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Vol. 65, No. 2, 2006
Issue release date: February 2006
Horm Res 2006;65:76–82

Autosomal-Dominant Isolated Growth Hormone Deficiency (IGHD Type II) with Normal GH-1 Gene

Fintini D. · Salvatori R. · Salemi S. · Otten B. · Ubertini G.M. · Cambiaso P. · Mullis P.-E.
aDivision of Endocrinology, Department of Medicine and the Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Md., USA; bDepartment of Pediatrics, Inselspital, University of Bern, Bern, Switzerland; cDepartment of Paediatric Endocrinology, University Medical Centre Nijmegen, Nijmegen, The Netherlands; dBambino Gesù Hospital and Research Institute, Rome, Italy

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Background: Autosomal-dominant isolated GH deficiency (IGHD) is a rare disorder that is commonly believed to be due to heterozygous mutations in the GH-1 gene (GH-1). These mutations cause the production of a protein that affects the release of the product of the normal allele. Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice. Subjects and Methods: We have sequenced the whole GH-1 in the index cases of 30 families with autosomal-dominant IGHD. In all the families other possible causes of GH deficiency and other pituitary hormones deficits were excluded. We here describe the clinical, biochemical and radiological picture of the families without GH-1 mutations. In these families, we also sequenced the HESX-1. Results: The index cases of the five families with autosomal-dominant IGHD had normal GH-1, including the intronic sequences. They had no HESX-1 mutations. Conclusion: This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.

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  1. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A: The somatomedin hypothesis: 2001. Endocr Rev 2001;22:53–74.
  2. Salvatori R: Growth hormone and IGF-1. Rev Endocr Metab Disord 2004;5:15–23.
  3. Vnencak-Jones CL, Phillips JA 3rd, Chen EY, Seeburg PH: Molecular basis of human growth hormone gene deletions. Proc Natl Acad Sci USA 1988;85:5615–5619.
  4. Bauman G: Growth hormone heterogeneity: genes, isohormones, variants and binding proteins. Endocr Rev 1991;12:424–449.
  5. Moseley CT, Mullis P, Prince MA, Phillips JA III: An exon splice enhancer mutation causes autosomal dominant GH deficiency. J Clin Endocrinol Metab 2002;87:847–852.
  6. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M: Utah growth study: growth standards and the prevalence of growth hormone deficiency. J Pediatr 1994;125:29–35.
  7. Mullis PE: Genetic control of growth. Eur J Endocrinol 2005;152:11–31.
  8. Mullis PE, Deladoey J, Dannies PS: Molecular and cellular basis of isolated dominant-negative growth hormone deficiency, IGHD type II: insights on the secretory pathway of peptide hormones. Horm Res 2002;58:53–66.
  9. Iliev DI, Wittekindt NE, Ranke MB, Binder G: Structural analysis of human growth hormone with respect to the dominant expression of growth hormone (GH) mutations in isolated GH deficiency type II. Endocrinology 2005;146:1411–1417.
  10. Binder G: Isolated growth hormone deficiency and GH-1 gene: update 2002. Horm Res 2002;58(suppl 3):2–6.
  11. Mullis PE, Robinson IC, Salemi S, Eble A, Besson A, Vuissoz JM, Deladoey J, Simon D, Czernichow P, Binder G: Isolated autosomal dominant growth hormone deficiency (IGHD II): an evolving pituitary deficit? A multi-center follow-up study. J Clin Endocrinol Metab 2005;90:2089–2096.
  12. Binder G, Nagel BHP, Ranke MB, Mullis PE: Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin. Eur J Endocrinol 2002;147:755–760.
  13. Parks JS, Brown MR, Hurley DL, Phelps CJ, Wajnrajch MP: Heritable disorders of pituitary development. J Clin Endocrinol Metab 1999;84:4362–4370.
  14. Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson CAF, Beddington RSP: heterozygous HESX-1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001;10:39–45.
  15. Cohen RN, Cohen LE, Botero D, Yu C, Sagar A, Jurkiewicz M, Radovick S: Enhanced repression by HESX-1 as a cause of hypopituitarism and septo-optic dysplasia. J Clin Endocrinol Metab 2003;88:4832–4839.
  16. Dattani MT: Novel insights into the aetiology and pathogenesis of hypopituitarism. Horm Res 2004;62(suppl 3):1–13.
  17. Dattani MT, Martinez Barbera JP, Thomas PQ, Brickmann JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC: Mutation in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998;19:125–133.
  18. Prader A, Largo RH, Molinari L, Issler C: Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Acta 1989;52(suppl):1–125.
  19. Ranke MB: Diagnosis of growth hormone deficiency and growth hormone stimulation tests; in Ranke MB (ed): Diagnostics of Endocrine Function in Children and Adolescents, ed 3 revised and extended edition. Basel, Karger, 2003, pp 107–128.
  20. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, Stanford University Press, 1959.
  21. Tanner JM: Normal growth and techniques of growth assessment. Clin Endocrinol Metab 1986;15:411–451.
  22. Wajnrajch MP, Gertner JM, Mullis PE, Deladoëy J, Cogan JD, Lekhakula S, Kim S, Dannies PS, Saenger P, Moshagn T, Phillips JA 3rd, Leibel RL: Arg183His, a new mutational ‘hot-spot’ in the growth hormone (GH) gene causing isolated GH deficiency type II. J Endocr Genet 2000;1:125–135.
  23. Wagner JK, Eble A, Cogan JD, Prince MA, Phillips JA 3rd, Mullis PE: Allelic variations in the human growth hormone-1 gene promoter of growth hormone-deficient patients and normal controls. Eur J Endocrinol 1997;137:125–135.

    External Resources

  24. Argyropoulou M, Pergnon F, Brunelle F, Brauner R, Rappaport R: Height of normal pituitary gland as a function of age evaluated by magnetic resonance imaging in children. Pediatr Radiol 1991;21:247–249.
  25. Tsunoda A, Okuda O, Sato K: MR height of the pituitary gland as a function of age and sex: especially physiological hypertrophy in adolescence and in climaterium. Am J Neuroradiol 1997;18:551–554.
  26. Murray RA, Maheshwari HG, Russell EJ, Baumann G: Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene. Am J Neuroradiol 2000;21:685–689.
  27. Oliveira HA, SalvatoriR, Krauss MPO, Oliveira CRP, Silva PRC, Aguiar-Oliveira MH: Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the growth hormone releasing hormone receptor gene. Eur J Endocrinol 2003;148:427–432.
  28. Fink AM, Vidmar S, Kumbla S, Pedreira CC, Kanumakala S, Williams C, Carlin JB, Cameron FJ: Age-related pituitary volumes in prepubertal children with normal endocrine function: volumetric magnetic resonance data. J Clin Endocrinol Metab 2005;90:3274–3278.

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