The variety of genes associated with Noonan syndrome spectrum disorders (NSSD) is expanding, and real-life experience with its management is increasing; however, phenotypic differences among genotypes remain poorly defined. We aimed to assess clinical characteristics and response to growth hormone (GH) therapy in a genetically confirmed, single-country multicentre NSSD cohort. We included 101 patients with NSSD (56 males) from six centres: 76 with (likely) pathogenic PTPN11 variants, 7 with SOS1 variants, and 18 with other gene variations. All completed at least one year of GH therapy; 23 reached final height. Parental heights were below average (fathers: - 0.33 SDS [- 1.19; 0.39], p < 0.01; mothers: - 0.68 SDS [- 1.47; 0.12], p < 0.001; medians [IQR]). SOS1-NS patients were born earlier (gestational week 36 [31; 37]) compared to PTPN11-NS. Birth length (- 1.23 SDS [- 1.74; - 0.57]) was more reduced than weight (- 0.29 SDS [- 1.10; 0.54]; p < 0.0001); PTPN11-NS/SOS1-NS had the lowest birth weights (p < 0.05). GH was started at 6.4 years (3.8; 9.5), with baseline height-SDS - 2.92 (- 3.64; - 2.47). Median annual height-SDS increments were similar across genotypes: 0.61 (year 1; n = 101), 0.28 (year 2; n = 92), 0.21 (year 3; n = 77), 0.07 (year 4; n = 63), and 0.09 (year 5; n = 41), leading to height-SDS - 1.97 (- 2.81; - 1.42) after 5 years. Menarche occurred at age 15.7 (13.8; 17.2) years (n = 13), and final height-SDS (available in 23 patients) reached - 1.68 (- 2.65; - 0.41). Conclusions Growth restriction in NSSD begins prenatally, especially in PTPN11-NS and SOS1-NS. GH therapy was associated with improved height SDS, with the largest height gains observed before puberty. Earlier treatment initiation may therefore be beneficial for growth outcomes. What is Known: • Noonan syndrome spectrum disorders (NSSD) are genetically heterogeneous, with pathogenic variants in the PTPN11 and SOS1 genes being most prevalent. Phenotypic differences among genotypes remain poorly defined. • Short stature is a key NSSD feature. Growth hormone (GH) therapy is beneficial, but prior studies lacked genetic justification or had limited sample sizes. What is New: • We analysed perinatal data and real-life GH outcomes in 101 genetically confirmed NSSD cases. • SOS1-NS was linked to prematurity. Birth length was more reduced than weight across genotypes; PTPN11/SOS1 cases had the lowest birth weights. GH therapy was associated with an increase in height SDS from - 2.92 to - 1.97 (median) following 5 years, and to - 1.68 in those with final height.

Department of Bioinformatics 2nd Faculty of Medicine Charles University Prague Czechia

Department of Paediatrics 2nd Faculty of Medicine Charles University Prague Czechia

Department of Paediatrics Faculty of Medicine Masaryk University and University Hospital Brno Czechia

Department of Paediatrics Faculty of Medicine Palacky University and University Hospital Olomouc Czechia

Department of Paediatrics Faculty of Medicine University of Ostrava and University Hospital Ostrava Czechia

Department of Paediatrics Hradec Kralove Faculty of Medicine Charles University and University Hospital Hradec Kralove Czechia

Department of Paediatrics Motol and Homolka University Hospital Prague Czechia

Department of Paediatrics Plzen Faculty of Medicine Charles University and University Hospital Plzen Czechia

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