Department of Health Sciences, University of Florence, Anna Meyer Children's University Hospital, Florence, Italy.
Medical Genetics Unit, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.
Front Endocrinol (Lausanne). 2022 Aug 18;13:951331. doi: 10.3389/fendo.2022.951331. eCollection 2022.
Noonan syndrome (NS) is a disorder characterized by a typical facial gestalt, congenital heart defects, variable cognitive deficits, skeletal defects, and short stature. NS is caused by germline pathogenic variants in genes coding proteins with a role in the RAS/mitogen-activated protein kinase signaling pathway, and it is typically associated with substantial genetic and clinical complexity and variability. Short stature is a cardinal feature in NS, with evidence indicating that growth hormone (GH) deficiency, partial GH insensitivity, and altered response to insulin-like growth factor I (IGF-1) are contributing events for growth failure in these patients. Decreased IGF-I, together with low/normal responses to GH pharmacological provocation tests, indicating a variable presence of GH deficiency/resistance, in particular in subjects with pathogenic variants, are frequently reported. Nonetheless, short- and long-term studies have demonstrated a consistent and significant increase in height velocity (HV) in NS children and adolescents treated with recombinant human GH (rhGH). While the overall experience with rhGH treatment in NS patients with short stature is reassuring, it is difficult to systematically compare published data due to heterogeneous protocols, potential enrolment bias, the small size of cohorts in many studies, different cohort selection criteria and varying durations of therapy. Furthermore, in most studies, the genetic information is lacking. NS is associated with a higher risk of benign and malignant proliferative disorders and hypertrophic cardiomyopathy, and rhGH treatment may further increase risk in these patients, especially as dosages vary widely. Herein we provide an updated review of aspects related to growth, altered function of the GH/IGF axis and cell response to GH/IGF stimulation, rhGH treatment and its possible adverse events. Given the clinical variability and genetic heterogeneity of NS, treatment with rhGH should be personalized and a conservative approach with judicious surveillance is recommended. Depending on the genotype, an individualized follow-up and close monitoring during rhGH treatments, also focusing on screening for neoplasms, should be considered.
努南综合征（Noonan syndrome，NS）是一种以典型面部特征、先天性心脏缺陷、认知功能障碍、骨骼缺陷和身材矮小为特征的疾病。NS 是由编码在 RAS/丝裂原活化蛋白激酶信号通路中起作用的蛋白的种系致病性变异引起的，通常与大量的遗传和临床复杂性和变异性相关。身材矮小是 NS 的一个主要特征，有证据表明生长激素（growth hormone，GH）缺乏、部分 GH 不敏感以及对胰岛素样生长因子 I（insulin-like growth factor I，IGF-1）的反应改变是这些患者生长发育不良的原因。IGF-1 降低，以及 GH 药理学激发试验的低/正常反应，表明 GH 缺乏/抵抗的存在具有变异性，尤其是在有致病性变异的患者中，这是经常报道的。尽管如此，短期和长期研究表明，接受重组人生长激素（recombinant human growth hormone，rhGH）治疗的 NS 儿童和青少年的身高速度（height velocity，HV）持续显著增加。虽然 rhGH 治疗 NS 矮小患者的总体经验令人放心，但由于方案存在异质性、潜在的入组偏倚、许多研究中队列规模较小、不同的队列选择标准和治疗持续时间不同，难以对已发表的数据进行系统比较。此外，在大多数研究中，缺乏遗传信息。NS 与良性和恶性增殖性疾病和肥厚型心肌病的风险增加有关，rhGH 治疗可能会进一步增加这些患者的风险，尤其是因为剂量差异很大。本文提供了与生长、GH/IGF 轴功能改变和细胞对 GH/IGF 刺激的反应、rhGH 治疗及其可能的不良反应相关的最新综述。鉴于 NS 的临床变异性和遗传异质性，rhGH 治疗应个体化，建议采取谨慎监测的保守方法。根据基因型，应考虑个体化随访和 rhGH 治疗期间的密切监测，同时还应关注肿瘤筛查。
