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.

Recombinant human growth hormone (rhGH) is a well-established treatment for children with growth deficiencies worldwide. However, its requirement for subcutaneous administration limits convenience compared to that of oral therapies. Starting from capromorelin, we designed, synthesized, and characterized a novel orally active GHSR-1a agonist, compound 4b (hGHSR-1a EC50 = 0.49 nM), which effectively stimulates endogenous GH release in rats at oral doses as low as 0.1 mg/kg─100-fold more potent than ibutamoren (10 mg/kg). Notably, 10 day oral administration of 4b increased body weight and length in 4-week-old rats. To date, comprehensive preclinical studies on oral agents for short stature remain limited, and existing GHSR-1a agonists lack approval for this indication. Compound 4b exhibited superior pharmacokinetic exposure in dogs (oral bioavailability: 43.6%; half-life: 1.2 h) relative to other species. This study details the optimization of 4b, which demonstrates a promising pharmacological profile for clinical translation as a growth hormone replacement therapy.

This study aimed to examine the correlation between the growth response in prepubertal children with idiopathic growth hormone (GH) deficiency after 1 year of treatment with GH to the initial clinical and biochemical parameters. Additionally, the secretion dynamics of GH was also studied by analyzing the GH stimulation test profiles in relation to the GH treatment response. This retrospective study included 84 prepubertal children (47 males and 37 females) with a definitive diagnosis of GH deficiency. The GH secretory indexes GHmax, GH secretion rate, and GH secretion volume were analyzed in relation to the response to recombinant human growth hormone (rhGH) treatment as defined by the index of responsiveness (IoR). Correlation and regression models were used to identify the best clinical and biochemical predictors to rhGH treatment. ResultsIoR was negatively correlated with the age (r=-0.607, p<0.01) and positively with the distance of child's height from its midparental height (MPH) r=0.466 (p<0.01) and pretreatment growth velocity (r=0.247, p<0.05). GH secretory indexes were correlated, and the highest association was observed between GHmax and GH secretion volume (r=0.883, p<0.01). Among the GH secretory indexes, GHmax was the best predictor of IoR (β coef. = -0.514, p<0.001) followed by the GH secretion volume (β coef. = -0.47, p<0.001) and GH secretion rate (β coef. = -0.367 p<0.001). The age and the distance of child's height from its MPH are major predictors of GH treatment response in children with idiopathic GH deficiency. The calculation of the other GH secretory indexes GHSR and GHSV are not better predictors of response to GH than GHmax. The combination of clinical and biochemical indexes may improve the pretreatment assessment of response to rhGH treatment.

The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c). In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively. Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.

Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight &lt;-2 SD for gestational age and life-minimum height &lt;-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.