Clinical and Genetic Characterization of a Cohort of Small-for-Gestational-Age Patients: Cost-Effectiveness of Whole-Exome Sequencing and Effectiveness of Treatment with GH

Overview

Journal J Clin Med

Specialty General Medicine

Date 2024 Jul 27

PMID 39064046

Authors

Ramon Arroyo-Ruiz

Cristina Urbano-Ruiz

Maria Belen Garcia-Berrocal

Elena Marcos-Vadillo

Maria Isidoro-Garcia

M Montserrat Martin-Alonso

Ana Fe Bajo-Delgado

Pablo Prieto-Matos

Juan Pedro Lopez-Siguero

Affiliations

Soon will be listed here.

Abstract

Develop a clinical and genetic characterization, in a group of small-for-gestational-age (SGA) patients who did not experience catch-up growth In an ambispective cohort study with (SGA) patients. These patients received one treatment with growth hormone (GH) over 14 years. This study analyzes their response to treatment and conducts a genetic analysis in order to identify cases with specific phenotypic and auxological characteristics, defined as presenting two or more dysmorphic traits and/or a stature below -3 SDS (standard deviation score). Whole-exome sequencing (WES) was performed on selected patients. : Forty-four SGA patients were examined, with an average age of 6.4 (2.49) years and an initial size of -3.3 SDS. The pubertal growth was 24.1 (5.2) cm in boys and 14.7 (4.3) cm in girls. WES in 11 SGA patients revealed conclusive genetic variants in eight, including two pathogenic ACAN variants, one 15q26.2-q26.3 deletion, and four variants of uncertain significance in other genes. : Treatment with GH in SGA patients was shown to be effective, with a similar response in the group with positive genetic results and in the group who did not undergo a genetic study. Genetic testing based on auxological and clinical criteria proved highly cost-effective.

References

Canton A, Costa S, Rodrigues T, Bertola D, Malaquias A, Correa F . Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways. Eur J Endocrinol. 2014; 171(2):253-62. DOI: 10.1530/EJE-14-0232. View

Lem A, van der Kaay D, Hokken-Koelega A . Bone mineral density and body composition in short children born SGA during growth hormone and gonadotropin releasing hormone analog treatment. J Clin Endocrinol Metab. 2012; 98(1):77-86. DOI: 10.1210/jc.2012-2492. View

Becker M, Thomas M, Brachet C, Heinrichs C, Dotremont H, De Schepper J . Growth response of syndromic versus non-syndromic children born small for gestational age (SGA) to growth hormone therapy: a Belgian study. Front Endocrinol (Lausanne). 2023; 14:1112938. PMC: 10272785. DOI: 10.3389/fendo.2023.1112938. View

de Bruin C, Dauber A . Growth Hormone Therapy in the Short SGA Child: Does Time Matter?. J Clin Endocrinol Metab. 2023; 108(7):e495-e496. DOI: 10.1210/clinem/dgad021. View

Rial Rodriguez J, De Arriba Munoz A, Munoz J, Rodriguez P, Canete Estrada R, Diez Lopez I . [Growth hormone treatment in small for gestational age children in Spain]. An Pediatr (Barc). 2016; 86(5):249-254. DOI: 10.1016/j.anpedi.2016.04.001. View

Strozewska W, Durda-Masny M, Szwed A . Mutations in and Genes as a Potential Reason for the Lack of Catch-Up Growth in SGA Children. Genes (Basel). 2022; 13(5). PMC: 9140854. DOI: 10.3390/genes13050856. View

van der Steen M, Pfundt R, Maas S, Bakker-van Waarde W, Odink R, Hokken-Koelega A . ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment. J Clin Endocrinol Metab. 2016; 102(5):1458-1467. DOI: 10.1210/jc.2016-2941. View

Dahlgren J, Albertsson Wikland K . Final height in short children born small for gestational age treated with growth hormone. Pediatr Res. 2004; 57(2):216-22. DOI: 10.1203/01.PDR.0000148716.71231.81. View

van der Steen M, Lem A, van der Kaay D, Bakker-van Waarde W, van der Hulst F, Neijens F . Metabolic Health in Short Children Born Small for Gestational Age Treated With Growth Hormone and Gonadotropin-Releasing Hormone Analog: Results of a Randomized, Dose-Response Trial. J Clin Endocrinol Metab. 2015; 100(10):3725-34. DOI: 10.1210/jc.2015-2619. View

10.

Ranke M, Lindberg A . Observed and predicted total pubertal growth during treatment with growth hormone in adolescents with idiopathic growth hormone deficiency, Turner syndrome, short stature, born small for gestational age and idiopathic short stature: KIGS analysis.... Horm Res Paediatr. 2011; 75(6):423-32. DOI: 10.1159/000324117. View

11.

Durda-Masny M, Strozewska W, Szwed A . Catch-Up Growth as a Risk Factor for Rapid Weight Gain, Earlier Menarche and Earlier Pubertal Growth Spurt in Girls Born Small for Gestational Age (SGA)-A Longitudinal Study. Int J Environ Res Public Health. 2022; 19(24). PMC: 9778860. DOI: 10.3390/ijerph192416808. View

12.

Zhu H, Lin S, Huang L, He Z, Huang X, Zhou Y . Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction. Prenat Diagn. 2016; 36(7):686-92. DOI: 10.1002/pd.4844. View

13.

Janchevska A, Dimovski A, Mironska K, Tasic V, Gucev Z . Gene Alterations in Small for Gestational Age (SGA) Children. Open Access Maced J Med Sci. 2018; 6(5):790-793. PMC: 5985885. DOI: 10.3889/oamjms.2018.209. View

14.

Inzaghi E, Deodati A, Loddo S, Mucciolo M, Verdecchia F, Sallicandro E . Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype. J Endocrinol Invest. 2021; 45(1):79-87. DOI: 10.1007/s40618-021-01617-1. View

15.

Ferrandez A, Carrascosa A, Audi L, Baguer L, Rueda C, Bosch-Castane J . Longitudinal pubertal growth according to age at pubertal growth spurt onset: data from a Spanish study including 458 children (223 boys and 235 girls). J Pediatr Endocrinol Metab. 2009; 22(8):715-26. DOI: 10.1515/jpem.2009.22.8.715. View

16.

Zahnleiter D, Uebe S, Ekici A, Hoyer J, Wiesener A, Wieczorek D . Rare copy number variants are a common cause of short stature. PLoS Genet. 2013; 9(3):e1003365. PMC: 3597495. DOI: 10.1371/journal.pgen.1003365. View

17.

Homma T, Krepischi A, Furuya T, Honjo R, Malaquias A, Bertola D . Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause. Horm Res Paediatr. 2017; 89(1):13-21. DOI: 10.1159/000481777. View

18.

Tauber M, Ester W, Auriol F, Molinas C, Fauvel J, Caliebe J . GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism. Clin Endocrinol (Oxf). 2007; 67(3):457-61. PMC: 2040241. DOI: 10.1111/j.1365-2265.2007.02911.x. View

19.

Carrascosa A, Yeste D, Moreno-Galdo A, Gussinye M, Ferrandez A, Clemente M . [Pubertal growth of 1,453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study]. An Pediatr (Engl Ed). 2018; 89(3):144-152. DOI: 10.1016/j.anpedi.2017.11.018. View

20.

Lem A, van der Kaay D, de Ridder M, Bakker-van Waarde W, van der Hulst F, Mulder J . Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. J Clin Endocrinol Metab. 2012; 97(11):4096-105. DOI: 10.1210/jc.2012-1987. View