Advertisement

Growth Hormone Therapy in Children with Turner Syndrome, Noonan Syndrome, and SHOX Gene Mutations

  • Philippe F. Backeljauw
  • Iris Gutmark-Little
Chapter

Abstract

This chapter will address several disorders characterized by varying degrees of growth failure. Turner syndrome (TS) is one of the most common human sex chromosome anomalies, occurring in about 1:2000 female live births. Girls with TS have an abnormal or missing X chromosome plus a phenotype that includes short stature, lymphedema, cardiac abnormalities, gonadal dysgenesis, and neurocognitive problems. Noonan syndrome (NS) is an autosomal dominant condition with a prevalence of 1 in 1000–2500 and part of a group of disorders known as RASopathies. Noonan syndrome occurs in both boys and girls. In addition to varying degrees of short stature, features also include congenital heart defects, facial dysmorphisms, and mild intellectual disabilities. Defects in the short stature homeobox-containing gene on the X chromosome (SHOX) lead to a variety of short-stare conditions: non-syndromic short stature and Leri-Weill dyschondrosteosis (LWD), both due to SHOX haploinsufficiency. Homozygous loss of SHOX leads to Langer mesomelic dysplasia, a rare form of a skeletal dysplasia.

Keywords

Turner syndrome Noonan syndrome SHOX gene mutation Short stature Growth failure Growth hormone therapy 

References

  1. 1.
    Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87:81–3.PubMedCrossRefGoogle Scholar
  2. 2.
    Bondy CA. Care of girls and women with turner syndrome: a guideline of the turner syndrome study group. J Clin Endocrinol Metab. 2007;92:10–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med. 2004;351:1227–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Kajii T, Ferrier A, Niikawa N, et al. Anatomic and chromosomal anomalies in 639 spontaneous abortuses. Hum Genet. 1980;55:87–98.PubMedCrossRefGoogle Scholar
  5. 5.
    Hook EB, Warburton D. The distribution of chromosomal genotypes associated with Turner’s syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet. 1983;64:24–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Clement-Jones M, Schiller S, Rao E, et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in turner syndrome. Hum Mol Genet. 2000;9:695–702.PubMedCrossRefGoogle Scholar
  7. 7.
    Urbach A, Benvenisty N. Studying early lethality of 45, XO (Turner’s syndrome) embryos using human embryonic stem cells. PLoS One. 2009;4:e4175.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Zinn AR, Roeltgen D, Stefanatos G, et al. A turner syndrome neurocognitive phenotype maps to Xp22.3. J Soc Gynecol Investig. 2001;8:S34–6.PubMedGoogle Scholar
  9. 9.
    Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet. 1999;89:186–200.PubMedCrossRefGoogle Scholar
  10. 10.
    Lippe BM, Saenger PH. Turner syndrome. In: Sperling MA, editor. Pediatric endocrinology. 2nd ed. Philadelphia, PA: Saunders; 2002. p. 519–64.Google Scholar
  11. 11.
    Massa GG, Vanderschueren-Lodeweyckx M. Age and height at diagnosis in turner syndrome: influence of parental height. Pediatrics. 1991;88:1148–52.PubMedGoogle Scholar
  12. 12.
    Savendahl L, Davenport ML. Delayed diagnoses of Turner’s syndrome: proposed guidelines for change. J Pediatr. 2000;137:455–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Sybert VP. Adult height in turner syndrome with and without androgen therapy. J Pediatr. 1984;104:365–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Ranke MB, Pfluger H, Rosendahl W, et al. Turner syndrome: spontaneous growth in 150 cases and review of the literature. Eur J Pediatr. 1983;141:81–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Even L, Cohen A, Marbach N, et al. Longitudinal analysis of growth over the first 3 years of life in Turner’s syndrome. J Pediatr. 2000;137:460–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Davenport ML, Punyasavatsut N, Gunther D, Savendahl L, Stewart PW. Turner syndrome: a pattern of early growth failure. Acta Paediatr Suppl. 1999;88:118–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Karlberg J, Albertsson-Wikland K, Nilsson KO, Ritzen EM, Westphal O. Growth in infancy and childhood in girls with Turner’s syndrome. Acta Paediatr Scand. 1991;80:1158–65.PubMedCrossRefGoogle Scholar
  18. 18.
    Mathisen B, Reilly S, Skuse D. Oral-motor dysfunction and feeding disorders of infants with turner syndrome. Dev Med Child Neurol. 1992;34:141–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Elder DA, Roper MG, Henderson RC, Davenport ML. Kyphosis in a turner syndrome population. Pediatrics. 2002;109:e93.PubMedCrossRefGoogle Scholar
  20. 20.
    Even L, Bronstein V, Hochberg Z. Bone maturation in girls with Turner’s syndrome. Eur J Endocrinol. 1998;138:59–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in turner syndrome. J Clin Epidemiol. 1998;51:147–58.PubMedCrossRefGoogle Scholar
  22. 22.
    Bakalov VK, Axelrod L, Baron J, 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Bakalov VK, Bondy CA. Fracture risk and bone mineral density in turner syndrome. Rev Endocr Metab Disord. 2008;9:145–51.PubMedCrossRefGoogle Scholar
  24. 24.
    Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pubertal development in Turner’s syndrome. Italian study Group for Turner’s syndrome. J Clin Endocrinol Metab. 1997;82:1810–3.PubMedGoogle Scholar
  25. 25.
    Crosignani PG, Rubin BL. Optimal use of infertility diagnostic tests and treatments. The ESHRE Capri workshop group. Hum Reprod. 2000;15:723–32.PubMedCrossRefGoogle Scholar
  26. 26.
    Conte FA, Grumbach MM, Kaplan SLA. Diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab. 1975;40:670–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Chrysis D, Spiliotis BE, Stene M, Cacciari E, Davenport ML. Gonadotropin secretion in girls with turner syndrome measured by an ultrasensitive immunochemiluminometric assay. Horm Res. 2006;65:261–6.PubMedGoogle Scholar
  28. 28.
    Gravholt CH, Naeraa RW, Andersson AM, Christiansen JS, Skakkebaek NE, Inhibin A. B in adolescents and young adults with Turner’s syndrome and no sign of spontaneous puberty. Hum Reprod. 2002;17:2049–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Wilson CA, Heinrichs C, Larmore KA, et al. Estradiol levels in girls with Turner’s syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay. J Pediatr Endocrinol Metab. 2003;16:91–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Sehested A, Juul AA, Andersson AM, et al. Serum inhibin a and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels. J Clin Endocrinol Metab. 2000;85:1634–40.PubMedGoogle Scholar
  31. 31.
    Chellakooty M, Schmidt IM, Haavisto AM, et al. Inhibin a, inhibin B, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls. J Clin Endocrinol Metab. 2003;88:3515–20.PubMedCrossRefGoogle Scholar
  32. 32.
    Hagen CP, Aksglaede L, Sørensen K, Main KM, Boas M, Cleemann L, Holm K, Gravholt CH, Andersson AM, Pedersen AT, Petersen JH, Linneberg A, Kjaergaard S, Juul A. Serum levels of anti-Müllerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 turner syndrome patients. J Clin Endocrinol Metab. 2010 Nov;95(11):5003–10.  https://doi.org/10.1210/jc.2010-0930.CrossRefPubMedGoogle Scholar
  33. 33.
    Visser JA, Hokken-Koelega AC, Zandwijken GR, Limacher A, Ranke MB, Flück CE. Anti-Müllerian hormone levels in girls and adolescents with turner syndrome are related to karyotype, pubertal development and growth hormone treatment. Hum Reprod. 2013 Jul;28(7):1899–907.PubMedCrossRefGoogle Scholar
  34. 34.
    Brant WO, Rajimwale A, Lovell MA, et al. Gonadoblastoma and turner syndrome. J Urol. 2006;175:1858–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev. 2006;27:468–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Zelaya G, López Marti JM, Marino R, Garcia de Dávila MT, Gallego MS. Gonadoblastoma in patients with Ullrich-turner syndrome. Pediatr Dev Pathol. 2015 Mar-Apr;18(2):117–21.PubMedCrossRefGoogle Scholar
  37. 37.
    Sutton EJ, McInerney-Leo A, Bondy CA, Gollust SE, King D, Biesecker B. Turner syndrome: four challenges across the lifespan. Am J Med Genet A. 2005;139A:57–66.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Oktay K, Rodriguez-Wallberg KA, Sahin G. Fertility preservation by ovarian stimulation and oocyte cryopreservation in a 14-year-old adolescent with turner syndrome mosaicism and impending premature ovarian failure. Fertil Steril. 2010;94:753–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Tarani L, Lampariello S, Raguso G, et al. Pregnancy in patients with Turner’s syndrome: six new cases and review of literature. Gynecol Endocrinol. 1998;12:83–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Sybert VP. Cardiovascular malformations and complications in turner syndrome. Pediatrics. 1998;101:E11.PubMedCrossRefGoogle Scholar
  41. 41.
    Mortensen KH, Hjerrild BE, Andersen NH, et al. Abnormalities of the major intrathoracic arteries in turner syndrome as revealed by magnetic resonance imaging. Cardiol Young. 2010;20:191–200.PubMedCrossRefGoogle Scholar
  42. 42.
    Kim HK, Gottliebson W, Hor K, et al. Cardiovascular anomalies in turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. AJR Am J Roentgenol. 2011;196:454–60.PubMedCrossRefGoogle Scholar
  43. 43.
    Mazzanti L, Cacciari E. Congenital heart disease in patients with Turner’s syndrome. Italian study Group for Turner Syndrome (ISGTS). J Pediatr. 1998;133:688–92.PubMedCrossRefGoogle Scholar
  44. 44.
    Gravholt CH, Landin-Wilhelmsen K, Stochholm K, et al. Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young. 2006;16:430–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Bordeleau L, Cwinn A, Turek M, Barron-Klauninger K, Victor G. Aortic dissection and Turner’s syndrome: case report and review of the literature. J Emerg Med. 1998;16:593–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with turner syndrome. Pediatrics. 1998;102:e12.PubMedCrossRefGoogle Scholar
  47. 47.
    Elsheikh M, Casadei B, Conway GS, Wass JA. Hypertension is a major risk factor for aortic root dilatation in women with Turner’s syndrome. Clin Endocrinol. 2001;54:69–73.CrossRefGoogle Scholar
  48. 48.
    Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. Blood pressure and turner syndrome. Clin Endocrinol. 2000;52:363–70.CrossRefGoogle Scholar
  49. 49.
    Rovet J. Turner syndrome: a review of genetic and hormonal influences on neuropsychological functioning. Neuropsychol Dev Cogn C. Child Neuropsychol. 2004;10:262–79.PubMedCrossRefGoogle Scholar
  50. 50.
    Ross J, Roeltgen D, Zinn A. Cognition and the sex chromosomes: studies in turner syndrome. Horm Res. 2006;65:47–56.PubMedGoogle Scholar
  51. 51.
    Kesler SR. Turner syndrome. Child Adolesc Psychiatr Clin N Am. 2007;16:709–22.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Rovet JF. The cognitive and neuropsychological characteristics of females with turner syndrome. In: Berch DB, Berger BG, editors. Sex chromosome abnormalities and human behavior. Boulder, CO: western press; 1990. p. 38–77.Google Scholar
  53. 53.
    Rovet JF. The psychoeducational characteristics of children with turner syndrome. J Learn Disabil. 1993;26:333–41.PubMedCrossRefGoogle Scholar
  54. 54.
    Mazzocco MMA. Process approach to describing mathematics difficulties in girls with turner syndrome. Pediatrics. 1998;102:492–6.PubMedGoogle Scholar
  55. 55.
    El Abd S, Patton MA, Turk J, Hoey H, Howlin P. Social, communicational, and behavioral deficits associated with ring X turner syndrome. Am J Med Genet. 1999;88:510–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Donnelly SL, Wolpert CM, Menold MM, et al. Female with autistic disorder and monosomy X (turner syndrome): parent-of-origin effect of the X chromosome. Am J Med Genet. 2000;96:312–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Sculerati N, Ledesma-Medina J, Finegold DN, Stool SE. Otitis media and hearing loss in turner syndrome. Arch Otolaryngol Head Neck Surg. 1990;116:704–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Stenberg AE, Nylen O, Windh M, Hultcrantz M. Otological problems in children with Turner’s syndrome. Hear Res. 1998;124:85–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Hederstierna C, Hultcrantz M, Rosenhall UA. Longitudinal study of hearing decline in women with turner syndrome. Acta Otolaryngol. 2009;129:1434–41.PubMedCrossRefGoogle Scholar
  60. 60.
    Roush J, Davenport ML, Carlson-Smith C. Early-onset sensorineural hearing loss in a child with turner syndrome. J Am Acad Audiol. 2000;11:446–53.PubMedGoogle Scholar
  61. 61.
    Bilge I, Kayserili H, Emre S, et al. Frequency of renal malformations in turner syndrome: analysis of 82 Turkish children. Pediatr Nephrol. 2000;14:1111–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Lippe B, Geffner ME, Dietrich RB, Boechat MI, Kangarloo H. Renal malformations in patients with turner syndrome: imaging in 141 patients. Pediatrics. 1988;82:852–6.PubMedGoogle Scholar
  63. 63.
    Larizza D, Calcaterra V, Martinetti M. Autoimmune stigmata in turner syndrome: when lacks an X chromosome. J Autoimmun. 2009;33:25–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Hayward PA, Satsangi J, Jewell DP. Inflammatory bowel disease and the X chromosome. QJM. 1996;89:713–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Medeiros CC, Marini SH, Baptista MT, Guerra G Jr, Maciel-Guerra AT. Turner’s syndrome and thyroid disease: a transverse study of pediatric patients in Brazil. J Pediatr Endocrinol Metab. 2000;13:357–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Zulian F, Schumacher HR, Calore A, Goldsmith DP, Athreya BH. Juvenile arthritis in Turner’s syndrome: a multicenter study. Clin Exp Rheumatol. 1998;16:489–94.PubMedGoogle Scholar
  67. 67.
    El-Mansoury M, Berntorp K, Bryman I, et al. Elevated liver enzymes in turner syndrome during a 5-year follow-up study. Clin Endocrinol. 2008;68:485–90.CrossRefGoogle Scholar
  68. 68.
    Roulot D, Degott C, Chazouilleres O, et al. Vascular involvement of the liver in Turner’s syndrome. Hepatology. 2004;39:239–47.PubMedCrossRefGoogle Scholar
  69. 69.
    Larizza D, Locatelli M, Vitali L, et al. Serum liver enzymes in Turner syndrome. Eur J Pediatr. 2000;159:143–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Bonamico M, Pasquino AM, Mariani P, Danesi HM, Culasso F, Mazzanti L, Petri A, Bona G. Prevalence and clinical picture of celiac disease in turner syndrome. J Clin Endocrinol Metab. 2002;87:5495–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Mortensen KH, Cleemann L, Hjerrild BE, et al. Increased prevalence of autoimmunity in turner syndrome—influence of age. Clin Exp Immunol. 2009;156:205–10.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Keating JP, Ternberg JL, Packman R. Association of Crohn disease and turner syndrome. J Pediatr. 1978;92:160–1.PubMedCrossRefGoogle Scholar
  73. 73.
    Weiss SW. Pedal hemangioma (venous malformation) occurring in Turner’s syndrome: an additional manifestation of the syndrome. Hum Pathol. 1988;19:1015–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Eroglu Y, Emerick KM, Chou PM, Reynolds M. Gastrointestinal bleeding in Turner’s syndrome: a case report and literature review. J Pediatr Gastroenterol Nutr. 2002;35:84–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Blackett PR, Rundle AC, Frane J, Blethen SL. Body mass index (BMI) in turner syndrome before and during growth hormone (GH) therapy. Int J Obes Relat Metab Disord. 2000;24:232–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Caprio S, Boulware S, Diamond M, et al. Insulin resistance: an early metabolic defect of Turner’s syndrome. J Clin Endocrinol Metab. 1991;72:832–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Gravholt CH, Naeraa RW, Nyholm B, et al. Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner’s syndrome. The impact of sex hormone replacement. Diabetes Care. 1998;21:1062–70.PubMedCrossRefGoogle Scholar
  78. 78.
    Bakalov VK, Cooley MM, Quon MJ, et al. Impaired insulin secretion in the turner metabolic syndrome. J Clin Endocrinol Metab. 2004;89:3516–20.PubMedCrossRefGoogle Scholar
  79. 79.
    Bekker MN, van den Akker NM, de Mooij YM, Bartelings MM, van Vugt JM, Gittenberger-de Groot AC. Jugular lymphatic maldevelopment in turner syndrome and trisomy 21: different anomalies leading to nuchal edema. Reprod Sci. 2008;15:295–304.PubMedCrossRefGoogle Scholar
  80. 80.
    Bellini C, Di BE, Boccardo F, et al. The role of lymphoscintigraphy in the diagnosis of lymphedema in turner syndrome. Lymphology. 2009;42:123–9.PubMedGoogle Scholar
  81. 81.
    Gicquel C, Gaston V, Cabrol S, Le BY. Assessment of Turner’s syndrome by molecular analysis of the X chromosome in growth-retarded girls. J Clin Endocrinol Metab. 1998;83:1472–6.PubMedGoogle Scholar
  82. 82.
    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;57:157–64.PubMedGoogle Scholar
  83. 83.
    Rongen-Westerlaken C, Corel L, Van den Broeck J, et al. Reference values for height, height velocity and weight in Turner’s syndrome. Swedish study group for GH treatment. Acta Paediatr. 1997;86:937–42.PubMedCrossRefGoogle Scholar
  84. 84.
    Lyon AJ, Preece MA, Grant DB. Growth curve for girls with turner syndrome. Arch Dis Child. 1985;60:932–5.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Saenger P. Growth-promoting strategies in Turner’s syndrome. J Clin Endocrinol Metab. 1999;84:4345–8.PubMedGoogle Scholar
  86. 86.
    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;63:238–44.PubMedGoogle Scholar
  87. 87.
    Stephure DK. Canadian growth hormone advisory committee. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005;90:3360–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Ross JL, Quigley CA, Cao D, et al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011;364:1230–42.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Menke LA, Sas TC. De Muinck Keizer-Schrama SM, et al. efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome. J Clin Endocrinol Metab. 2010;95:1151–60.PubMedCrossRefGoogle Scholar
  90. 90.
    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;75:38–46.PubMedCrossRefGoogle Scholar
  91. 91.
    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.PubMedCrossRefGoogle Scholar
  92. 92.
    Donaldson MD. Growth hormone therapy in turner syndrome—current uncertainties and future strategies. Horm Res. 1997;48(Suppl 5):35–44.PubMedCrossRefGoogle Scholar
  93. 93.
    Haeusler G, Schmitt K, Blumel P, Plochl E, Waldhor T, Frisch H. Growth hormone in combination with anabolic steroids in patients with turner syndrome: effect on bone maturation and final height. Acta Paediatr. 1996;85:1408–14.PubMedGoogle Scholar
  94. 94.
    Ranke MB, Lindberg A, Ferrandez LA, et al. Major determinants of height development in turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS. Pediatr Res. 2007;61:105–10.PubMedCrossRefGoogle Scholar
  95. 95.
    Sas TC. De Muinck Keizer-Schrama SM, Stijnen T, 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;84:4607–12.PubMedGoogle Scholar
  96. 96.
    Davenport ML, Crowe BJ, Travers SH, et al. Growth hormone treatment of early growth failure in toddlers with turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007;92:3406–16.PubMedCrossRefGoogle Scholar
  97. 97.
    Davenport ML, Fechner PY, Ross JL, Eugster EA, Jia N, Patel HN, Zagar AJ, Quigley CA. Effect of very early growth hormone (GH) treatment on long-term growth in girls with Turner Syndrome (TS): a multicenter, open-label, extension study. Poster at The Endocrine Society’s 98th Annual Meeting. doi: https://doi.org/10.1210/endo-meetings.2016.PE.6.LBSat-01.
  98. 98.
    Carel JC, Ecosse E, Bastie-Sigeac I, 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;90:1992–7.PubMedCrossRefGoogle Scholar
  99. 99.
    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;83:1462–6.PubMedGoogle Scholar
  100. 100.
    Rosenfeld RG, Frane J, Attie KM, et al. Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in turner syndrome. J Pediatr. 1992;121:49–55.PubMedCrossRefGoogle Scholar
  101. 101.
    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(1):18.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    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;85:2439–45.PubMedGoogle Scholar
  103. 103.
    van Pareren YK. De Muinck Keizer-Schrama SM, Stijnen T, 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;88:1119–25.PubMedCrossRefGoogle Scholar
  104. 104.
    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.PubMedCrossRefGoogle Scholar
  105. 105.
    Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, Cutler GB Jr. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. N Engl J Med. 2011 Mar 31;364(13):1230–42.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Sas TC, Gerver WJ, de Bruin R, 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;84:4622–8.PubMedGoogle Scholar
  107. 107.
    Sato N, Nimura A, Horikawa R, Katumata N, Tanae A, Tanaka T. Bone mineral density in turner syndrome: relation to GH treatment and estrogen treatment. Endocr J. 2000;47(Suppl):S115–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Rubin K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics. 1998;102(2Pt3):481–5.PubMedGoogle Scholar
  109. 109.
    Hass AD, Simmons KE, Davenport ML, Proffit WR. The effect of growth hormone on craniofacial growth and dental maturation in turner syndrome. Angle Orthod. 2001;71:50–9.PubMedGoogle Scholar
  110. 110.
    Rongen-Westerlaken C. Van den born E, Prahl-Andersen B, et al. effect of growth hormone treatment on craniofacial growth in Turner’s syndrome. Acta Paediatr. 1993;82:364–8.PubMedCrossRefGoogle Scholar
  111. 111.
    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;82:1814–7.PubMedGoogle Scholar
  112. 112.
    Huisman J, Slijper FM, Sinnema G, et al. Psychosocial effects of two years of human growth hormone treatment in turner syndrome. The Dutch working group: psychologists and growth hormone. Horm Res. 1993;39(Suppl 2):56–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Siegel PT, Clopper R, Stabler B. The psychological consequences of turner syndrome and review of the National Cooperative Growth Study psychological substudy. Pediatrics. 1998;102:488–91.PubMedGoogle Scholar
  114. 114.
    Rovet J, Holland J. Psychological aspects of the Canadian randomized controlled trial of human growth hormone and low-dose ethinyl oestradiol in children with turner syndrome. The Canadian growth hormone advisory group. Horm Res. 1993;39(Suppl 2):60–4.PubMedCrossRefGoogle Scholar
  115. 115.
    Amundson E, Boman UW, Barrenas ML, Bryman I, Landin-Wilhelmsen K. Impact of growth hormone therapy on quality of life in adults with turner syndrome. J Clin Endocrinol Metab. 2010;95:1355–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Bolar K, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in turner syndrome. J Clin Endocrinol Metab. 2008;93:344–51.PubMedCrossRefGoogle Scholar
  117. 117.
    Matura LA, Sachdev V, Bakalov VK, Rosing DR, Bondy CA. Growth hormone treatment and left ventricular dimensions in turner syndrome. J Pediatr. 2007;150:587–91.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    van den Berg J, Bannink EM, Wielopolski PA, et al. Cardiac status after childhood growth hormone treatment of turner syndrome. J Clin Endocrinol Metab. 2008;93:2553–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in turner syndrome—integrating cardiology, genetics, and endocrinology. Endocr Rev. October 2012;33(5):677–714.PubMedCrossRefGoogle Scholar
  120. 120.
    Joss EE, Zurbrugg RP, Tonz O, Mullis PE. Effect of growth hormone and oxandrolone treatment on glucose metabolism in turner syndrome. A longitudinal study. Horm Res. 2000;53:1–8.PubMedGoogle Scholar
  121. 121.
    Saenger P. Metabolic consequences of growth hormone treatment in paediatric practice. Horm Res. 2000;53(Suppl 1):60–9.PubMedGoogle Scholar
  122. 122.
    Sas T. De Muinck Keizer-Schrama S, Aanstoot HJ, Stijnen T, drop S. Carbohydrate metabolism during growth hormone treatment and after discontinuation of growth hormone treatment in girls with turner syndrome treated with once or twice daily growth hormone injections. Clin Endocrinol. 2000;52:741–7.CrossRefGoogle Scholar
  123. 123.
    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;93:2109–14.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Rosenfeld RG, Hintz RL, Johanson AJ, et al. Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in turner syndrome. J Pediatr. 1988;113:393–400.PubMedCrossRefGoogle Scholar
  125. 125.
    Cavallo L, Gurrado R. Endogenous growth hormone secretion does not correlate with growth in patients with Turner’s syndrome. Italian study Group for Turner Syndrome. J Pediatr Endocrinol Metab. 1999;12:623–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Schrier L, de Kam ML, McKinnon R, Che Bakri A, Oostdijk W, Sas TC, Menke LA, Otten BJ. De Muinck Keizer-Schrama SM, Kristrom B, Ankarberg-Lindgren C, Burggraaf J, Albertsson-Wikland K, wit JM. Comparison of body surface area versus weight-based growth hormone dosing for girls with turner syndrome. Horm Res Paediatr. 2014;81(5):319–30.PubMedCrossRefGoogle Scholar
  127. 127.
    Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333–42.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Bezniakow N, Gos M, Obersztyn E. The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med. 2014;18(3):285–96.PubMedGoogle Scholar
  129. 129.
    Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, et al. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet. 2004;75(3):492–7.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S. The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. Horm Res Paediatr. 2015;83(3):167–76.PubMedCrossRefGoogle Scholar
  131. 131.
    Zenker M. Genetic and pathogenetic aspects of Noonan syndrome and related disorders. Horm Res. 2009;72(Suppl 2):57–63.PubMedCrossRefGoogle Scholar
  132. 132.
    Otten BJ, Noordam C. Growth in Noonan syndrome. Horm Res. 2009;72(Suppl 2):31–5.PubMedCrossRefGoogle Scholar
  133. 133.
    Ranke MB, Heidemann P, Knupfer C, Enders H, Schmaltz AA, Bierich JR. Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr. 1988;148(3):220–7.PubMedCrossRefGoogle Scholar
  134. 134.
    Noonan JA, Raaijmakers R, Hall BD. Adult height in Noonan syndrome. Am J Med Genet A. 2003;123A(1):68–71.PubMedCrossRefGoogle Scholar
  135. 135.
    Shaw AC, Kalidas K, Crosby AH, Jeffery S, Patton MA. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007;92(2):128–32.PubMedCrossRefGoogle Scholar
  136. 136.
    Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. Clin Genet. 1986;30(3):150–3.PubMedCrossRefGoogle Scholar
  137. 137.
    Wit JM, de Luca F. Atypical defects resulting in growth hormone insensitivity. Growth Hormon IGF Res. 2016;28:57–61.CrossRefGoogle Scholar
  138. 138.
    Sharland M, Burch M, McKenna WM, Paton MAA. Clinical study of Noonan syndrome. Arch Dis Child. 1992;67(2):178–83.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Puri P, Walker WH. The regulation of male fertility by the PTPN11 tyrosine phosphatase. Semin Cell Dev Biol. 2016;59:27–34.PubMedCrossRefGoogle Scholar
  140. 140.
    Ankarberg-Lindgren C, Westphal O, Dahlgren J. Testicular size development and reproductive hormones in boys and adult males with Noonan syndrome: a longitudinal study. Eur J Endocrinol. 2011;165(1):137–44.PubMedCrossRefGoogle Scholar
  141. 141.
    Yaoita M, Niihori T, Mizuno S, Okamoto N, Hayashi S, Watanabe A, et al. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet. 2016;135(2):209–22.PubMedCrossRefGoogle Scholar
  142. 142.
    Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.PubMedCrossRefGoogle Scholar
  143. 143.
    Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93(1):173–80.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Hickey EJ, Mehta R, Elmi M, Asoh K, McCrindle BW, Williams WG, et al. Survival implications: hypertrophic cardiomyopathy in Noonan syndrome. Congenit Heart Dis. 2011;6(1):41–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Wilkinson JD, Lowe AM, Salbert BA, Sleeper LA, Colan SD, Cox GF, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric cardiomyopathy registry. Am Heart J. 2012;164(3):442–8.PubMedCrossRefGoogle Scholar
  147. 147.
    Gelb BD, Roberts AE, Tartaglia M. Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol. 2015;39(1):13–9.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Briggs BJ, Dickerman JD. Bleeding disorders in Noonan syndrome. Pediatr Blood Cancer. 2012;58(2):167–72.PubMedCrossRefGoogle Scholar
  149. 149.
    van der Burgt I, Thoonen G, Roosenboom N, Assman-Hulsmans C, Gabreels F, Otten B, et al. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr. 1999;135(6):707–13.PubMedCrossRefGoogle Scholar
  150. 150.
    Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Seidenberg MS. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009;8(3):275–82.PubMedCrossRefGoogle Scholar
  151. 151.
    Lee DA, Portnoy S, Hill P, Gillberg C, Patton MA. Psychological profile of children with Noonan syndrome. Dev Med Child Neurol. 2005;47(1):35–8.PubMedCrossRefGoogle Scholar
  152. 152.
    Ryu HH, Lee YS. Cell type-specific roles of RAS-MAPK signaling in learning and memory: implications in neurodevelopmental disorders. Neurobiol Learn Mem. 2016;135:13–21.PubMedCrossRefGoogle Scholar
  153. 153.
    Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Rauen KA, et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010;152A(3):591–600.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Pierpont EI, Tworog-Dube E, Roberts AE. Attention skills and executive functioning in children with Noonan syndrome and their unaffected siblings. Dev Med Child Neurol. 2015;57(4):385–92.PubMedCrossRefGoogle Scholar
  155. 155.
    Verhoeven W, Wingbermuhle E, Egger J, Van der Burgt I, Tuinier S. Noonan syndrome: psychological and psychiatric aspects. Am J Med Genet A. 2008;146A(2):191–6.PubMedCrossRefGoogle Scholar
  156. 156.
    Smpokou P, Tworog-Dube E, Kucherlapati RS, Roberts AE. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. Am J Med Genet A. 2012;158A(12):3106–11.PubMedCrossRefGoogle Scholar
  157. 157.
    Wingbermuehle E, Egger J, van der Burgt I, Verhoeven W. Neuropsychological and behavioral aspects of Noonan syndrome. Horm Res. 2009;72(Suppl 2):15–23.PubMedCrossRefGoogle Scholar
  158. 158.
    Lee NB, Kelly L, Sharland M. Ocular manifestations of Noonan syndrome. Eye (Lond). 1992;6(Pt 3):328–34.CrossRefGoogle Scholar
  159. 159.
    Guerin A, So J, Mireskandari K, Jougeh-Doust S, Chisholm C, Klatt R, et al. Expanding the clinical spectrum of ocular anomalies in Noonan syndrome: Axenfeld-anomaly in a child with PTPN11 mutation. Am J Med Genet A. 2015;167A(2):403–6.PubMedCrossRefGoogle Scholar
  160. 160.
    van Trier DC, van Nierop J, Draaisma JM, van der Burgt I, Kunst H, Croonen EA, et al. External ear anomalies and hearing impairment in Noonan syndrome. Int J Pediatr Otorhinolaryngol. 2015;79(6):874–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, et al. Cancer Spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer. 2015;112(8):1392–7.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet. 2014;51(10):689–97.PubMedCrossRefGoogle Scholar
  163. 163.
    Hasle H. Malignant diseases in Noonan syndrome and related disorders. Horm Res. 2009;72(Suppl 2):8–14.PubMedCrossRefGoogle Scholar
  164. 164.
    McWilliams GD, SantaCruz K, Hart B, Clericuzio C. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy. Am J Med Genet A. 2016;170A(1):195–201.PubMedCrossRefGoogle Scholar
  165. 165.
    Myers A, Bernstein JA, Brennan ML, Curry C, Esplin ED, Fisher J, et al. Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. Am J Med Genet A. 2014;164A(11):2814–21.PubMedCrossRefGoogle Scholar
  166. 166.
    Binder G, Grathwol S, von Loeper K, Blumenstock G, Kaulitz R, Freiberg C, et al. Health and quality of life in adults with Noonan syndrome. J Pediatr. 2012;161(3):501–5. e1PubMedCrossRefGoogle Scholar
  167. 167.
    Colquitt JL, Noonan JA. Cardiac findings in Noonan syndrome on long-term follow-up. Congenit Heart Dis. 2014;9(2):144–50.PubMedCrossRefGoogle Scholar
  168. 168.
    MacFarlane CE, Brown DC, Johnston LB, Patton MA, Dunger DB, Savage MO, et al. Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up. J Clin Endocrinol Metab. 2001;86(5):1953–6.PubMedGoogle Scholar
  169. 169.
    Osio D, Dahlgren J, Wikland KA, Westphal O. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr. 2005;94(9):1232–7.PubMedCrossRefGoogle Scholar
  170. 170.
    Noordam C, Peer PG, Francois I, De Schepper J, van den Burgt I, Otten BJ. Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11. Eur J Endocrinol. 2008;159(3):203–8.PubMedCrossRefGoogle Scholar
  171. 171.
    Raaijmakers R, Noordam C, Karagiannis G, Gregory JW, Hertel NT, Sipila I, et al. Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database. J Pediatr Endocrinol Metab. 2008;21(3):267–73.PubMedCrossRefGoogle Scholar
  172. 172.
    Tamburrino F, Gibertoni D, Rossi C, Scarano E, Perri A, Montanari F, et al. Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: patterns of growth, puberty and final height data. Am J Med Genet A. 2015;167A(11):2786–94.PubMedCrossRefGoogle Scholar
  173. 173.
    Noordam C, Draaisma JM, van den Nieuwenhof J, van der Burgt I, Otten BJ, Daniels O. Effects of growth hormone treatment on left ventricular dimensions in children with Noonan's syndrome. Horm Res. 2001;56(3-4):110–3.PubMedGoogle Scholar
  174. 174.
    Fukami M, Seki A, Ogata TSHOX. Haploinsufficiency as a cause of Syndromic and Nonsyndromic short stature. Mol Syndromol. 2016;7(1):3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr. 2011;75(2):81–9.PubMedCrossRefGoogle Scholar
  176. 176.
    Benito-Sanz S, Barroso E, Heine-Suner D, Hisado-Oliva A, Romanelli V, Rosell J, et al. Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS). J Clin Endocrinol Metab. 2011;96(2):E404–12.PubMedCrossRefGoogle Scholar
  177. 177.
    Fukami M, Naiki Y, Muroya K, Hamajima T, Soneda S, Horikawa R, et al. Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature. J Hum Genet. 2015;60(9):553–6.PubMedCrossRefGoogle Scholar
  178. 178.
    Iughetti L, Capone L, Elsedfy H, Bertorelli R, Predieri B, Bruzzi P, et al. Unexpected phenotype in a boy with trisomy of the SHOX gene. J Pediatr Endocrinol Metab. 2010;23(1-2):159–69.PubMedCrossRefGoogle Scholar
  179. 179.
    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.CrossRefPubMedGoogle Scholar
  180. 180.
    Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, et al. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab. 2002;87(3):1402–6.PubMedCrossRefGoogle Scholar
  181. 181.
    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.PubMedCrossRefGoogle Scholar
  182. 182.
    Munns CF, Glass IA, Flanagan S, Hayes M, Williams B, Berry M, et al. Familial growth and skeletal features associated with SHOX haploinsufficiency. J Pediatr Endocrinol Metab. 2003;16(7):987–96.PubMedGoogle Scholar
  183. 183.
    Binder G, Renz A, Martinez A, Keselman A, Hesse V, Riedl SW, et al. SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity. J Clin Endocrinol Metab. 2004;89(9):4403–8.PubMedCrossRefGoogle Scholar
  184. 184.
    Salmon-Musial AS, Rosilio M, David M, Huber C, Pichot E, Cormier-Daire V, et al. Clinical and radiological characteristics of 22 children with SHOX anomalies and familial short stature suggestive of Leri-Weill Dyschondrosteosis. Horm Res Paediatr. 2011;76(3):178–85.PubMedCrossRefGoogle Scholar
  185. 185.
    Binder G, Ranke MB, Martin DD. Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in school-age children with unexplained short stature. J Clin Endocrinol Metab. 2003;88(10):4891–6.PubMedCrossRefGoogle Scholar
  186. 186.
    Ross JL, Scott C Jr, Marttila P, Kowal K, Nass A, Papenhausen P, et al. Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab. 2001;86(12):5674–80.PubMedCrossRefGoogle Scholar
  187. 187.
    Donze SH, Meijer CR, Kant SG, Zandwijken GR, van der Hout AH, van Spaendonk RM, et al. The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects. Eur J Endocrinol. 2015;173(5):611–21.PubMedCrossRefGoogle Scholar
  188. 188.
    Ross JL, Kowal K, Quigley CA, Blum WF, Cutler GB Jr, Crowe B, et al. The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and turner syndrome. J Pediatr. 2005;147(4):499–507.PubMedCrossRefGoogle Scholar
  189. 189.
    Soucek O, Zapletalova J, Zemkova D, Snajderova M, Novotna D, Hirschfeldova K, et al. Prepubertal girls with turner syndrome and children with isolated SHOX deficiency have similar bone geometry at the radius. J Clin Endocrinol Metab. 2013;98(7):E1241–7.PubMedCrossRefGoogle Scholar
  190. 190.
    Rosilio M, Huber-Lequesne C, Sapin H, Carel JC, Blum WF, Cormier-Daire V. Genotypes and phenotypes of children with SHOX deficiency in France. J Clin Endocrinol Metab. 2012;97(7):E1257–65.PubMedCrossRefGoogle Scholar
  191. 191.
    Iughetti L, Vannelli S, Street ME, Pirazzoli P, Bertelloni S, Radetti G, et al. Impaired GH secretion in patients with SHOX deficiency and efficacy of recombinant human GH therapy. Horm Res Paediatr. 2012;78(5-6):279–87.PubMedCrossRefGoogle Scholar
  192. 192.
    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 of a multicenter trial. J Clin Endocrinol Metab. 2013;98(8):E1383–92.PubMedCrossRefGoogle Scholar
  193. 193.
    Scalco RC, Melo SS, Pugliese-Pires PN, Funari MF, Nishi MY, Arnhold IJ, et al. Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency. J Clin Endocrinol Metab. 2010;95(1):328–32.PubMedCrossRefGoogle Scholar
  194. 194.
    Child CJ, Kalifa G, Jones C, Ross JL, Rappold GA, Quigley CA, et al. Radiological features in patients with short stature Homeobox-containing (SHOX) gene deficiency and turner syndrome before and after 2 years of GH treatment. Horm Res Paediatr. 2015;84(1):14–25.PubMedCrossRefGoogle Scholar
  195. 195.
    Kirk JM, Betts PR, Butler GE, Donaldson MD, Dunger DB, Johnston DI, et al. Short stature in Noonan syndrome: response to growth hormone therapy. Arch Dis Child. 2001;84(5):440–3.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Stochholm K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006;91(10):3897–902.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric EndocrinologyCincinnati Children’s Hospital Medical Center, University of CincinnatiCincinnatiUSA
  2. 2.Division of Pediatric EndocrinologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations