ESPE Abstracts

Objective: This study analyzed ten short stature patients with growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis gene variants, and aim ed to explore both clinical and genetic characteristics, as well as the recombinant human growth hormone (rhGH) treatment response through a review of the literature.

Methods: The clinical characteristics and response to rhGH treatment in 10 patients with GH1, GHR, IGF1R and IGFALS variants were analyzed. Subsequently, a literature review was conducted to summarize the clinical characteristics of patients with GH-IGF-1 axis gene variants.

Results: Seven GH1 variants and one each for GHR, IGF1R, as well as IGFALS variants were detected in 10 short stature patients. There were 11 pathogenic or likely pathogenic variants were identified, including eight GH1 gene variants (c.240delC, c.334T>C, c.291+1G>A, c.291+2T>A, exon 1-3del, chr17:g.61995333_61996636del, chr17:g.61994673_61996232del, chr17:g.61994532_61996232del), and one IGF1R variant (c.397G>A), one IGF1R variant (c.743G>C) and one IGFALS variant (c.1700_1701delAG), of which eight variants were novel. The types of variants included 4 large fragment deletions, 3 missense, 2 splicing, and 2 frameshift. With 7 boys and 3 girls among the 10 patients, the mean age at diagnosis was (5.1 ± 2.6) years. Patients had proportionate short stature (n = 10), special facial features (n = 4), abnormal pituitary development (n = 2), micropenis (n = 2) and cryptorchidism (n = 1), pulmonary hypertension (n = 1), small gestational age and microcephaly (n = 1), and peak GH <10 ng/mL (n = 8). While one patient with the GH1 variant presented with pulmonary hypertension—a phenotype not previously reported in literatures. Eight patients were treated with rhGH for (1.8±1.6) years, and the ΔHtSDS was (1.91±0.94), with a statistically significant diffrerence between HtSDS before and after treatment (P <0.05).

Conclusion: In this study, eight novel variants were identified in 10 patients, expanding the spectrum of genetic variants in GH-IGF-1 axis-associated diseases. Patients with GH-IGF-1 axis gene variations were mainly characterized by symmetrical short stature, and some of them may have a combination of multi-system abnormal phenotypes. There is a correlation between genotype and phenotype. Heterozygous deletion of a large segment of the GH1 causing short stature in patients is reported rarely. Pulmonary hypertension may be a new phenotype of the GH1 variant. Treatment with rhGH could increase the growth rate of patients with GH1, GHR, and IGFALS variations. rhGH treatment may benefit certain patients with GH insensitivity caused by GHR variations.

Keywords: the GH-IGF-1 axis, gene variants, short stature, rhGH