Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort

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.