Abstract 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. <Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> 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. </entry> </row> <row> <entry nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

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

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2026年1月24日

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Barbora Jirova,
Maria Najdekova,
Jana Cerna,
Petra Dusatkova,
Kristina Holotova,
Stanislava Kolouskova,
Ivana Kotvalova,
Olga Magnova,
Martin Modrak,
Dana Novotna,
Barbora Obermannova,
Jan Pavlicek,
Lukas Plachy,
Renata Pomahacova,
Stepanka Pruhova,
Jitka Rezabkova,
Jiri Strnadel,
Marta Snajderova,
Zdenek Sumnik,
Jirina Zapletalova,
Jan Lebl

摘要

Abstract

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.