Growth hormone treatment outcomes in children with genetic isolated growth hormone deficiency

The aim of this study is to analyze the clinical characteristics of isolated growth hormone deficiency (IGHD) patients with GH1, GHRHR, and GHSR variants and their response to growth hormone (GH) treatment. Growth characteristics were retrospectively analyzed from GH treatment initiation in the Genhypopit cohort with likely pathogenic or pathogenic variants in GH1, GHRHR, or GHSR. Twenty-one patients (GH1: n = 13, GHRHR: n = 4, GHSR: n = 4) were followed up for 8.9 years (0.4; 19.6). GHD was diagnosed earlier in patients with GH1 or GHRHR variants than in those with GHSR variants (mean age at diagnosis: 3.1 and 2.0 years vs. 6.9 years, respectively). Patients with a family history of IGHD tend to have less severe short stature at diagnosis (- 2.2 vs. - 3.2 SDS, p = 0.053). Total height gain was significantly higher in patients with GH1 and GHRHR variants (+ 3.4 and + 3.8 SDS) than in those with GHSR variants (+ 1.8 SDS; p = 0.047). Total height gain was also associated with more severe initial growth delay (p < 0.001), greater difference from target height (p = 0.003), and earlier treatment initiation (p = 0.006). Patients born small for gestational age (SGA) experienced a growth gain similar to patients born eutrophic without the need to increase GH doses. This height gain under GH treatment was higher than reported previously in patients with non-genetic IGHD.

Identifying a genetic cause of IGHD, particularly those involving variants in GH1 and GHRHR, is associated with significant height gain under GH treatment, regardless of their SGA status.

• Recombinant growth hormone reliably improves growth in children with GHD.

• Children with genetic IGHD, have very favorable GH treatment responses, unaffected by SGA status. • There are genotype-specific differences in growth outcomes under treatment.