矮身材是儿科内分泌与遗传代谢领域的常见就诊原因,近年来其遗传性病因日益受到重视。任何影响身高增长相关基因的缺陷均可能导致矮身材,这些缺陷主要通过干扰生长板软骨细胞的正常增殖与分化来实现。其中,生长激素-胰岛素样生长因子轴的功能异常是经典机制,但营养状态、炎性因子、旁分泌信号、细胞外基质以及细胞内信号通路等多种因素也共同参与调控。此类患儿在临床上多伴有身体比例异常、阳性家族史或多系统畸形及功能异常,且特定基因变异常对应特征性表型。因此,系统收集表型信息并结合遗传学检测,已成为实现基因相关矮身材精准诊疗的核心策略。
Abstract
Short stature is a common reason for consultation in the field of pediatric endocrinology and genetic metabolism, and its genetic etiology has garnered increasing attention in recent years.Defects in any genes involved in the process of height growth can lead to short stature, primarily by disrupting the normal proliferation and differentiation of growth plate chondrocytes.While dysfunction of the growth hormone-insulin-like growth factor (GH-IGF) axis represents a classic mechanism, multiple other factors—such as nutritional status, inflammatory cytokines, paracrine signaling, extracellular matrix, and intracellular signaling pathways—are also jointly involved in its regulation.Affected children often present clinically with abnormal body proportions, a positive family history, multisystem malformations or functional impairments, with specific genetic variants frequently correlating with distinct phenotypic profiles.Therefore, the systematic collection of phenotypic information combined with genetic testing has become a core strategy for achieving precision diagnosis and treatment of genetic-related short stature.
关键词
矮身材 /
生长板 /
遗传病 /
致病性变异 /
分子诊断
Key words
short stature /
growth plate /
genetic disorder /
pathogenic variants /
molecular diagnosis
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参考文献
[1] 中华医学会儿科学分会内分泌遗传代谢学组,中国医师协会青春期健康与医学专业委员会,福棠儿童医学发展研究中心,等.儿童特发性矮身材诊断与治疗中国专家共识[J].中国实用儿科杂志, 2023, 38(11):801-813.
[2] Li X, Yao R, Chang G,et al.Clinical profiles and genetic spectra of 814 Chinese children with short stature[J].J Clin Endocrinol Metab, 2022,107(4):972-985.
[3] Cohen LE, Rogol AD.Children with idiopathic short stature: An expanding role for genetic investigation in their medical evaluation[J].Endocr Pract, 2024, 30(7):679-686.
[4] Mazziotti G, Lania AG, Canalis E.Skeletal disorders associated with the growth hormone-insulin-like growth factor 1 axis[J].Nat Rev Endocrinol, 2022, 18(6):353-365.
[5] Andrade AC, Jee YH, Nilsson O.New genetic diagnoses of short stature provide insights into local regulation of childhood growth[J].Horm Res Paediatr, 2017, 88(1):22-37.
[6] Li Q, Xu Z, Zhang M,et al.Mutations in GH1 gene and isolated growth hormone deficiency (IGHD): A familial case of IGHD type I and systematic review[J].Growth Horm IGF Res, 2021,60-61:101423.
[7] Correa FA, Nakaguma M, Madeira JLO,et al.Combined pituitary hormone deficiency caused by PROP1 mutations: Update 20 years post-discovery[J].Arch Endocrinol Metab, 2019, 63(2):167-174.
[8] Laron Z, Werner H.Laron syndrome-A historical perspective[J].Rev Endocr Metab Disord, 2021, 22(1):31-41.
[9] Ornitz DM, Legeai-Mallet L.Achondroplasia: Development, pathogenesis, and therapy[J].Dev Dyn, 2017, 246(4):291-309.
[10] Obiezu F, Boyce A, Jüppner H,et al.PTH1R-related jansen metaphyseal chondrodysplasia[M]//Adam MP, Feldman J, Mirzaa GM, et al.GeneReviews®[Internet].Seattle (WA): University of Washington, Seattle,2025.
[11] Karamanos NK, Theocharis AD, Piperigkou Z,et al.A guide to the composition and functions of the extracellular matrix[J].FEBS J, 2021, 288(24):6850-6912.
[12] Tang W, Wu KM, Zhou Q,et al.Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review[J].Mol Genet Genomic Med, 2024,12(4):e2439.
[13] Zhou L, Chen J, Liu Q,et al.Case Report: Whole-exome sequencing identified two novel COMP variants causing pseudoachondroplasia[J].Front Endocrinol (Lausanne), 2023, 14:1267946.
[14] Hebron KE, Hernandez ER, Yohe ME.The RASopathies:From pathogenetics to therapeutics[J].Dis Model Mech, 2022, 15(2):dmm049107.
[15] Chen H, Li X, Liu X,et al.Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: Results from a Chinese cohort[J].Orphanet J Rare Dis, 2019, 14(1):29.
[16] Elsayed S, Elmakkawy GA, Abdelrazek IM,et al.An update on 3M syndrome: Review of clinical and molecular aspects and report of additional families[J].Am J Med Genet A, 2025, 197(8):e64068.
[17] Nazaryan-Petersen L, Bjerregaard VA, Nielsen FC,et al.Chromothripsis and DNA repair disorders[J].J Clin Med, 2020, 9(3):613.
[18] Ababou M.Bloom syndrome and the underlying causes of genetic instability[J].Mol Genet Metab, 2021,133(1):35-48.
[19] Biggs SE, Gilchrist B, May KR.Chromosome 22q11.2 Deletion (DiGeorge Syndrome): Immunologic features, diagnosis, and management[J].Curr Allergy Asthma Rep, 2023, 23(4):213-222.
[20] Kozel BA, Barak B, Kim CA,et al.Williams syndrome[J].Nat Rev Dis Primers, 2021, 7(1):42.
[21] Jacquin C, Landais E, Poirsier C, et al.1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients[J].Am J Med Genet A, 2023, 191(2):445-458.
[22] Barlow DP, Bartolomei MS.Genomic imprinting in mammals[J].Cold Spring Harb Perspect Biol, 2014, 6(2):a018382.
[23] Wakeling EL, Brioude F, Lokulo-Sodipe O, et al.Diagnosis and management of Silver-Russell syndrome: First international consensus statement[J].Nat Rev Endocrinol,2017,13(2):105-124.
[24] Kalsner L, Chamberlain SJ.Prader-Willi, Angelman, and 15q11-q13 duplication syndromes[J].Pediatr Clin North Am,2015,62(3):587-606.
[25] Wit JM, Oostdijk W, Losekoot M,et al.Mechanisms in endocrinology: Novel genetic causes of short stature[J].Eur J Endocrinol, 2016, 174(4):R145-R173.
[26] Zhou E, Hauser BR, Jee YH.Genetic evaluation in children with short stature[J].Curr Opin Pediatr, 2021,33(4):458-463.
[27] Dauber A, Rosenfeld RG, Hirschhorn JN.Genetic evaluation of short stature[J].J Clin Endocrinol Metab, 2014, 99(9):3080-3092.
[28] Aggarwal S.Role of whole exome sequencing for unidentified genetic syndromes[J].Curr Opin Obstet Gynecol, 2021, 33(2):112-122.
[29] Gravholt CH, Andersen NH, Christin-Maitre S, et al.Clinical practice guidelines for the care of girls and women with Turner syndrome[J].Eur J Endocrinol, 2024, 190(6):G53-G151.
[30] Dawson AJ, Cox J, Hovanes K,et al.PWS/AS MS-MLPA confirms maternal origin of 15q11.2 microduplication[J].Case Rep Genet, 2015, 2015:474097.
基金
国家自然科学基金(82170910);上海儿童脑与发育科学重点实验室(24dz2260100);国家临床重点专科建设项目(10000015 Z155080000004);国家重点研发计划(2022YFC2703102)
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