Skip to main content
SpringerLink
Log in

Pattern and Etiology of Growth Disturbance in Turner Syndrome and Outcomes of Growth-Promoting Treatments

  • Chapter
  • First Online:
Turner Syndrome

  • 774 Accesses

Abstract

The growth pattern of untreated girls with Turner syndrome (TS) is one of inexorable growth failure from intrauterine life to the early 20s resulting in average adult height around 143–146 cm, which is about 20 cm shorter than women in the general population. The growth disturbance of TS appears to be multifactorial, due to combined effects of haploinsufficiency of the SHOX gene and disturbances of estrogen secretion and GH/IGF-I physiology. The goal of growth hormone (GH) treatment is to preserve height potential; prevent ongoing growth failure; optimize height during childhood, adolescence, and adulthood; and allow puberty (either spontaneous or induced) to proceed at an age similar to girls without TS. Randomized, controlled trials and observational studies of GH treatment demonstrate average adult height of treated groups around 148–150 cm, but there is wide variation in the range of attained adult heights for individual patients (~136–164 cm). Factors associated with taller adult height following GH treatment include younger age and taller height at start of treatment, taller parental heights, and greater GH dose.

Because girls with TS are at increased risk for disturbances of carbohydrate metabolism, and GH acts as a physiological insulin antagonist, they should be monitored for potential development of insulin resistance and type 2 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    For detailed review and analysis of various international Turner syndrome growth charts, see reference [37].

  2. 2.

    Height velocity is alternatively referred to in some publications as growth velocity. However, as growth can refer to any measurable parameter, such as head circumference, weight, body mass index, etc., the more specific term height velocity (HV) is used in this chapter.

  3. 3.

    According to the 2000 data from the US National Center for Health Statistics, 1 SD for height at age 20 years is ~6.5 cm [www.cdc.gov].

  4. 4.

    In this review the terms adult height (AH) and near-adult height (NAH) or final height (FH) refer to the most mature heights of study subjects, typically obtained after demonstration of minimal remaining growth potential (e.g., HV < 2.0 cm/year or bone age > 14 years). It is expected that most women will gain an additional ~1–2 cm after attainment of this milestone.

  5. 5.

    Calculated by conversion of height SDS to centimeters using height data from US Centers from Disease Control for age 20 years [www.cdc.gov]

  6. 6.

    Calculated by analysis of Ref. [47], Fig. 2.

  7. 7.

    Some clinicians choose to prescribe GH injections on 6 rather than 7 days per week to give the child one injection-free night per week.

References

  1. Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology. 1938;23(5):566–74.

    Article  Google Scholar 

  2. Tesch LG, Rosenfeld RG. Morgagni, Ullrich and Turner: the discovery of gonadal dysgenesis. Endocrinology. 1995;5:327–8.

    Article  Google Scholar 

  3. Ullrich O. Uber typische Kombinationsbilder multipler Abartung. Z Kinderheilkd. 1930;49:271–6.

    Article  Google Scholar 

  4. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child. 1985;60(10):932–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ranke MB, Pfluger H, Rosendahl W, Stubbe P, Enders H, Bierich JR, et al. Turner syndrome: spontaneous growth in 150 cases and review of the literature. Eur J Pediatr. 1983;141(2):81–8.

    Google Scholar 

  6. Pelz L, Timm D, Eyermann E, Hinkel GK, Kirchner M, Verron G. Body height in Turner’s syndrome. Clin Genet. 1982;22:62–6.

    Article  CAS  PubMed  Google Scholar 

  7. Lenko HL, Perheentupa J, Soderholm A. Growth in Turner’s syndrome: spontaneous and fluoxymesterone stimulated. Acta Paediatr Scand Suppl. 1979;227:57–63.

    Article  Google Scholar 

  8. Rosenberg D, Tell G. Syndrome de Turner. A propos d’une statistique de 60 observations. Pediatrie. 1972;27:831–50.

    CAS  PubMed  Google Scholar 

  9. Garcia-Rudaz C, Martinez AS, Heinrich JJ, Lejarraga H, Keselman A, Laspiur M, et al. Growth of Argentinian girls with Turner syndrome. Ann Hum Biol. 1995;22(6):533–44.

    Google Scholar 

  10. Haeusler G, Schemper M, Frisch H, Blumel P, Schmitt K, Plochl E. Spontaneous growth in Turner syndrome: evidence for a minor pubertal growth spurt. Eur J Pediatr. 1992;151(4):283–7.

    Article  CAS  PubMed  Google Scholar 

  11. Massa G, Vanderschueren-Lodeweyckx M, Malvaux P. Linear growth in patients with Turner syndrome: influence of spontaneous puberty and parental height. Eur J Pediatr. 1990;149(4):246–50.

    Article  CAS  PubMed  Google Scholar 

  12. Park E, Bailey JD, Cowell CA. Growth and maturation of patients with Turner’s syndrome. Pediatr Res. 1983;17:1–7.

    Article  CAS  PubMed  Google Scholar 

  13. Naeraa RW, Nielsen J. Standards for growth and final height in Turner’s syndrome. Acta Paediatr Scand. 1990;79:182–90.

    Article  CAS  PubMed  Google Scholar 

  14. Rongen-Westerlaken C, Corel L, van den Broeck J, Massa G, Karlberg J, Albertsson-Wikland K, et al. Reference values for height, height velocity and weight in Turner’s syndrome. Swedish Study Group for GH treatment. Acta Paediatr. 1997;86(9):937–42.

    Google Scholar 

  15. El-Bassyouni HT, Afifi HH, Aglan MS, Mahmoud WM, Zaki ME. Growth curves of Egyptian patients with Turner syndrome. Am J Med Genet Part A. 2012;158:2687–91.

    Article  Google Scholar 

  16. Sempé M, Hansson Bondallaz C, Limoni C. Growth curves in untreated Ullrich-Turner syndrome: French reference standards 1–22 years. Eur J Pediatr. 1996;155:862–9.

    Article  PubMed  Google Scholar 

  17. Suwa S. Standards for growth and growth velocity in Turner’s syndrome. Acta Paediatr Jpn. 1992;34(2):206–21.

    Article  CAS  PubMed  Google Scholar 

  18. Isojima T, Yokoya S, Ito J, Horikawa R, Tanaka T. New reference growth charts for Japanese girls with Turner syndrome. Pediatr Int. 2009;51(5):709–14.

    Article  PubMed  Google Scholar 

  19. Isojima T, Yokoya S, Ito J, Naiki Y, Horikawa R, Tanaka T. Proposal of new auxological standards for Japanese girls with Turner syndrome. Clin Pediatr Endocrinol. 2010;19(3):69–82.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Even L, Cohen A, Marbach N, Brand M, Kauli R, Sippell W, et al. Longitudinal analysis of growth over the first 3 years of life in Turner’s syndrome. J Pediatr. 2000;137(4):460–4.

    Article  CAS  PubMed  Google Scholar 

  21. Bernasconi S, Larizza D, Benso L, Volta C, Vannelli S, Milani S, et al. Turner’s syndrome in Italy: familial characteristics, neonatal data, standards for birth weight and for height and weight from infancy to adulthood. Acta Paediatr. 1994;83(3):292–8.

    Google Scholar 

  22. Davenport ML, Punyasavatsut N, Stewart PW, Gunther DF, Savendahl L, Sybert VP. Growth failure in early life: an important manifestation of Turner syndrome. Horm Res. 2002;57(5–6):157–64.

    CAS  PubMed  Google Scholar 

  23. Woelfle J, Lindberg A, Aydin F, Ong KC, Camach-Hubner C, Gohlke B. Secular trends on birth parameters, growth, and pubertal timing in girls with Turner syndrome. Front Endocrinol. 2018;9:54.

    Article  Google Scholar 

  24. Ranke MB, Stubbe P, Majewski F, Bierich JR. Spontaneous growth in Turner syndrome. Acta Paediatr Scand Suppl. 1988;343:22–30.

    CAS  PubMed  Google Scholar 

  25. Brook CG, Murset G, Zachmann M, Prader A. Growth in children with 45, XO Turner’s syndrome. Arch Dis Child. 1974;49(10):789–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hausler G, Schemper M, Frisch H, Blümel P, Schmitt K, Plöchl E. Spontaneous growth in Turner syndrome: evidence for a minor pubertal growth spurt. In: Ranke MB, Rosenfeld RG, editors. Amsterdam: Elsevier Science BV; 1991. p. 67–73.

    Google Scholar 

  27. Rochiccioli P, David M, Malpuech G, Colle M, Limal JM, Battin J, et al. Study of final height in Turner’s syndrome: ethnic and genetic influences. Acta Paediatr. 1994;83(3):305–8.

    Google Scholar 

  28. Tuschy U. Spontaneous growth in Turner’s syndrome. Padiatr Grenzgeb. 1990;29(5):419–23.

    CAS  PubMed  Google Scholar 

  29. Lenko HL, Perheentupa J, Soderholm A. Growth in Turner syndrome: spontaneous and fluoximesterone stimulated. Acta Paediatr Scand Suppl. 1979;277:57–63.

    Article  CAS  PubMed  Google Scholar 

  30. Ranke MG, Chavez-Meyer H, Blank B, Frisch H, Hausler G. Spontaneous growth and bone age development in Turner syndrome: results of a multicentric study 1990. In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies. Amsterdam: Elsevier Science BV; 1991. p. 101–6.

    Google Scholar 

  31. Rochiccioli P, Pienkowsky C, Tauber MT. Spontaneous growth in Turner syndrome: a study of 61 cases. In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies. Amsterdam: Elsevier Science BV; 1991. p. 107–12.

    Google Scholar 

  32. Lippe B, Frane J. Growth in Turner syndrome: the United States experience. In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies. Amsterdam: Elsevier Science BV; 1991. p. 59–65.

    Google Scholar 

  33. FitzSimmons J, Fantel A, Shepard TH. Growth parameters in mid-trimester fetal Turner syndrome. Early Hum Dev. 1994;38(2):121–9.

    Article  CAS  PubMed  Google Scholar 

  34. Holl RW, Kunze D, Etzrodt H, Teller W, Heinze E. Turner syndrome: final height, glucose tolerance, bone density and psychosocial status in 25 adult patients. Eur J Pediatr. 1994;153(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  35. Karlberg J, Albertsson-Wikland K, Nilsson KO, Ritzén EM, Westphal O. Growth in infancy and childhood in girls with Turner’s syndrome. Acta Paediatr Scand. 1991;80(12):1158–65.

    Article  CAS  PubMed  Google Scholar 

  36. Karlberg J, Albertsson-Wikland K, Naeraa RW, on behalf of the Swedish Pediatric Study Group for GH Treatment. The infancy-childhood-puberty model of growth for Turner girls. In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies. Amsterdam: Elsevier Science; 1991. p. 89–94.

    Google Scholar 

  37. Bertapelli F, Barros-Filho A de A, Antonio MÂ, Barbeta CJ, de Lemos-Marini SH, Guerra-Junior G. Growth curves for girls with Turner syndrome. Biomed Res Int. 2014;2014:687978.

    Google Scholar 

  38. Gunther DF, Eugster E, Zagar AJ, Bryant CG, Davenport ML, Quigley CA. Ascertainment bias in Turner syndrome: fewer clinical manifestations in girls diagnosed incidentally in prenatal life. Pediatrics. 2004;114:640–4.

    Article  PubMed  Google Scholar 

  39. Karlberg J, Engstrom I, Karlberg P, Fryer JG. Analysis of linear growth using a mathematical model. I. From birth to three years. Acta Paediatr Scand. 1987;76:478–88.

    Article  CAS  PubMed  Google Scholar 

  40. Courant F, Aksglaede L, Antignac J-P, Monteau F, Sorensen K, Andersson A-M, et al. Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method. J Clin Endocrinol Metab. 2010;95(82–92):2010.

    Google Scholar 

  41. Frane J, Sherman B, Genentech Collaborative Group. Predicted adult height in Turner syndrome. In: Rosenfeld RG, Grumbach MM, editors. Turner syndrome. New York: Marcel Dekker; 1990. p. 405–19.

    Google Scholar 

  42. Hamelin CE, Anglin DG, Quigley CA, Deal CL. Genomic imprinting in Turner syndrome: effects on response to growth hormone and on risk of sensorineural hearing loss. J Clin Endocrinol Metab. 2006;91(8):3002–10.

    Article  CAS  PubMed  Google Scholar 

  43. Ko JM, Kim JM, Kim GH, Lee BH, Yoo HW. Influence of parental origin of the X chromosome on physical phenotypes and GH responsiveness of patients with Turner syndrome. Clin Endocrinol. 2010;73(1):66–71.

    CAS  Google Scholar 

  44. Bondy CA, Hougen HY, Zhou J, Cheng CM. Genomic imprinting and Turner syndrome. Pediatr Endocrinol Rev. 2012;9(Suppl 2):728–32.

    PubMed  Google Scholar 

  45. Naeraa RW, Eiken M, Legarth EG, Nielsen J. Prediction of final height in Turner’s syndrome: a comparative study. Acta Paediatr Scand. 1990;79:776–83.

    Article  CAS  PubMed  Google Scholar 

  46. van Teunenbroek A, Stijnen T, Otten B, de Muinck Keizer-Schrama S, Naeraa RW, Rongen-Westerlaken C, et al. A regression method including chronological and bone age for predicting final height in Turner’s syndrome, with a comparison of existing methods. Acta Paediatr. 1996;85(4):413–20.

    Google Scholar 

  47. Stephure DK. Impact of growth hormone supplementation on adult height in Turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005;90(6):3360–6.

    Article  CAS  PubMed  Google Scholar 

  48. Rongen-Westerlaken C, Rikken B, Vastrick P, Jeuken AH, de Lange MY, Wit JM, et al. Body proportions in individuals with Turner syndrome. Eur J Pediatr. 1993;152(10):813–7.

    Article  CAS  PubMed  Google Scholar 

  49. Gravholt CH, Naeraa RW. Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome. Am J Med Genet. 1997;72(4):403–8.

    Article  CAS  PubMed  Google Scholar 

  50. Sas TC, Gerver WJ, de Bruin R, Stijnen T, de Muinck Keizer-Schrama SM, Cole TJ, et al. Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial. J Clin Endocrinol Metab. 1999;84(12):4622–8.

    Google Scholar 

  51. Uematsu A, Yorifuji T, Muroi J, Yamanaka C, Momoi T. Relatively longer hand in patients with Ullrich-Turner syndrome. Am J Med Genet. 1999;82(3):254–6.

    Article  CAS  PubMed  Google Scholar 

  52. Binder G, Fritsch H, Schweizer R, Ranke MB. Radiological signs of Leri-Weill dyschondrosteosis in Turner syndrome. Horm Res. 2001;55(2):71–6.

    CAS  PubMed  Google Scholar 

  53. Saenger P, Wikland KA, Conway GS, Davenport M, Gravholt CH, Hintz R, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab. 2001;86:3061–9.

    CAS  PubMed  Google Scholar 

  54. Lubin MB, Gruber HE, Rimoin DL, Lachman RS. Skeletal abnormalities in the Turner syndrome. In: Rosenfeld RG, Grumbach MM, editors. Turner syndrome. New York: Marcel Dekker; 1990. p. 281–300.

    Google Scholar 

  55. Ricotti S, Petrucci L, Carenzio G, Klersy C, Calcaterra V, Larizza D, et al. Prevalence and incidence of scoliosis in Turner syndrome: a study in 49 girls followed-up for 4 years. Eur J Phys Rehabil Med. 2011;47:447–53.

    CAS  PubMed  Google Scholar 

  56. Elder DA, Roper MG, Henderson RC, Davenport ML. Kyphosis in a Turner syndrome population. Pediatrics. 2002;109(6):e93.

    Article  PubMed  Google Scholar 

  57. Kim JY, Rosenfeld SR, Keyak JH. Increased prevalence of scoliosis in Turner syndrome. J Pediatr Orthop. 2001;21(6):765–6.

    CAS  PubMed  Google Scholar 

  58. Hochberg Z. Endocrine control of skeletal maturation. Basel: Karger; 2002. p. 60–3.

    Book  Google Scholar 

  59. Ross JL, Long LM, Loriaux DL, Cutler GB. Growth hormone secretory dynamics in Turner syndrome. J Pediatr. 1985;106:202–6.

    Article  CAS  PubMed  Google Scholar 

  60. Massarano AA, Brook CG, Hindmarsh PC, Pringle PJ, Teale JD, Stanhope R, et al. Growth hormone secretion in Turner’s syndrome and influence of oxandrolone and ethinyl oestradiol. Arch Dis Child. 1989;64:587–92.

    Google Scholar 

  61. Massa G, Vanderschueren-Lodeweyckx M, Craen M, Vandeweghe M, Van VG. Growth hormone treatment of Turner syndrome patients with insufficient growth hormone response to pharmacological stimulation tests. Eur J Pediatr. 1991;150:460–3.

    Article  CAS  PubMed  Google Scholar 

  62. Reiter JC, Craen M, Van VG. Decreased growth hormone response to growth hormone-releasing hormone in Turner’s syndrome: relation to body weight and adiposity. Acta Endocrinol. 1991;125:38–42.

    Article  CAS  Google Scholar 

  63. Pirazzoli P, Mazzanti L, Bergamaschi R, Perri A, Scarano E, Nanni S, et al. Reduced spontaneous growth hormone secretion in patients with Turner’s syndrome. Acta Paediatr. 1999;88:610–3.

    Google Scholar 

  64. Wit JM, Massarano AA, Kamp GA, Hindmarsh PC, van Es A, Brook CG, et al. Growth hormone secretion in patients with Turner’s syndrome as determined by time series analysis. Acta Endocrinol. 1992;127:7–12.

    Google Scholar 

  65. Cianfarani S, Vaccaro F, Pasquino AM, Marchione SA, Passeri F, Spadoni GL, et al. Reduced growth hormone secretion in Turner syndrome: is body weight a key factor? Horm Res. 1994;41:27–32.

    Google Scholar 

  66. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, et al. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci U S A. 1989;86:10001–5.

    Google Scholar 

  67. Ogata T, Goodfellow P, Petit C, Aya M, Matsuo N. Short stature in a girl with a terminal Xp deletion distal to DXYS15: localisation of a growth gene(s) in the pseudoautosomal region. J Med Genet. 1992;29(7):455–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ogata T, Petit C, Rappold G, Matsuo N, Matsumoto T, Goodfellow P. Chromosomal localisation of a pseudoautosomal growth gene(s). J Med Genet. 1992;29(9):624–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ogata T, Matsuo N. Sex chromosome aberrations and stature: deduction of the principal factors involved in the determination of adult height. Hum Genet. 1993;91:551–62.

    Article  CAS  PubMed  Google Scholar 

  70. Ogata T, Matsuo N. Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features. Hum Genet. 1995;95:607–29.

    Article  CAS  PubMed  Google Scholar 

  71. Rao E, Weiss B, Fukami M, Mertz A, Meder J, Ogata T, et al. FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes. Hum Genet. 1997;100:236–9.

    Google Scholar 

  72. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 1997;16(1):54–63.

    Google Scholar 

  73. Ellison JW, Wardak Z, Young MF, Robey PG, Webster M, Chiong W. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet. 1997;6:1341–7.

    Article  CAS  PubMed  Google Scholar 

  74. van der Eerden BC, Karperien M, Wit JM. Systemic and local regulation of the growth plate. Endocr Rev. 2003;24(6):782–801.

    Article  CAS  PubMed  Google Scholar 

  75. Manolagas SC, O’Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol. 2013;9(12):699–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kosho T, Muroya K, Nagai T, Fujimoto M, Yokoya S, Sakamoto H, et al. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J Clin Endocrinol Metab. 1999;84(12):4613–21.

    Google Scholar 

  77. Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet. 2007;44(5):306–13.

    Google Scholar 

  78. Ross JL, Kowal K, Quigley CA, Blum WF, Cutler GB, Crowe B, et al. The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Léri-Weill dyschondrosteosis and Turner syndrome. J Pediatr. 2005;147(4):499–507.

    Google Scholar 

  79. Andrade AC, Baron J, Manolagas SC, Shaw NJ, Rappold GA, Donaldson MD, et al. Hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome. Horm Res Paediatr. 2010;73(3):161–5.

    Google Scholar 

  80. Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr. 2011;75(2):81–9.

    Article  CAS  PubMed  Google Scholar 

  81. Child CJ, Rappold GA, Blum WF. Short Stature Homeobox-containing (SHOX) gene deficiency: genetics and growth response to growth hormone treatment in comparison with Turner syndrome. In: Preedy VR, editor. The handbook of growth and growth monitoring in health and disease. New York: Springer Science+Business Media, LLC; 2012. p. 2299–318.

    Chapter  Google Scholar 

  82. Blaschke RJ, Rappold G. The pseudoautosomal regions, SHOX and disease. Curr Opin Genet Dev. 2006;16:233–9.

    Article  CAS  PubMed  Google Scholar 

  83. Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet. 2000;9:695–702.

    Google Scholar 

  84. Hristov G, Marttila T, Durand C, Niesler B, Rappold GA. SHOX triggers the lysosomal pathway of apoptosis via oxidative stress. Hum Mol Genet. 2014;23:1619–30.

    Article  CAS  PubMed  Google Scholar 

  85. Marchini A, Marttila T, Winter A, Caldeira S, Malanchi I, Blaschke RJ, et al. The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes. J Biol Chem. 2004;279:37103–14.

    Google Scholar 

  86. Munns CJ, Haase HR, Crowther LM, Hayes MT, Blaschke R, Rappold G, et al. Expression of SHOX in human fetal and childhood growth plate. J Clin Endocrinol Metab. 2004;89:4130–5.

    Google Scholar 

  87. Marchini A, Hacker B, Marttila T, Hesse V, Emons J, Weiss B, et al. BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum Mol Genet. 2007;16:3081–7.

    Google Scholar 

  88. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92(1):10–25.

    Article  CAS  PubMed  Google Scholar 

  89. Haverkamp F, Wolfle J, Zerres K, Butenandt O, Amendt P, Hauffa BP, et al. Growth retardation in Turner syndrome: aneuploidy, rather than specific gene loss, may explain growth failure. J Clin Endocrinol Metab. 1999;84(12):4578–82.

    Google Scholar 

  90. Bakalov VK, Axelrod L, Baron J, Hanton L, Nelson LM, Reynolds JC, et al. Selective reduction in cortical bone mineral density in Turner syndrome independent of ovarian hormone deficiency. J Clin Endocrinol Metab. 2003;88:5717–22.

    Google Scholar 

  91. Brook CGD. Growth hormone deficiency in Turner’s syndrome. N Engl J Med. 1978;298:1203–4.

    CAS  PubMed  Google Scholar 

  92. Albertsson-Wikland K, Rosberg S. Growth hormone secretory dynamics in Turners. In: Rosenfeld R, Grumbach M, editors. Turner syndrome. New York: Marcel Dekker; 1990.

    Google Scholar 

  93. Ranke MB, Blum WF, Haug F, Rosendahl W, Attanasio A, Enders H, et al. Growth hormone, somatomedin levels and growth regulation in Turner’s syndrome. Acta Endocrinol. 1987;116:305–13.

    Google Scholar 

  94. Hochberg Z, Aviram M, Rubin D, Pollack S. Decreased sensitivity to insulin-like growth factor I in Turner’s syndrome: a study of monocytes and T lymphocytes. Eur J Clin Investig. 1997;27:543–7.

    Article  CAS  Google Scholar 

  95. Foster CM, Borondy M, Markovs ME, Hopwood NJ, Kletter GB, Beitins IZ. Growth hormone bioactivity in girls with Turner’s syndrome: correlation with insulin-like growth factor I. Pediatr Res. 1994;35:218–22.

    Article  CAS  PubMed  Google Scholar 

  96. Attie KM, Julius JR, Stoppani C, Rundle AC. National Cooperative Growth Study substudy VI: the clinical utility of growth-hormone binding protein, insulin-like growth factor I, and insulin-like growth factor-binding protein 3 measurements. J Pediatr. 1997;131:S56–60.

    Article  CAS  PubMed  Google Scholar 

  97. Leung K-C, Johannsson G, Leong GM, Ho KKY. Estrogen regulation of growth hormone action. Endocr Rev. 2004;25(5):693–721.

    Article  CAS  PubMed  Google Scholar 

  98. Bas F, Darendeliler F, Aycan Z, Çetinkaya E, Berberoğlu M, Sıklar Z, et al. The exon 3-deleted/full-length growth hormone receptor polymorphism and response to growth hormone therapy in growth hormone deficiency and Turner syndrome: a multicenter study. Horm Res Paediatr. 2012;77(2):85–93.

    Google Scholar 

  99. Ko JM, Kim JM, Cheon CK, Kim DH, Lee DY, Cheong WY, et al. The common exon 3 polymorphism of the growth hormone receptor gene and the effect of growth hormone therapy on growth in Korean patients with Turner syndrome. Clin Endocrinol. 2010;72(2):196–202.

    Google Scholar 

  100. Gravholt CH. Epidemiological, endocrine and metabolic features in Turner syndrome. Eur J Endocrinol. 2004;151:657–87.

    Article  CAS  PubMed  Google Scholar 

  101. Gravholt CH, Frystyk J, Flyvbjerg A, Orskov H, Christiansen JS. Reduced free IGF-I and increased IGFBP-3 proteolysis in Turner syndrome: modulation by female sex steroids. Am J Physiol Endocrinol Metab. 2001;280:E308–14.

    Article  CAS  PubMed  Google Scholar 

  102. Lebl J, Pruhova S, Zapletalova J, Pechova M. IGF-I resistance and Turner’s syndrome. J Pediatr Endocrinol Metab. 2001;14:37–41.

    Article  CAS  PubMed  Google Scholar 

  103. Bannink EM, van Doorn J, Stijnen T, Drop SL, de Muinck Keizer-Schrama SM. Free dissociable insulin-like growth factor I (IGF-I), total IGF-I and their binding proteins in girls with Turner syndrome during long-term growth hormone treatment. Clin Endocrinol. 2006;65(3):310–9.

    Article  CAS  Google Scholar 

  104. Weiss L. Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner’s syndrome. J Med Genet. 1971;8(4):540–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20:358–417.

    Article  CAS  PubMed  Google Scholar 

  106. Nilsson O, Marino R, De Luca F, Phillip M, Baron J. Endocrine regulation of the growth plate. Horm Res. 2005;64(4):157–65.

    CAS  PubMed  Google Scholar 

  107. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB Jr. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest. 1994;94:2475–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V, Baron J. Effects of estrogen on growth plate senescence and epiphyseal fusion. Proc Natl Acad Sci U S A. 2001;98(12):6871–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nilsson O, Weise M, Landman EB, Meyers IL, Barnes KM, Baron J. Evidence that estrogen hastens epiphyseal fusion and cessation of longitudinal bone growth by irreversibly depleting the number of resting zone progenitor cells in female rabbits. Endocrinology. 2014;155(8):2892–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, et al. Estrogen resistance caused by a mutation in the estrogen receptor gene in a man. N Engl J Med. 1994;331:1056–60.

    Google Scholar 

  111. Quaynor SD, Stradtman EW Jr, Kim H-G, Shen Y, Chorich LP, Schreihofer DA, Layman LC. Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant. N Engl J Med. 2013;369(2):164–71.

    Article  CAS  PubMed  Google Scholar 

  112. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995;80(12):3689–98.

    CAS  PubMed  Google Scholar 

  113. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 1999;84(12):4677–94.

    CAS  PubMed  Google Scholar 

  114. Ross JL, Cassorla FG, Skerda MC, Valk IM, Loriaux DL, Cutler GB Jr. A preliminary study of the effect of estrogen dose on growth in Turner’s syndrome. N Engl J Med. 1983;309(18):1104–6.

    Article  CAS  PubMed  Google Scholar 

  115. Ranke MB. Why treat girls with Turner syndrome with growth hormone: growth and beyond. Pediatr Endocrinol Rev. 2015;12(4):297–306.

    Google Scholar 

  116. Ranke MB, Lindberg A, Ferrández Longás A, Darendeliler F, Albertsson-Wikland K, Dunger D, et al. Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS. Pediatr Res. 2007;61(1):105–10.

    Google Scholar 

  117. Baxter L, Bryant J, Cave CB, Milne R. Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database Syst Rev. 2007;1:CD003887.

    Google Scholar 

  118. Li P, Cheng F, Xiu L. Height outcome of the recombinant human growth hormone treatment in Turner syndrome: a meta-analysis. Endocr Connect. 2018;7(4):573–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Buchanan CR, Law CM, Milner RDG. Growth hormone in short, slowly growing children and those with Turner’s syndrome. Arch Dis Child. 1987;62:912–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Underwood LE. Report of the conference on uses and possible abuses of biosynthetic human growth hormone. N Engl J Med. 1984;311(9):606–8.

    Article  CAS  PubMed  Google Scholar 

  121. Rosenfeld RG. Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. J Endocrinol Investig. 1989;12:49–51.

    CAS  Google Scholar 

  122. Vanderschueren-Lodeweyckx M, Massa G, Maes M, Craen M, van Vliet G, Heinrichs C, et al. Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner’s syndrome. J Clin Endocrinol Metab. 1990;70:122–6.

    Google Scholar 

  123. Werther GA. A multi-centre double-blind study of growth hormone and low-dose estrogen in Turner syndrome: an interim analysis. In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies. Philadelphia: Elsevier Science BV; 1991.

    Google Scholar 

  124. Quigley CA, Crowe BJ, Anglin DG, Chipman JJ, and the US Turner Syndrome Study Group. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. J Clin Endocrinol Metab. 2002;87(5):2033–41.

    Article  CAS  PubMed  Google Scholar 

  125. Kollmann F, Damm M, Reinhardt D, Stover B, Heinrich U, Brendel L, et al. Growth-promoting effects of human recombinant growth hormone in subjects with Ullrich-Turner syndrome (UTS). In: Ranke MB, Rosenfeld RG, editors. Turner syndrome: growth promoting therapies, vol. 924. Amsterdam: Elsevier Science BV; 1991. p. 201–7.

    Google Scholar 

  126. Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY, et al. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007;92(9):3406–16.

    Google Scholar 

  127. Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, et al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011;364(13):1230–42.

    Google Scholar 

  128. Ranke MB, Lindberg A. Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab. 2010;95(3):1229–37.

    Article  CAS  PubMed  Google Scholar 

  129. Tanner JM, Davies PW. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107(3):317–29.

    Article  CAS  PubMed  Google Scholar 

  130. Plotnick L, Attie KM, Blethen SL, Sy JP. Growth hormone treatment of girls with Turner syndrome: the National Cooperative Growth Study Experience. Pediatrics. 1998;102(2):479–81.

    CAS  PubMed  Google Scholar 

  131. Wasniewska M, De Luca F, Bergamaschi R, Guarneri MP, Mazzanti L, Matarazzo P, et al. Early treatment with GH alone in Turner syndrome: prepubertal catchup growth and waning effect. Eur J Endocrinol. 2004;151(5):567–72.

    Google Scholar 

  132. Quigley CA, Fechner PY, Geffner ME, Eugster EA, Ross JL, Habiby RL, et al. Long-term results of early growth hormone treatment in the “Toddler Turner” cohort. J Clin Endocrinol Metab. 2020;

    Google Scholar 

  133. Rosenfeld RG, Attie KM, Frane J, Brasel JA, Burstein S, Cara JF, et al. Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr. 1998;132(2):319–24.

    Google Scholar 

  134. Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J. Growth hormone therapy of Turner syndrome; the impact of age of estrogen replacement on final height. Genentech Inc. Collaborative Study Group. J Clin Endocrinol Metab. 2000;85(7):2439–45.

    CAS  PubMed  Google Scholar 

  135. Pasquino AM, Pucarelli I, Segni M, Tarani L, Calcaterra V, Larizza D. Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group. J Endocrinol Investig. 2005;28:350–6.

    Article  CAS  Google Scholar 

  136. Ranke MB, Partsch CJ, Lindberg A, Dorr HG, Bettendorf M, Hauffa BP, et al. Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001. Eur J Endocrinol. 2002;147(5):625–33.

    Google Scholar 

  137. Carel JC, Mathivon L, Gendrel C, Ducret JP, Chaussain JL. Near normalization of final height with adapted doses of growth hormone in Turner’s syndrome. J Clin Endocrinol Metab. 1998;83(5):1462–6.

    CAS  PubMed  Google Scholar 

  138. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, Jansen M, Otten BJ, Hoorweg-Nijman JJ, et al. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. J Clin Endocrinol Metab. 1999;84(12):4607–12.

    Google Scholar 

  139. van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ, et al. Final height in girls with Turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab. 2003;88(3):1119–25.

    Google Scholar 

  140. Gault EJ, Perry RJ, Cole TJ, Casey SR, Paterson WF, Hindmarsh PC, et al. Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial. BMJ. 2011;342:d1980.

    Google Scholar 

  141. Menke LA, Sas TC, de Muinck Keizer-Schrama SM, Zandwijken GR, de Ridder MA, Odink RJ, et al. Efficacy and safety of oxandrolone in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab. 2010;95(3):1151–60.

    Article  CAS  PubMed  Google Scholar 

  142. Nilsson KO, Albertsson-Wikland K, Alm J, Aronson S, Gustafsson J, Hagenäs L, et al. Improved final height in girls with Turner’s syndrome treated with growth hormone and oxandrolone. J Clin Endocrinol Metab. 1996;81(2):635–40.

    Google Scholar 

  143. Wasniewska M, Aversa T, Mazzanti L, Guarneri MP, Matarazzo P, De Luca F, et al. Adult height in girls with Turner syndrome treated from before 6 years of age with a fixed per kilogram GH dose. Eur J Endocrinol. 2013;169(4):439–43.

    Google Scholar 

  144. Linglart A, Cabrol S, Berlier P, Stuckens C, Wagner K, de Kerdanet M, et al. French Collaborative Young Turner Study Group. Growth hormone treatment before the age of 4 years prevents short stature in young girls with Turner syndrome. Eur J Endocrinol. 2011;164(6):891–7.

    Google Scholar 

  145. Vanderschueren-Lodeweyckx M, Massa G, Maes M, Craen M, van Vliet G, Heinrichs C, et al. Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner’s syndrome. J Clin Endocrinol Metab. 1990;70(1):122–6.

    Google Scholar 

  146. Johnston DI, Betts P, Dunger D, Barnes N, Swift PGF, Buckler JMH, et al. A multicentre trial of recombinant growth hormone and low-dose oestrogen in Turner syndrome: near final height analysis. Arch Dis Child. 2001;84:76–81.

    Google Scholar 

  147. Quigley CA, Wan X, Garg S, Kowal K, Cutler GB Jr, Ross JL. Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab. 2014;99(9):E1754–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Blum WF, Ross JL, Zimmermann AG, Quigley CA, Child CJ, Kalifa G, et al. GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results from a multicenter trial. J Clin Endocrinol Metab. 2013;98:E1383–92.

    Google Scholar 

  149. Pasquino AM, Pucarelli I, Segni M, Tarani L, Calcaterra V, Larizza D. Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group. J Endocrinol Investig. 2005;28(4):350–6.

    Article  CAS  Google Scholar 

  150. Reiter EO, Blethen SL, Baptista J, Price L. Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner’s syndrome. J Clin Endocrinol Metab. 2001;86(5):1936–41.

    CAS  PubMed  Google Scholar 

  151. Soriano-Guillen L, Coste J, Ecosse E, Léger J, Tauber M, Cabrol S, et al. Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metab. 2005;90(9):5197–204.

    Google Scholar 

  152. Bolar K, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in Turner syndrome. J Clin Endocrinol Metab. 2008;93:344.

    Article  CAS  PubMed  Google Scholar 

  153. Carel JC, Ecosse E, Bastie-Sigeac I, Cabrol S, Tauber M, Léger J, et al. Quality of life determinants in young women with Turner’s syndrome after growth hormone treatment: results of the StaTur population-based cohort study. J Clin Endocrinol Metab. 2005;90(4):1992–7.

    Google Scholar 

  154. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies and the hierarchy of research designs. NEJM. 2000;342(25):1887–92.

    Article  CAS  PubMed  Google Scholar 

  155. Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, et al. Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. KIGS International Board. Kabi International Growth Study. J Clin Endocrinol Metab. 2000;85(11):4212–8.

    Google Scholar 

  156. Ranke MB, Lindberg A, Brosz M, Kaspers S, Loftus J, Wollmann H, et al. Accurate long-term prediction of height during the first four years of growth hormone treatment in prepubertal children with growth hormone deficiency or Turner syndrome. Horm Res Paediatr. 2012;78(1):8–17.

    Google Scholar 

  157. Ranke MB, Schweizer R, Martin DD, Ehehalt S, Schwarze CP, Serra F, et al. Analyses from a centre of short- and long-term growth in Turner’s syndrome on standard growth hormone doses confirm growth prediction algorithms and show normal IGF-I levels. Horm Res Paediatr. 2012;77(4):214–21.

    Google Scholar 

  158. Ross JL, Lee PA, Gut R, Germak J. Impact of age and duration of growth hormone therapy in children with Turner syndrome. Horm Res Pediatr. 2011;76:392–9.

    Article  CAS  Google Scholar 

  159. Prader A, Largo RH, Molinari L, Issler C. Physical growth of Swiss children from birth to 20 years of age First Zurich longitudinal study of growth and development. Helv Paediatr Acta. 1989;52(suppl S2):1–25.

    CAS  Google Scholar 

  160. Stevens A, Murray P, Wojcik J, Raelson J, Koledova E, Chatelain P, et al. Validating genetic markers of response to recombinant growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study. Eur J Endocrinol. 2016;175:633–43.

    Google Scholar 

  161. Braz AF, Costalonga EF, Trarbach EB, Scalco RC, Malaquias AC, Guerra-Junior G, et al. Genetic predictors of long-term response to growth hormone (GH) therapy in children with GH deficiency and Turner syndrome: the influence of a SOCS2 polymorphism. J Clin Endocrinol Metab. 2014 Sep;99(9):E1808–13.

    Google Scholar 

  162. Wit JM, Ranke MB, Albertsson-Wikland K, Carrascosa A, Rosenfeld RG, Van Buuren S, et al. Personalized approach to growth hormone treatment: clinical use of growth prediction models. Horm Res Paediatr. 2013;79(5):257–70.

    Google Scholar 

  163. Ranke MB, Lindberg A, KIGS International Board. Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables J Clin Endocrinol Metab 2010;95:1229–1237.

    Google Scholar 

  164. Ranke MB, 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 and review. Horm Res Paediatr. 2011;75:423–32.

    Article  CAS  PubMed  Google Scholar 

  165. Carel JC, Mathivon L, Gendrel C, Chaussain JL. Growth hormone therapy for Turner syndrome: evidence for benefit. Horm Res. 1997;48(Suppl 5):31–4.

    Article  CAS  PubMed  Google Scholar 

  166. Hofman P, Cutfield WS, Robinson EM, Clavano A, Ambler GR, Cowell C. Factors predictive of response to growth hormone therapy in Turner’s syndrome. J Pediatr Endocrinol Metab. 1997;10(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  167. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner syndrome meeting. Eur J Endocrinol. 2017;177:G1–G70.

    Google Scholar 

  168. Hughes IP, Choong CS, Harris M, Ambler GR, Cutfield WS, Hofman PL, et al. Growth hormone treatment for Turner syndrome in Australia reveals that younger age and increased dose interact to improve response. Clin Endocrinol. 2011;74(4):473–80.

    Google Scholar 

  169. Bettendorf M, Inta IM, Doerr HG, Hauffa BP, Mehls O, Ranke MB. Height gain in Ullrich-Turner syndrome after early and late growth hormone treatment start: results from a large retrospective German study and potential basis for an individualized treatment approach. Horm Res Paediatr. 2013;80(5):356–62.

    Article  CAS  PubMed  Google Scholar 

  170. van Teunenbroek A, de Muinck Keizer-Schrama SM, Stijnen T, Jansen M, Otten BJ, Delemarre-van de Waal HA, et al. Yearly stepwise increments of the growth hormone dose results in a better growth response after 4 years in girls with Turner syndrome. J Clin Endocrinol Metab. 1996;81(11):4013–21.

    Google Scholar 

  171. Coelho R, Brook CGD, Preece MA, Stanhope RG, Dattani MT, Hindmarsh PC. A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency. Horm Res. 2008;70:85–8.

    Article  CAS  PubMed  Google Scholar 

  172. Schrier L, de Kam ML, McKinnon R, Che Bakri A, Oostdijk W, Sas TC, et al. Comparison of body surface area versus weight-based growth hormone dosing for girls with Turner syndrome. Horm Res Paediatr. 2014;81(5):319–30.

    Google Scholar 

  173. Cohen P, Weng W, Rogol AD, Rosenfeld RG, Kappelgaard AM, Germak J. Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations. Clin Endocrinol. 2014;81(1):71–6.

    Article  CAS  Google Scholar 

  174. Cohen P, Germak J, Rogol AD, Weng W, Kappelgaard A-M, Rosenfeld RG. Variable degree of growth hormone (GH) and insulin-like growth factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: evidence from an IGF-based dosing study of short children. J Clin Endocrinol Metab. 2010;95:2089–98.

    Article  CAS  PubMed  Google Scholar 

  175. Albertsson-Wikland K. The effect of human growth hormone injection frequency on linear growth rate. Acta Paediatr Scand Suppl. 1987;337:110–6.

    Article  CAS  PubMed  Google Scholar 

  176. Kastrup KW, Christiansen JS, Andersen JK, Orskov H. Increased growth rate following transfer to daily sc administration from three weekly im injections of hGH in growth hormone deficient children. Acta Endocrinol. 1983;104(2):148–52.

    Article  CAS  Google Scholar 

  177. Hopwood NJ, Hintz RL, Gertner JM, Attie KM, Johanson AJ, Baptista J, et al. Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy. J Pediatr. 1993;123(2):215–22.

    Google Scholar 

  178. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, van Teunenbroek A, Hokken-Koelega AC, Waelkens JJ, et al. Final height in girls with Turner’s syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone. Arch Dis Child. 1999;80(1):36–41.

    Google Scholar 

  179. Otero SC, Eiser C, Wright NP, Butler G. Implications of parent and child quality of life assessments for decisions about growth hormone treatment in eligible children. Child Care Health Dev. 2013;39(6):782–8.

    CAS  PubMed  Google Scholar 

  180. Bannink EM, Raat H, Mulder PG, de Muinck Keizer-Schrama SM. Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome. J Pediatr. 2006;148(1):95–101.

    Article  CAS  PubMed  Google Scholar 

  181. van Pareren YK, Duivenvoorden HJ, Slijper FM, Koot HM, Drop SL, de Muinck Keizer-Schrama SM. Psychosocial functioning after discontinuation of long-term growth hormone treatment in girls with Turner syndrome. Horm Res. 2005;63(5):238–44.

    PubMed  Google Scholar 

  182. Lagrou K, Xhrouet-Heinrichs D, Heinrichs C, Craen M, Chanoine JP, Malvaux P, et al. Age-related perception of stature, acceptance of therapy, and psychosocial functioning in human growth hormone-treated girls with Turner’s syndrome. J Clin Endocrinol Metab. 1998;83(5):1494–501.

    Google Scholar 

  183. Rovet JF, Ireland L. Behavioral phenotype in children with Turner syndrome. J Pediatr Psychol. 1994;19(6):779–90.

    Article  CAS  PubMed  Google Scholar 

  184. Rovet JF, Holland J. Psychological aspects of the Canadian randomised controlled trial of human growth hormone and low-dose ethinyl oestradiol in children with Turner syndrome. Horm Res. 1993;39(Suppl 2):60–4.

    Article  PubMed  Google Scholar 

  185. Rovet JF, Van Vliet G. Growth hormone supplementation and psychosocial functioning to adult height in Turner syndrome: a questionnaire study of participants in the Canadian Randomized Trial. Front Endocrinol. 2019;10:125.

    Article  Google Scholar 

  186. Krantz E, Landin-Wilhelmsen K, Trimpou P, Bryman I, Wide U. Health-related quality of life in Turner syndrome and the influence of growth hormone therapy: a 20-year follow-up. J Clin Endocrinol Metab. 2019;104(11):5073–83.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Ross JL, Feuillan P, Kushner H, Roeltgen D, Cutler GB Jr. Absence of growth hormone effects on cognitive function in girls with Turner syndrome. J Clin Endocrinol Metab. 1997;82(6):1814–7.

    CAS  PubMed  Google Scholar 

  188. Reis CT, de Assumpção MS, Guerra-Junior G, de Lemos-Marini SHV. Systematic review of quality of life in Turner syndrome. Qual Life Res. 2018;27(8):1985–2006.

    Article  PubMed  Google Scholar 

  189. Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height velocity targets from the National Cooperative Growth Study for first-year growth hormone responses in short children. J Clin Endocrinol Metab. 2008;93(2):352–7.

    Article  CAS  PubMed  Google Scholar 

  190. Bannink EM, van der Palen RL, Mulder PG, de Muinck Keizer-Schrama SM. Long-term follow-up of GH-treated girls with Turner syndrome: BMI, blood pressure, body proportions. Horm Res. 2009;71(6):336–42.

    CAS  PubMed  Google Scholar 

  191. Van Pareren YK, De Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Drop SL. Effect of discontinuation of long-term growth hormone treatment on carbohydrate metabolism and risk factors for cardiovascular disease in girls with Turner syndrome. J Clin Endocrinol Metab. 2002;87(12):5442–8.

    Article  CAS  PubMed  Google Scholar 

  192. Radetti G, Crepaz R, Milanesi O, Paganini C, Cesaro A, Rigon F, et al. Cardiac performance in Turner’s syndrome patients on growth hormone therapy. Horm Res. 2001;55(5):240–4.

    Google Scholar 

  193. Sas TC, Cromme-Dijkhuis AH, de Muinck Keizer-Schrama SM, Stijnen T, van Teunenbroek A, Drop SL. The effects of long-term growth hormone treatment on cardiac left ventricular dimensions and blood pressure in girls with Turner’s syndrome. Dutch Working Group on Growth Hormone. J Pediatr. 1999;135(4):470–6.

    Article  CAS  PubMed  Google Scholar 

  194. Bannink EM, van der Palen RL, Mulder PG, de Muinck Keizer-Schrama SM. Long-term follow-up of GH-treated girls with Turner syndrome: metabolic consequences. Horm Res. 2009;71(6):343–9.

    CAS  PubMed  Google Scholar 

  195. Wooten N, Bakalov VK, Hill S, Bondy CA. Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab. 2008;93(6):2109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Mazzanti L, Bergamaschi R, Castiglioni L, Zappulla F, Pirazzoli P, Cicognani A. Turner syndrome, insulin sensitivity and growth hormone treatment. Horm Res. 2005;64(Suppl 3):51–7.

    CAS  PubMed  Google Scholar 

  197. Ari M, Bakalov VK, Hill S, Bondy CA. The effects of growth hormone treatment on bone mineral density and body composition in girls with Turner syndrome. J Clin Endocrinol Metab. 2006;91(11):4302–5.

    Article  CAS  PubMed  Google Scholar 

  198. Davenport ML, Roush J, Lui C, Zagar AJ, Eugster E, Travers SH, et al. Growth hormone treatment does not affect incidences of middle ear disease or hearing loss in infants and toddlers with Turner syndrome. Horm Res Paediatr. 2010;74(1):23–32.

    Google Scholar 

  199. Quigley CA, Gill AM, Crowe BJ, Robling K, Chipman JJ, Rose SR, et al. Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab. 2005;90:5188–96.

    Google Scholar 

  200. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010;95(1):167–77.

    Article  CAS  PubMed  Google Scholar 

  201. Darendeliler F, Karagiannis G, Wilton P. Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. Horm Res. 2007;68(Suppl 5):41–7.

    PubMed  Google Scholar 

  202. Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, Blum WF, et al. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab. 2011;96(6):E1025–34.

    Google Scholar 

  203. Child CJ, Zimmermann AG, Chrousos GP, Cummings E, Deal CL, Hasegawa T, et al. Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program. J Clin Endocrinol Metab. 2019;104(2):379–89.

    Google Scholar 

  204. Allen DB. Safety of human growth hormone therapy: current topics. J Pediatr. 1996;128(5 Pt 2):S8–13.

    Article  CAS  PubMed  Google Scholar 

  205. Blethen SL, Rundle AC. Slipped capital femoral epiphysis in children treated with growth hormone. A summary of the National Cooperative Growth Study experience. Horm Res. 1996;46(3):113–6.

    Article  CAS  PubMed  Google Scholar 

  206. Lowenstein EJ, Kim KH, Glick SA. Turner’s syndrome in dermatology. J Am Acad Dermatol. 2004;50(5):767–76.

    Article  PubMed  Google Scholar 

  207. Wyatt D. Melanocytic nevi in children treated with growth hormone. Pediatrics. 1999;104(4Pt 2):1045–50.

    CAS  PubMed  Google Scholar 

  208. Gravholt CH, Jund S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51(2):147–58.

    Article  CAS  PubMed  Google Scholar 

  209. Shoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA, United Kingdom Clinical Cytogenetics Group. Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93:4735–42.

    Article  CAS  Google Scholar 

  210. Quigley CA, Child CJ, Zimmermann AG, Rosenfeld RG, Blum WF, Robison L. Mortality in children receiving growth hormone treatment for growth disorders: data from the GeNeSIS observational program. J Clin Endocrinol Metab. 2017;102(9):3195–205.

    Article  PubMed  Google Scholar 

  211. Bondy CA, Van PL, Bakalov VK, Ho VB. Growth hormone treatment and aortic dimensions in Turner syndrome. J Clin Endocrinol Metab. 2006;91(5):1785–8.

    Article  CAS  PubMed  Google Scholar 

  212. Lin AE, Silberbach M. Focus on the heart and aorta in Turner syndrome. J Pediatr. 2007;150(6):572–4.

    Article  PubMed  Google Scholar 

  213. Lopez L, Arheart KL, Colan SD, Stein NS, Lopez-Mitnik G, Lin AE, et al. Turner syndrome is an independent risk factor for aortic dilation in the young. Pediatrics. 2008;121(6):e1622–7.

    Google Scholar 

  214. van den Berg J, Bannink EM, Wielopolski PA, Pattynama PM, de Muinck Keizer-Schrama SM, Helbing WA. Aortic distensibility and dimensions and the effects of growth hormone treatment in the Turner syndrome. Am J Cardiol. 2006;97(11):1644–9.

    Article  CAS  PubMed  Google Scholar 

  215. Cabanas P, García-Caballero T, Barreiro J, Castro-Feijóo L, Gallego R, Arévalo T, et al. Papillary thyroid carcinoma after recombinant GH therapy for Turner syndrome. Eur J Endocrinol. 2005;153(4):499–502.

    Google Scholar 

  216. Morotti RA, Killackey M, Shneider BL, Repucci A, Emre S, Thung SN. Hepatocellular carcinoma and congenital absence of the portal vein in a child receiving growth hormone therapy for Turner syndrome. Semin Liver Dis. 2007;27(4):427–31.

    Article  PubMed  Google Scholar 

  217. Tuffli GA, Johanson A, Rundle AC, Allen DB. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab. 1995;80(4):1416–22.

    CAS  PubMed  Google Scholar 

  218. Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR, et al. Risk of neoplasia in pediatric patients receiving growth hormone therapy—a report from the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab. 2015;100:2192–203.

    Google Scholar 

  219. Park P, Cohen P. The role of insulin-like growth factor I monitoring in growth hormone-treated children. Horm Res. 2004;62(Suppl 1):59–65.

    CAS  PubMed  Google Scholar 

  220. Blum WF, Crowe BJ, Quigley CA, Jung H, Cao D, Ross JL, et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007;92(1):219–28.

    Google Scholar 

  221. Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol. 2011;7(1):11–24.

    Article  CAS  PubMed  Google Scholar 

  222. Albertsson-Wikland K, Mårtensson A, Sävendahl L, Niklasson A, Bang P, Dahlgren J, et al. Mortality is not increased in recombinant human growth hormone-treated patients when adjusting for birth characteristics. J Clin Endocrinol Metab. 2016;101(5):2149–59.

    Google Scholar 

  223. Cutfield WS, Lundgren F. Insulin-like growth factor I and growth responses during the first year of growth hormone treatment in KIGS patients with idiopathic growth hormone deficiency, acquired growth hormone deficiency, Turner syndrome and born small for gestational age. Horm Res. 2009;71(Suppl 1):39–45.

    CAS  PubMed  Google Scholar 

  224. Nielsen J, Johansen K, Yde H. The frequency of diabetes mellitus in patients with Turner’s syndrome and pure gonadal dysgenesis. Blood glucose, plasma insulin and growth hormone level during an oral glucose tolerance test. Acta Endocrinol. 1969;62(2):251–69.

    Article  CAS  Google Scholar 

  225. Caprio S, Boulware D, Tamborlane V. Growth hormone and insulin interactions. Horm Res. 1992;38(Suppl 2):47–9.

    Article  CAS  PubMed  Google Scholar 

  226. Bakalov VK, Cooley MM, Quon MJ, Luo ML, Yanovski JA, Nelson LM, et al. Impaired insulin secretion in the Turner metabolic syndrome. J Clin Endocrinol Metab. 2004;89(7):3516–20.

    Google Scholar 

  227. Radetti G, Pasquino B, Gottardi E, Boscolo Contadin I, Aimaretti G, Rigon F. Insulin sensitivity in Turner’s syndrome: influence of GH treatment. Eur J Endocrinol. 2004;151(3):351–4.

    Article  CAS  PubMed  Google Scholar 

  228. Wilson DM, Frane JW, Sherman B, Johanson AJ, Hintz RL, Rosenfeld RG. Carbohydrate and lipid metabolism in Turner syndrome: effect of therapy with growth hormone, oxandrolone, and a combination of both. J Pediatr. 1988;112:210–7.

    Article  CAS  PubMed  Google Scholar 

  229. Weise M, James D, Leitner CH, Hartmann KK, Bohles HJ, Attanasio A. Glucose metabolism in Ullrich Turner syndrome: long-term effects of therapy with human growth hormone. German Lilly UTS Study Group. Horm Res. 1993;39(1–2):36–41.

    Article  CAS  PubMed  Google Scholar 

  230. Saenger P, Attie KM, Martino-Nardi J, Fine RN. Carbohydrate metabolism in children receiving growth hormone for 5 years. Chronic renal insufficiency compared with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Genentech Collaborative Group. Pediatr Nephrol. 1996;10(3):261–3.

    Article  CAS  PubMed  Google Scholar 

  231. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, Aanstoot HJ, Drop SL. Carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone. J Clin Endocrinol Metab. 2000;85(2):769–75.

    CAS  PubMed  Google Scholar 

  232. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355(9204):610–3.

    Google Scholar 

  233. American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care. 2016;39(Suppl 1):S13–22.

    Google Scholar 

  234. Zeitler P, Fu J, Tandon N, Nadeau K, Urakami T, Barrett T, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Type 2 diabetes in the child and adolescent. Pediatr Diabetes. 2014;15(Suppl 20):26–46.

    Google Scholar 

  235. Growth Hormone Research Society. Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab. 2001;86(5):1868–70.

    Google Scholar 

  236. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021426s004lbl.pdf.

  237. Zeger MP, Shah K, Kowal K, Cutler GB Jr, Kushner H, Ross JL. Prospective study confirms oxandrolone-associated improvement in height in growth hormone-treated adolescent girls with Turner syndrome. Horm Res Paediatr. 2011;75(1):38–46.

    Article  CAS  PubMed  Google Scholar 

  238. Sas TC, Gault EJ, Bardsley MZ, Menke LA, Freriks K, Perry RJ, et al. Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use. Horm Res Paediatr. 2014;81(5):289–97.

    Google Scholar 

  239. Sheanon NM, Backeljauw PF. Effect of oxandrolone therapy on adult height in Turner syndrome patients treated with growth hormone: a meta-analysis. Int J Pediatr Endocrinol. 2015;2015:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Freriks K, Sas TC, Traas MA, Netea-Maier RT, den Heijer M, Hermus AR, et al. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome. Eur J Endocrinol. 2012;168(1):91–9.

    Google Scholar 

  241. Ross JL, Mazzocco MM, Kushner H, Kowal K, Cutler GB Jr, Roeltgen D. Effects of treatment with oxandrolone for 4 years on the frequency of severe arithmetic learning disability in girls with Turner syndrome. J Pediatr. 2009;155(5):714–20.

    Article  CAS  PubMed  Google Scholar 

  242. Menke LA, Sas TC, Visser M, Kreukels BP, Stijnen T, Zandwijken GR, et al. The effect of the weak androgen oxandrolone on psychological and behavioural characteristics in growth hormone-treated girls with Turner syndrome. Horm Behav. 2010;57(3):297–305.

    Google Scholar 

  243. Freriks K, Verhaak CM, Sas TC, Menke LA, Wit JM, Otten BJ, et al. Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome. Horm Behav. 2015;69(5):59–67.

    Google Scholar 

  244. Cutler GB Jr. The role of estrogen in bone growth and maturation during childhood and adolescence. J Steroid Biochem Mol Biol. 1997;61(3–6):141–4.

    Article  CAS  PubMed  Google Scholar 

  245. Ross JL, Cassorla FG, Skerda MC, Valk IM, Loriaux DL, Cutler GB Jr. A preliminary study of the effect of estrogen dose on growth in Turner’s syndrome. N Engl J Med. 1983;309:1104–6.

    Article  CAS  PubMed  Google Scholar 

  246. Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB Jr. Effects of estrogen on nonverbal processing speed and motor function in girls with Turner’s syndrome. J Clin Endocrinol Metab. 1998;83(9):3198–204.

    CAS  PubMed  Google Scholar 

  247. Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB. Use of estrogen in young girls with Turner syndrome: effects on memory. Neurology. 2000;54(1):164–70.

    Article  CAS  PubMed  Google Scholar 

  248. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab. 2010;95:1487–95.

    Article  CAS  PubMed  Google Scholar 

  249. Rosenfield RL, Devine N, Hunold JJ, Mauras N, Moshang T Jr, Root AW. Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome. J Clin Endocrinol Metab. 2005;90:6424–30.

    Article  CAS  PubMed  Google Scholar 

  250. Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, et al. Metabolic effects of oral versus transdermal 17β-estradiol (E2): a randomized clinical trial in girls with Turner syndrome. J Clin Endocrinol Metab. 2013;98:2716–24.

    Google Scholar 

  251. Nabhan ZM, DiMeglio LA, Qi R, Perkins SM, Eugster EA. Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab. 2009;94:2009–14.

    Article  CAS  PubMed  Google Scholar 

  252. Davenport ML. Evidence for early initiation of growth hormone and transdermal estradiol therapies in girls with Turner syndrome. Growth Hormon IGF Res. 2006;16(Suppl):91–7.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sydney Children’s Hospital, Randwick, NSW, Australia

    Charmian A. Quigley

Authors
  1. Charmian A. Quigley
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Endocrinology, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

    Patricia Y. Fechner

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Quigley, C.A. (2020). Pattern and Etiology of Growth Disturbance in Turner Syndrome and Outcomes of Growth-Promoting Treatments. In: Fechner, P. (eds) Turner Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-34150-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-34150-3_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-34148-0

  • Online ISBN: 978-3-030-34150-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation