OBJECTIVES: Subsequent to early life feeding issues, children with Prader-Willi syndrome (PWS) develop hyperphagia and severe obesity. Growth hormone (GH) therapy has been approved in PWS to improve growth, body composition, and BMI. We aimed to clarify the role of age at GH therapy onset on growth and BMI trajectories in children with PWS. METHODS: We analyzed height and BMI in 114 patients (58 boys) from REPAR - Czech national GH registry. From them, 69 started GH therapy prior to 2 y/o (age 0.8 ± 0.4 years; mean ± SD; early-onset group [EO]), and 45 later (age 7.1 ± 4.1 years; late-onset group [LO]). RESULTS: Height-SDS before therapy was similar in all (EO: -1.9 ± 1.2 [mean ± SD]; LO: -1.7 ± 1.1). After the first year of GH therapy, height-SDS in the EO group increased to -1.0 ± 1.2, in the LO group to -0.9 ± 1.1. After 5 years, height fully normalized in all (-0.1 ± 1.1 SDS). The LO children were already obese at treatment initiation (BMI-SDS: 2.9 ± 2.2), and their BMI-SDS decreased after 1 year of GH therapy by 0.9 (p=0.003). The weight in EO children was below average before GH treatment (BMI-SDS: -0.9 ± 1.2) and their BMI-SDS increased to the overweight range of 1.3 ± 2.2 (p<0.001) within the oncoming 3 years. Albeit BMI-SDS was around the obesity limit in most children after 5 years on GH therapy, the highest lifetime BMI-SDS was lower in EO (2.2 ± 2.6) than in LO (3.7 ± 2.2; p<0.001). CONCLUSIONS: GH treatment in PWS normalizes body height. After 5 years of GH therapy, BMI-SDS in EO and LO groups are similar; however, the EO group is exposed to lower maximal BMI-SDS values.

Department of Pediatrics 2nd Faculty of Medicine 48359 Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics 3rd Faculty of Medicine Charles University and University Hospital Královské Vinohrady Prague Czech Republic

Department of Pediatrics Faculty of Medicine Charles University and University Hospital Hradec Králové Czech Republic

Department of Pediatrics Faculty of Medicine Charles University and University Hospital Plzeň Czech Republic

Department of Pediatrics Faculty of Medicine Masaryk University and University Hospital Brno Czech Republic

Department of Pediatrics Faculty of Medicine Palacky University and Olomouc University Hospital Olomouc Czech Republic

Department of Pediatrics Faculty of Medicine University of Ostrava and University Hospital Ostrava Czech Republic

Department of Pediatrics Masaryk Hospital Ústí nad Labem Czech Republic

Institute of Biostatistics and Analyzes s r o Brno Czech Republic

Institute of Endocrinology Prague Czech Republic

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Angulo, MA, Butler, MG, Cataletto, ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Investig 2015;38:1249–63. https://doi.org/10.1007/s40618-015-0312-9 . DOI

Manzardo, AM, Weisensel, N, Ayala, S, Hossain, W, Butler, MG. Prader-Willi syndrome genetic subtypes and clinical neuropsychiatric diagnoses in residential care adults. Clin Genet 2018;93:622–31. https://doi.org/10.1111/cge.13142 . DOI

Cassidy, SB, Schwartz, S, Miller, JL, Driscoll, DJ. Prader-Willi syndrome. Genet Med 2012;14:10–26. https://doi.org/10.1038/gim.0b013e31822bead0 . DOI

Ranke, MB, Wit, JM. Growth hormone – past, present and future. Nat Rev Endocrinol 2018;14:285–300. https://doi.org/10.1038/nrendo.2018.22 . DOI

Burman, P, Ritzén, EM, Lindgren, AC. Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev 2001;22:787–99. https://doi.org/10.1210/edrv.22.6.0447 . DOI

Deal, CL, Tony, M, Höybye, C, Allen, DB, Tauber, M, Christiansen, JS. Growth hormone research society workshop summary: consensus guidelines for recombinant human growth hormone therapy in prader-willi syndrome. J Clin Endocrinol Metab 2013;98:E1072–87. https://doi.org/10.1210/jc.2012-3888 . DOI

Takeda, A, Cooper, K, Bird, A, Baxter, L, Frampton, G, Gospodarevskaya, E, et al.. Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. Health Technol Assess 2010;14:1–209. https://doi.org/10.3310/hta14420 . DOI

Angulo, MA, Castr-Magana, M, Lamerson, M, Arguello, R, Accacha, S, Khan, A. Final adult height in children with prader–willi syndrome with and without human growth hormone treatment. Am J Med Genet 2007;143A:1456–61.

Lindgren, AC, Lindberg, A. Growth hormone treatment completely normalizes adult height and improves body composition in Prader-Willi syndrome: experience from KIGS (Pfizer international growth database). Horm Res 2008;70:182–7. https://doi.org/10.1159/000145019 . DOI

Bakker, NE, Lindberg, A, Heissler, J, Wollmann, HSCA, Camacho-Hübner, C, Hokken-Koelega, AC. Growth hormone treatment in children with prader-willi syndrome: three years of longitudinal data in prepubertal children and adult height data from the KIGS database. J Clin Endocrinol Metab 2017;102:1702–11. https://doi.org/10.1210/jc.2016-2962 . DOI

Festen, DAM, De Lind Van Wijngaarden, R, Van Eekelen, M, Otten, BJ, Wit, JM, Duivenvoorden, HJ, et al.. Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome. Clin Endocrinol 2008;69:443–51. https://doi.org/10.1111/j.1365-2265.2008.03228.x . DOI

Donze, SH, Damen, L, Mahabier, EF, Hokken-Koelega, ACS. Cognitive functioning in children with Prader-Willi syndrome during 8 years of growth hormone treatment. Eur J Endocrinol 2020;182:405–11. https://doi.org/10.1530/eje-19-0479 . DOI

Luo, Y, Zheng, Z, Yang, Y, Bai, X, Yang, H, Zhu, H, et al.. Effects of growth hormone on cognitive, motor, and behavioral development in Prader-Willi syndrome children: a meta-analysis of randomized controlled trials. Endocrine 2021;71:321–30. https://doi.org/10.1007/s12020-020-02547-3 . DOI

Lecka-Ambroziak, A, Wysocka-Mincewicz, M, Doleżal-Ołtarzewska, K, Zygmunt-Górska, A, Wędrychowicz, A, Żak, T, et al.. Effects of recombinant human growth hormone treatment, depending on the therapy start in different nutritional phases in paediatric patients with prader–willi syndrome: a polish multicentre study. J Clin Med 2021;10:1–19. https://doi.org/10.3390/jcm10143176 . DOI

Gao, Y, Yang, LL, Dai, YL, Shen, Z, Zhou, Q, Zou, CC. Effects of early recombinant human growth hormone treatment in young Chinese children with Prader–Willi syndrome. Orphanet J Rare Dis 2023;18:1–10. https://doi.org/10.1186/s13023-023-02615-7 . DOI

Corripio, R, Tubau, C, Calvo, L, Brun, C, Capdevila, N, Larramona, H, et al.. Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study. J Pediatr Endocrinol Metab 2019;32:879–84. https://doi.org/10.1515/jpem-2018-0539 . DOI

Kodytková, A, Al Lababidi, E, Čermáková, I, Černá, J, Čížek, J, Kalvachová, B, et al.. Analýza dat z celostátního registru pacientů léčených růstovým hormonem REPAR. Česko-Slovenská Pediatr 2020;75:205–12.

Kodytková, A, Zemková, D, Koloušková, S, Lebl, J. Růstové databáze a registry – cesta k poznání fyziologických účinků růstového hormonu. Česko-Slovenská Pediatr 2020;75:251–5.

Hughes, IP, Harris, M, Cotterill, A, Ambler, G, Cowell, CT, Cutfield, WS, et al.. Comparison of weight- vs body surface area-based growth hormone dosing for children: implications for response. Clin Endocrinol 2014;80:384–94. https://doi.org/10.1111/cen.12315 . DOI

Bláha, P, Hrušková, M, Krejčovský, L, Al, E. Growth and development of Czech children aged from birth to six years: Anthropological research 2001–2003 . Prague: Charles University; 2010.

Grootjen, LN, Trueba-Timmermans, DJ, Damen, L, Mahabier, EF, Kerkhof, GF, Hokken-Koelega, ACS. Long-term growth hormone treatment of children with PWS: the earlier the start, the better the outcomes? J Clin Med 2022;11. https://doi.org/10.3390/jcm11092496 . DOI

Wolfgram, PM, Carrel, AL, Allen, DB. Long-term effects of recombinant human growth hormone therapy in children with Prader-Willi syndrome. Curr Opin Pediatr 2013;25:509–14. https://doi.org/10.1097/mop.0b013e328362c7a2 . DOI

Bakker, NE, Kuppens, RJ, Siemensma, EPC, Tummers De Lind Van Wijngaarden, RFA, Festen, DAM, Bindels-De Heus, GCB, et al.. Eight years of growth hormone treatment in children with prader-willi syndrome: maintaining the positive effects. J Clin Endocrinol Metab 2013;98:4013–22. https://doi.org/10.1210/jc.2013-2012 . DOI

Group WHO Multicentre Growth Reference Study . WHO Child Growth Standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development . Geneva: World Health Organization; 2006.

Brambilla, P, Crinò, A, Bedogni, G, Bosio, L, Cappa, M, Corrias, A, et al.. Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity. Nutr Metabol Cardiovasc Dis 2011;21:269–76. https://doi.org/10.1016/j.numecd.2009.10.004 . DOI

O’Neill, S, O’Driscoll, L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 2015;16:1–12. https://doi.org/10.1111/obr.12229 . DOI

Goldstone, AP, Holland, AJ, Hauffa, BP, Hokken-Koelega, AC, Tauber, M. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab 2008;93:4183–97. https://doi.org/10.1210/jc.2008-0649 . DOI

Maniatis, AK, Carakushansky, M, Galcheva, S, Prakasam, G, Fox, LA, Dankovcikova, A, et al.. Treatment burden of weekly somatrogon vs daily somatropin in children with growth hormone deficiency: a randomized study. J Endocr Soc 2022;6:1–10. https://doi.org/10.1210/jendso/bvac117 . DOI

Freedman, DS, Butte, NF, Taveras, EM, Lundeen, EA, Blanck, HM, Goodman, AB, et al.. BMI z-Scores are a poor indicator of adiposity among 2- to 19-year-olds with very high BMIs, NHANES 1999-2000 to 2013-2014. Obesity 2017;25:739–46. https://doi.org/10.1002/oby.21782 . DOI