Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Early childhood is a critical period for obesity prevention. This randomized controlled study evaluated the effectiveness of an educational intervention preventing obesity in preschool-age children. A nutritional education intervention, with a follow-up session one year later, was conducted with parents of children aged 3 to 4 years of public schools in the province of Málaga. The main outcome variable was the body mass index z-score (zBMI). The prevalence of overweight or obesity was the secondary outcome variable. The sample comprised 261 students (control group = 139). Initial BMI, weight, height-for-age and prevalence of overweight and obesity were similar for both groups. After the first year of the intervention, the zBMI of the intervention group decreased significantly from 0.23 to 0.10 (p = 0.002), and the subgroup of patients with baseline zBMI above the median decreased from 1 to 0.72 (p = 0.001), and in the second year from 1.01 to 0.73 (p = 0.002). The joint prevalence of overweight and obesity increased in the control group (12.2% to 20.1%; p = 0.027), while in the intervention group, there were no significant changes. This preschool educational intervention with parents improved their children’s BMI, especially those with a higher BMI for their age, and favored the prevention of overweight or obesity.

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with non-specific features and can be difficult to diagnose. Here, we undertook next-generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort 0.102 vs 0.0026 in gnomAD, pA, Thr330=; c.1173C>T, Ser391=). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an E. coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affect splicing and that p.Glu314Lys produces a non-functional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted “benign” variant in CYP11A1 is a significant contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when in combination with other very rare disruptive changes.

Objective In children born small for gestational age (SGA), the relationship between growth hormone (GH) treatment and insulin resistance (IR) has only been investigated for a short period, necessitating a longer observation period. This study aimed to evaluate the long-term (10 years) effect of GH to SGA-children on IR and safety during treatment. Design This was a multicenter observational study. Patients: SGA-children who received GH treatment in Spain (stratified by Tanner-stage and age at GH onset [two groups: ≤6 years old or >6 years old]). Measurements: The analysed variables (yearly measures) included auxologic, metabolic (insulin-like growth factor-1 (IGF-1), height velocity [HV], weight and homeostatic model assessment-IR [HOMA-IR]) and safety data. Data were collected prospectively (since the study approval: 2007) and retrospectively (since the initiation of GH treatment: 2005–2007). Results A total of 389 SGA children (369 Tanner-I) were recruited from 27 centres. The mean age (standard deviation) of the children at GH treatment onset was 7.2 (2.8) years old. IGF-1 (standard deviation score [SDS]) and HOMA-IR values tended to increase until the sixth year of GH-treatment, with significant differences being observed only during the first year, while these remained stable in the later years (within normal ranges). Height (SDS) increased significantly (basal: −3.0; tenth year: −1.13), and the maximum HV (SDS) occurred during the first year (2.75 ± 2.39). Conclusions HOMA-IR values increased significantly in SGA-children during the first year of GH-treatment, remained stable and were within normal ranges in all cases. Our 10-year data suggests that long-term GH treatment does not promote IR and is well-tolerated, safe and effective.

Introduction: Treatment with growth hormone (GH) is not approved for idiopathic short stature (ISS) in Europe. Objectives: To compare the growth of children treated with isolated GH deficiency (IGHD) vs. ISS-treated and untreated children. Methods: A retrospective descriptive study of patients treated in the last 14 years for IGHD (Group A), in comparison with ISS-treated (Group B) and untreated (Group C) subjects. Results: Group A had 67 males, who showed a height gain of 1.24 SD. Group B had 30 boys, who showed a height gain of 1.47 SD. Group C had 42 boys, who showed an improvement of 0.37 SD. The final heights were −1.52 SD, −1.31 SD, and −2.03 SD, respectively. Group A and C did not reach their target heights (with differences of 0.27 SD and 0.59 SD, respectively). Group B surpassed their target height by 0.29 SD. Conclusions: The final heights of the IGHD and treated ISS are similar. Treated groups were taller than untreated groups.

An initial Phase III clinical trial has evaluated the efficacy and safety of biosimilar recombinant human growth hormone (rhGH; Omnitrope^®, Sandoz) in Spanish children with growth hormone deficiency (GHD). At the end of the study, those patients still growing were offered to remain on treatment (as in usual clinical practice), and continued to be monitored. The aim of this study was to determine the adult height achieved by the Spanish children who participated in the initial Phase III clinical trial, and to evaluate the long-term safety of rhGH treatment.