努南综合征的生长发育规律与身材矮小的临床治疗进展

doi:10.7499/j.issn.1008-8830.2409047

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摘要努南综合征（Noonan syndrome, NS）患者出生时身长和体重正常或略低于正常，出生后身高逐渐落后于正常人群，出现生长发育迟缓、青春期发育延迟等临床特征。我国NS患者身材矮小的发生率约为65%。NS患者身材矮小涉及多种病因，与婴幼儿喂养困难、合并先天性心脏病、遗传异质性、生长激素/胰岛素样生长因子-1轴紊乱等有关，常使用生长激素改善矮小症状。该文通过总结NS各阶段生长发育规律，分析身材矮小病因，以及临床治疗的最新进展，为诊断和治疗NS身材矮小提供新思路。

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	李辛
	温湉
	冯碧云
	王秀敏

关键词 ：努南综合征, 生长发育, 身材矮小, 生长激素

Abstract：Patients with Noonan syndrome (NS) are born with normal or slightly lower body length and weight compared to the normal ranges. However, their height gradually falls behind that of the general population, leading to growth retardation and delayed puberty. In China, the incidence of short stature in patients with NS is approximately 65%. Short stature in these patients arises from multiple causes, including feeding difficulties in infancy, comorbidities such as congenital heart disease, genetic heterogeneity, and disorders of the growth hormone/insulin-like growth factor-1 axis. Growth hormone is commonly used to alleviate symptoms of short stature. This article reviews the growth and development patterns at different stages of NS, analyzes the causes of short stature, and summarizes the latest advances in treatment to provide new insights for the diagnosis and management of short stature in patients with NS.

Key words： Noonan syndrome Growth and development Short stature Growth hormone

收稿日期: 2024-09-09

基金资助:RAS通路病临床研究中心（上海交通大学医学院-儿科学院ELYZX202107）；中央高校基本科研业务费专项资金资助（YG2023QNA35）。

通讯作者: 王秀敏，女，主任医师。Email：wangxiumin@scmc.com.cn。 E-mail: wangxiumin@scmc.com.cn

作者简介: 李辛，女，博士，主治医师；

引用本文:

李辛,温湉,冯碧云等. 努南综合征的生长发育规律与身材矮小的临床治疗进展[J]. 中国当代儿科杂志, 2025, 27(1): 33-38.

LI Xin,WEN Tian,FENG Bi-Yun et al. Growth and development patterns of Noonan syndrome and advances in the treatment of short stature[J]. CJCP, 2025, 27(1): 33-38.

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http://www.zgddek.com/CN/10.7499/j.issn.1008-8830.2409047 或 http://www.zgddek.com/CN/Y2025/V27/I1/33

	Rodríguez F, Gaete X, Cassorla F. Etiology and treatment of growth delay in Noonan syndrome[J]. Front Endocrinol (Lausanne), 2021, 12: 691240. PMID: 34149626. PMCID: PMC8212989. DOI: 10.3389/fendo.2021.691240.
	Johnston JJ, van der Smagt JJ, Rosenfeld JA, et al. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants[J]. Genet Med, 2018, 20(10): 1175-1185. PMID: 29469822. PMCID: PMC6105555. DOI: 10.1038/gim.2017.249.
	中华医学会医学遗传学分会遗传病临床实践指南撰写组. Noonan综合征的临床实践指南[J]. 中华医学遗传学杂志, 2020, 37(3): 324-328. PMID: 32128752. DOI: 10.3760/cma.j.issn.1003-9406.2020.03.017.
	Li X, Yao R, Tan X, et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients[J]. Clin Genet, 2019, 96(4): 290-299. PMID: 31219622. DOI: 10.1111/cge.13588.
	Sodero G, Cipolla C, Pane LC, et al. Efficacy and safety of growth hormone therapy in children with Noonan syndrome[J]. Growth Horm IGF Res, 2023, 69-70: 101532. PMID: 37084633. DOI: 10.1016/j.ghir.2023.101532.
	Cessans C, Ehlinger V, Arnaud C, et al. Growth patterns of patients with Noonan syndrome: correlation with age and genotype[J]. Eur J Endocrinol, 2016, 174(5): 641-650. PMID: 26903553. DOI: 10.1530/EJE-15-0922.
	Stagi S, Ferrari V, Ferrari M, et al. Inside the Noonan "universe": literature review on growth, GH/IGF axis and rhGH treatment: facts and concerns[J]. Front Endocrinol (Lausanne), 2022, 13: 951331. PMID: 36060964. PMCID: PMC9434367. DOI: 10.3389/fendo.2022.951331.
	Rezende RC, Noronha RM, Keselman A, et al. Delayed puberty phenotype observed in Noonan syndrome is more pronounced in girls than boys[J]. Horm Res Paediatr, 2022, 95(1): 51-61. PMID: 35176743. DOI: 10.1159/000522670.
	Rohrer TR, Abuzzahab J, Backeljauw P, et al. Long-term effectiveness and safety of childhood growth hormone treatment in Noonan syndrome[J]. Horm Res Paediatr, 2020, 93(6): 380-395. PMID: 33440388. DOI: 10.1159/000512429.
	Libraro A, D'Ascanio V, Cappa M, et al. Growth in children with Noonan syndrome and effects of growth hormone treatment on adult height[J]. Front Endocrinol (Lausanne), 2021, 12: 761171. PMID: 35002956. PMCID: PMC8730290. DOI: 10.3389/fendo.2021.761171.
	Tamburrino F, Scarano E, Schiavariello C, et al. Endocrinological manifestations in RASopathies[J]. Am J Med Genet C Semin Med Genet, 2022, 190(4): 471-477. PMID: 36401574. DOI: 10.1002/ajmg.c.32013.
	Dahlgren J, Noordam C. Growth, endocrine features, and growth hormone treatment in Noonan syndrome[J]. J Clin Med, 2022, 11(7): 2034. PMID: 35407641. PMCID: PMC8999676. DOI: 10.3390/jcm11072034.
	13 国家卫生健康委员会. 7岁以下儿童生长标准（代替WS/T 423—2013）[EB/OL]. (2022-11-09)[2024-07-30].
	14 李辉, 季成叶, 宗心南, 等. 中国0~18岁儿童、青少年身高、体重的标准化生长曲线[J]. 中华儿科杂志, 2009, 47(7): 487-492. DOI:10.3760/cma.j.issn.0578-1310.2009.07.003.
	Edouard T, Zenker M, ?stman-Smith I, et al. Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: a sub-analysis of a European clinical practice survey[J]. Eur J Med Genet, 2022, 65(1): 104404. PMID: 34896604. DOI: 10.1016/j.ejmg.2021.104404.
	Shoji Y, Hata A, Maeyama T, et al. Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome[J]. Clin Pediatr Endocrinol, 2024, 33(2): 50-58. PMID: 38572385. PMCID: PMC10985011. DOI: 10.1297/cpe.2024-0005.
	中华医学会儿科学分会内分泌遗传代谢学组, 《中华儿科杂志》编辑委员会, 梁雁. 基因重组人生长激素儿科临床规范应用的建议[J]. 中华儿科杂志, 2013, 51(6): 426-432. PMID: 24120059. DOI: 10.3760/cma.j.issn.0578-1310.2013.06.007.
	上官华坤, 徐源彬, 陈瑞敏. 12例努南综合征患儿的临床特征及重组人生长激素疗效观察[J]. 浙江大学学报（医学版）, 2021, 50(4): 500-505. PMID: 34704406. PMCID: PMC8714484. DOI: 10.3724/zdxbyxb-2021-0263.
	Wu X, Wu J, Yuan Y, et al. Noonan syndrome: rhGH treatment and PTPN11 mutation[J]. Mol Genet Genomic Med, 2023, 11(11): e2266. PMID: 37525886. PMCID: PMC10655517. DOI: 10.1002/mgg3.2266.
	Seok EM, Park HK, Rho JG, et al. Effectiveness of growth hormone therapy in children with Noonan syndrome[J]. Ann Pediatr Endocrinol Metab, 2020, 25(3): 182-186. PMID: 32871657. PMCID: PMC7538297. DOI: 10.6065/apem.1938154.077.
	Dahlgren J, Albertsson-Wikland K. GH responsiveness in children with Noonan syndrome compared to Turner syndrome[J]. Front Endocrinol (Lausanne), 2021, 12: 737893. PMID: 34858328. PMCID: PMC8631177. DOI: 10.3389/fendo.2021.737893.
	Olwi D, Day F, Ong K. Effect of growth hormone therapy on pubertal timing: systematic review and meta-analysis[J]. Horm Res Paediatr, 2024, 97(1): 1-10. PMID: 37075730. DOI: 10.1159/000530578.
	Tanaka T, Soneda S, Sato N, et al. Early growth hormone treatment accelerates delayed onset of puberty in patients with growth hormone deficiency[J]. Endocr J, 2022, 69(2): 199-207. PMID: 34588397. DOI: 10.1507/endocrj.EJ21-0209.
	Ozono K, Ogata T, Horikawa R, et al. Efficacy and safety of two doses of Norditropin? (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients[J]. Endocr J, 2018, 65(2): 159-174. PMID: 29109363. DOI: 10.1507/endocrj.EJ17-0313.
	Horikawa R, Ogata T, Matsubara Y, et al. Long-term efficacy and safety of two doses of Norditropin? (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients[J]. Endocr J, 2020, 67(8): 803-818. PMID: 32269181. DOI: 10.1507/endocrj.EJ19-0371.
	Osio D, Dahlgren J, Wikland KA, et al. Improved final height with long-term growth hormone treatment in Noonan syndrome[J]. Acta Paediatr, 2005, 94(9): 1232-1237. PMID: 16203673. DOI: 10.1111/j.1651-2227.2005.tb02081.x.
	Limal JM, Parfait B, Cabrol S, et al. Noonan syndrome: relationships between genotype, growth, and growth factors[J]. J Clin Endocrinol Metab, 2006, 91(1): 300-306. PMID: 16263833. DOI: 10.1210/jc.2005-0983.
	Jo KJ, Kim YM, Yoon JY, et al. Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome[J]. Korean J Pediatr, 2019, 62(7): 274-280. PMID: 30514065. PMCID: PMC6642922. DOI: 10.3345/kjp.2018.06842.
	Tamburrino F, Gibertoni D, Rossi C, et al. Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: patterns of growth, puberty and final height data[J]. Am J Med Genet A, 2015, 167A(11): 2786-2794. PMID: 26227443. DOI: 10.1002/ajmg.a.37260.
	Wolf CM, Zenker M, Burkitt-Wright E, et al. Management of cardiac aspects in children with Noonan syndrome: results from a European clinical practice survey among paediatric cardiologists[J]. Eur J Med Genet, 2022, 65(1): 104372. PMID: 34757052. DOI: 10.1016/j.ejmg.2021.104372.
	Romano A, Kaski JP, Dahlgren J, et al. Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence[J]. Endocr Connect, 2022, 11(1): e210549. PMID: 34939937. PMCID: PMC8859970. DOI: 10.1530/EC-21-0549.
	Seo GH, Yoo HW. Growth hormone therapy in patients with Noonan syndrome[J]. Ann Pediatr Endocrinol Metab, 2018, 23(4): 176-181. PMID: 30599478. PMCID: PMC6312920. DOI: 10.6065/apem.2018.23.4.176.
	K?z?lcan ?etin S, Ramo?lu MG, ??klar Z, et al. The effect of growth hormone therapy on cardiac outcomes in Noonan syndrome: long term follow-up results[J]. J Clin Res Pediatr Endocrinol, 2022, 14(4): 422-432. PMID: 35859537. PMCID: PMC9724055. DOI: 10.4274/jcrpe.galenos.2022.2022-12-13.
	Apperley LJ, Ramakrishnan R, Dharmaraj P, et al. Effect of growth hormone therapy in patients with noonan syndrome: a retrospective study[J]. Int J Endocrinol Metab, 2020, 18(4): e107292. PMID: 33613679. PMCID: PMC7887459. DOI: 10.5812/ijem.107292.
	Bowers DC, Verbruggen LC, Kremer LCM, et al. Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group[J]. Lancet Oncol, 2021, 22(5): e196-e206. PMID: 33845037. DOI: 10.1016/S1470-2045(20)30688-4.
	Boguszewski MCS, Boguszewski CL, Chemaitilly W, et al. Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement[J]. Eur J Endocrinol, 2022, 186(6): P35-P52. PMID: 35319491. PMCID: PMC9066587. DOI: 10.1530/EJE-21-1186.
	Saint-Laurent C, Mazeyrie L, Yart A, et al. Novel therapeutic perspectives in Noonan syndrome and RASopathies[J]. Eur J Pediatr, 2024, 183(3): 1011-1019. PMID: 37863846. PMCID: PMC10951041. DOI: 10.1007/s00431-023-05263-y.
	38 Savarirayan R, Wilcox WR, Harmatz P, et al. Persistence of growth promoting effects in infants and toddlers with achondroplasia: results from a phase II extension study with vosoritide[EB/OL]. [2024-07-30]. https://medical.biomarin.com/en-us/wp-content/uploads/sites/2/2024/03/ACMG-2024-208-Results_Approved-for-use.pdf?v=1.0.