Growth response of syndromic versus non-syndromic children born small for gestational age (SGA) to growth hormone therapy: a Belgian study

Introduction A substantial proportion of SGA patients present with a syndrome underlying their growth restriction. Most SGA cohorts comprise both syndromic and non-syndromic patients impeding delineation of the recombinant human growth hormone (rhGH) response. We present a detailed characterization of a SGA cohort and analyze rhGH response based on adult height (AH). Methods Clinical and auxological data of SGA patients treated with rhGH, who had reached AH, were retrieved from BELGROW, a national database of all rhGH treated patients held by BESPEED (BElgian Society for PEdiatric Endocrinology and Diabetology). SGA patients were categorized in syndromic or non-syndromic patients. Results 272 patients were included, 42 classified as syndromic (most frequent diagnosis (n=6): fetal alcohol syndrome and Silver-Russell syndrome). Compared with non-syndromic patients, syndromic were younger [years (median (P10/P90)] 7.43 (4.3/12.37) vs 10.21 (5.43/14.03), p=0.0005), shorter (height SDS -3.39 (-5.6/-2.62) vs -3.07 (-3.74/-2.62), p=0.0253) and thinner (BMI -1.70 (-3.67/0.04) vs -1.14 (-2.47/0.27) SDS, p=0.0054) at start of rhGH treatment. First year rhGH response was comparable (delta height SDS +0.54 (0.24/0.94) vs +0.56 (0.26/0.92), p=0.94). Growth pattern differed with syndromic patients having a higher prepubertal (SDS +1.26 vs +0.83, p=0.0048), but a lower pubertal height gain compared to the non-syndromic group (SDS -0.28 vs 0.44, p=0.0001). Mean rhGH dose was higher in syndromic SGA patients (mg/kg body weight/day 0.047 (0.039/0.064) vs 0.043 (0.035/0.056), p=0.0042). AH SDS was lower in syndromic SGA patients (-2.59 (-4.99/-1.57) vs -2.32 (-3.3/-1.2), p=0.0107). The majority in both groups remained short (<-2 SDS: syndromic 71%, non-syndromic 63%). Total height gain was comparable in both groups (delta height SDS +0.76 (-0.70/1.48) vs +0.86 (-0.12/1.86), p=0.41). Conclusions Compared to non-syndromic SGA patients, syndromic SGA patients were shorter when starting rhGH therapy, started rhGH therapy earlier, and received a higher dose of rhGH. At AH, syndromic SGA patients were shorter than non-syndromic ones, but their height gain under rhGH therapy was comparable.

[1]  G. d’Annunzio,et al.  Pubertal timing in children with Silver Russell syndrome compared to those born small for gestational age , 2022, Frontiers in Endocrinology.

[2]  A. Bossowski,et al.  Response to Treatment with Recombinant Human Growth Hormone (rhGH) of Short Stature Children Born Too Small for Gestational Age (SGA) in Selected Centres in Poland , 2022, Journal of clinical medicine.

[3]  M. Fernández-Cancio,et al.  Seventy eight children born small for gestational age without catch-up growth treated with growth hormone from the prepubertal stage until adult height age. An evaluation of puberty and changes in the metabolic profile. , 2021, Endocrinologia, diabetes y nutricion.

[4]  M. Fernández-Cancio,et al.  Seventy eight children born small for gestational age without catch-up growth treated with growth hormone from the prepubertal stage until adult height age. An evaluation of puberty and changes in the metabolic profile. , 2021, Endocrinologia, diabetes y nutricion.

[5]  Gabriela A. Vasques,et al.  Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing. , 2019, The Journal of pediatrics.

[6]  C. Bouvattier,et al.  Determinants of Final Height in Patients Born Small for Gestational Age Treated with Recombinant Growth Hormone , 2019, Hormone Research in Paediatrics.

[7]  Gabriela A. Vasques,et al.  Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature. , 2019, The Journal of clinical endocrinology and metabolism.

[8]  Raoul Rooman,et al.  Poor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria , 2018, International Journal of Pediatric Endocrinology.

[9]  G. Binder,et al.  Adrenarche in Silver‐Russell Syndrome: Timing and Consequences , 2017, The Journal of clinical endocrinology and metabolism.

[10]  A. Hokken-Koelega,et al.  Long-Term Results of GH Treatment in Silver-Russell Syndrome (SRS): Do They Benefit the Same as Non-SRS Short-SGA? , 2016, The Journal of clinical endocrinology and metabolism.

[11]  T. Fenton,et al.  INTERGROWTH-21st very preterm size at birth reference charts , 2016, The Lancet.

[12]  S. Richter,et al.  Results of a randomized controlled study of personalized care plans in breast cancer survivors from a single institution. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  J. Rotteveel,et al.  New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial , 2015, Clinical endocrinology.

[14]  José Villar,et al.  International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project , 2014, The Lancet.

[15]  T. Eggermann,et al.  Adult Height and Epigenotype in Children with Silver-Russell Syndrome Treated with GH , 2013, Hormone Research in Paediatrics.

[16]  A. Hokken-Koelega,et al.  Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. , 2012, The Journal of clinical endocrinology and metabolism.

[17]  M. Ranke,et al.  Height at Start, First-Year Growth Response and Cause of Shortness at Birth Are Major Determinants of Adult Height Outcomes of Short Children Born Small for Gestational Age and Silver-Russell Syndrome Treated with Growth Hormone: Analysis of Data from KIGS , 2010, Hormone Research in Paediatrics.

[18]  C. Azcona,et al.  Effect of Long-Term Growth Hormone Treatment on Final Height of Children with Russell-Silver Syndrome , 2010, Hormone Research in Paediatrics.

[19]  M. Roelants,et al.  References for growth and pubertal development from birth to 21 years in Flanders, Belgium , 2009, Annals of human biology.

[20]  A. Maiorana,et al.  Impact of Growth Hormone Therapy on Adult Height of Children Born Small for Gestational Age , 2009, Pediatrics.

[21]  P. Czernichow,et al.  Small for gestational age: short stature and beyond. , 2007, Endocrine reviews.

[22]  J. Dahlgren,et al.  Final Height in Short Children Born Small for Gestational Age Treated with Growth Hormone , 2005, Pediatric Research.

[23]  A. Hokken-Koelega,et al.  Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  P. Chatelain,et al.  Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. , 2003, The Journal of clinical endocrinology and metabolism.

[25]  H. Wollmann,et al.  Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. , 2000, The Journal of clinical endocrinology and metabolism.

[26]  P. Czernichow,et al.  Prediction Factors in the Determination of Final Height in Subjects Born Small for Gestational Age , 1998, Pediatric Research.

[27]  J. Coste,et al.  Short stature associated with intrauterine growth retardation: final height of untreated and growth hormone-treated children. , 1998, The Journal of clinical endocrinology and metabolism.

[28]  S. Lafranchi,et al.  Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group. , 1997, The Journal of clinical endocrinology and metabolism.

[29]  K. Albertsson-Wikland,et al.  Growth in Full- Term Small-for-Gestational-Age Infants: From Birth to Final Height , 1995, Pediatric Research.

[30]  A. Hokken-Koelega,et al.  Children Born Small for Gestational Age: Do They Catch Up? , 1995, Pediatric Research.

[31]  J. Fryer,et al.  An Update of the Swedish Reference Standards for Weight, Length and Head Circumference at Birth for Given Gestational Age (1977‐1981) , 1991, Acta paediatrica Scandinavica.

[32]  A. de Arriba Muñoz,et al.  Adult height in short children born small for gestational age treated with growth hormone. , 2019, Medicina clínica (Ed. impresa).

[33]  A. Hokken-Koelega,et al.  Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls. , 2007, The Journal of clinical endocrinology and metabolism.

[34]  C. Cowell,et al.  Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). , 2003, The Journal of clinical endocrinology and metabolism.

[35]  T. Cole,et al.  Some questions about how growth standards are used. , 1996, Hormone research.

[36]  J. Tanner.  Use and Abuse of Growth Standards , 1986 .