recessive GHR mutations (n = 100); AR pseudoexon, GHR pseudoexon 6Ψ mutations (n = 21); DN, dominant negative GHR mutations (n = 16). STAT5B defects: DN, dominant negative STAT5B mutations (n = 11); AR, autosomal recessive STAT5B mutations (n = 10); AR carriers, STAT5B mutation carriers (n = 14). Box (median, 25th and 75th percentiles) and whiskers (minimum and maximum values) plots. Statistical analysis was by the Student t test. *P < 0.05, ***P < 0.001. n.s., not significant (122). [Reproduced with permission from Klammt J, Neumann D, Gevers EF, et al. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun 2018;9:2105.]

Figure 5.

Genetic diagnoses obtained from candidate gene and WES in a selected group of 107 patients with GH insensitivity (15). [Reproduced with permission from Shapiro L, Chatterjee S, Ramadan DG, et al. Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity. Eur J Endocrinol 2017;177:485–501.]

Figure 6.

Algorithm for investigation of GHI in the child with short stature.

Figure 7.

Height velocity at four different time points during treatment with rhIGF1. Box-and-whisker plots show the median, upper and lower quartiles, and range. IQR, interquartile range; n, number of patients data available/included for each time point. P values were calculated by ANOVA with Dunn-Bonferroni post hoc pairwise comparison. *P = 0.001 (74). [Reproduced with permission from Chatterjee S, Shapiro L, Rose SJ, et al. Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation. Eur J Endocrinol 2018;178:481–489.]