Молекулярно-генетические исследования при идиопатической низкорослости

Идиопатическая низкорослость - самая распространенная среди форм задержки роста, гетерогенная группа состояний с крайне вариабельной клинической картиной. Молекулярно-генетический поиск при идиопатической задержке роста основывается на совокупности сопутствующих клинических признаков и лабораторных данных. В обзоре представлены принципы диагностического поиска при идиопатической низкорослости и наиболее часто встречающиеся молекулярно-генетические дефекты генов системы ростовой оси гормон роста - инсулиноподобный ростовой фактор 1.

идиопатическая низкорослость, молекулярно-генетическая диагностика, гормон роста, инсулиноподобный ростовой фактор 1

1. Руководство "Детская эндокринология". По ред. И.И. Дедова, В.А. Петеркова. М: Универсум Паблишинг 2006.

2. Rosenbloom A.L. Idiopathic short stature: conundrums of definition and treatment. Int J Pediatr Endocrinol 2009; doi: 10.1155/2009/470378.

3. Wit J.M., Clayton P.E., Rogol A.D., Savage M.O. et al. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008; 18: 2: 89-110.

4. 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: 1: 29-35.

5. Strobi J.S., Thomas M.J. Human growth hormone. Pharmacol Rev 1994; 46: 1-34.

6. Cohen P., Rogol A.D., Deal C.L., Saenger P., Reiter E.O., Ross J.L., Chernausek S.D., Savage M.O., Wit J.M. On behalf of the 2007 ISS Consensus Workshop participants. Consensus Guidelines for the Diagnosis and Treatment of Children with Idiopathic Short Stature: a Summary Statement of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2008; 93: 4210-4217.

7. Vimpani G., Vimpani A., Lidgard G. Prevalence of severe growth hormone deficiency. Br Med J 1977; 2: 427-430.

8. Rona R., Tanner J. Aetiology of idiopathic growth hormone deficiency in England and Wales. Arch Dis Child 1977; 52: 197-208.

9. Дедов И.И., Петеркова В.А., Нагаева Е.В., Чикулаева О.А. Атлас "Соматотропная недостаточность у детей". М 2009.

10. Дедов И.И., Петеркова В.А., Безлепкина О.Б., Нагаева Е.В. "Соматотропная недостаточность у взрослых". АТЛАС. М: Арт-Инфо 2004.

11. Дедов И.И., Петеркова В.А. и др. Соматотропная недостаточность и другие формы нарушений роста у детей. Атлас 1999.

12. Дедов И.И., Тюльпаков А.Н., Петеркова В.А. Соматотропная недостаточность. М 1998; 172-191, 206, 207, 291-293.

13. Sybert V.P., McCauley E. Turner's Syndrome. N Engl J Med 2004; 351: 1227-1238.

14. Van der Burgt I. Noonan syndrome. Review. Orphanet J Rare Dis 2007; 2: 4.

15. Rosenbloom A.L., Guevara-Aguirre J. Controversy in clinical endocrinology: reclassification of insulin-like growth factor I production and action disorders. J Clin Endocrinol Metab 2006; 91: 11: 4232-4234.

16. Savage M.O., Attie K.M., David A., Metherell L.A., Clark A.J., Camacho-Hübner C. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endocrinol Metab 2006; 2: 7: 395-407.

17. Rosenfeld R.G., Hwa V. Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 2004; 89: 3: 1066-1067.

18. Netchine I., Azzi S., Houang M., Seurin D., Daubas C., Ricort J., Legay C., Perin L., Heirich R., Godeau F., Le Bouc Y. Partial IGF-I deficiency demonstrates the critical role of IGF-I in growth and brain development. Horm Res 2006; 65: Suppl 4: 29.

19. Wheeler P.G., Bresnahan K., Shephard B.A. et al. Short stature and functional impairment: A systematic review. Arch Pediatr Adolesc Med 2004; 158: 3: 236-243.

20. Lee J., Menon R.K. Molecular defects in the growth hormone-IGF axis. Indian J Pediatr 2005; 72: 145-148.

21. Mullis P.E. Genetic control of growth. Eur J Endocrinol 2005; 152: 11-31.

22. Roith D., Bondy C., Yakar S., Liu J.-L., Butler A. The somatomedin hypothesis: 2001. Endocrinol Rev 2001; 22: 1: 53-74.

23. Cohen P., Germak J., Rogol A.D., Weng W., Kappelgaard A.-M., Rosenfeld R.G. 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: 5: 2089-2098.

24. Walenkamp M.J., Wit J.M. Genetic disorders in the growth hormone-insulin-like growth factor-1-axis. Horm Res 2006; 66: 221-230.

25. Iida K., Takahashi Y., Kaji H., Nose O., Okimura Y., Abe H., Chihara K. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab 1998; 83: 531-537.

26. Ayling R.M., Ross R., Towner P., Von Laue S., Finidori J., Moutoussamy S., Buchanan C.R., Clayton P.E., Norman M.R. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet 1997; 16: 13-14.

27. Woods K.A., Fraser N.C., Postel-Vinay M.C., Savage M.O., Clark A.J. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab 1996; 81: 1686-1690.

28. Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab 2004; 89: 3: 1031-1044.

29. Kofoed E.M., Hwa V., Little B., Woods K.A., Buckway C.K., Tsubaki J., Pratt K.L., Bezrodnik L., Jasper H., Tepper A., Heinrich J.J., Rosenfeld R.G. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003; 349: 1139-1147.

30. Fang P., Kofoed E.M., Little B.M., Wang X., Ross R.J.M., Frank S.J., Hwa V., Rosenfeld R.G. A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor. J Clin Endocrinol Metab 2006; 91: 1526-1534.

31. Hwa V., Camacho-Hubner C., Little B., David A., Metherell L., Savage M., Rosenfeld R.G. Growth hormone insensitivity and severe short stature in siblings due to a novel splice mutation in exon 13 of the STAT5b gen (Abstract). The Endocrine Society's 88th. Ann Meeting 2006; 1-839: 379.

32. Marino R., Ciaccio M., Bernasconi A., Rossi J., Oleastro M., Omani A., Zelasko M., Rivarola M.A., Belgorosky A. Identification of a novel nonsense mutation in the STAT5b gene associated with growth hormone insensitivity. Horm Res 2005; 64: Suppl 1: 44.

33. Vidarsdottir S., Walenkamp M.J., Pereira A.M., Karperien M., Van Doorn J., van Duyven-voorde H.A., White S., Breuning M.H., Roelfsema F., Kruithof M.F., van Dissel J., Janssen R., Wit J.M., Romijn J.A. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab 2006.

34. Hwa V., Little B., Adiyaman P., Kofoed E.M., Pratt K.L., Ocal G., Berberoglu M., Rosenfeld R.G. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab 2005; 90: 4260-4266.

35. Hwa V., Nadeau K., Wit J.M., Rosenfeld R.G. STAT5b deficiency: lessons from STAT5b gene mutations. Best Pract Res Clin Endocrinol Metab 2011; 25: 1: 61-75.

36. Walenkamp M.J., Karperien M., Pereira A.M., Hilhorst-Hofstee Y., Van Doorn J., Chen J.W., Mohan S., Denley A., Forbes B., van Duyven-voorde H.A., van Thiel S.W., Sluimers C.A., Bax J.J., de Laat J.A., Breuning M.B., Romijn J.A., Wit J.M. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 2005; 90: 2855-2864.

37. Bonapace G., Concolino D., Formicola S., Strisciuglio P. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet 2003; 40: 913-917.

38. Woods K.A, Camacho-Hubner C., Savage M.O., Clark A.J. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996; 335: 1363-1367.

39. Woods K. et al. Genetic defects of the growth-hormone-IGF axis associated with growth hormone insensitivity. Endocr Dev 2007; 11: 6-15.

40. Смирнов А.Н. Элементы эндокринной регуляции. М: Гэотар-медиа 2006.

41. Hwa V., Haeusler G., Pratt K.L., Little B.M., Frisch H., Koller D., Rosenfeld R.G. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab 2006; 91: 1826-1831.

42. Domene H.M., Bengolea S.V., Martinez A.S., Ropelato M.G., Pennisi P., Scaglia P., Heinrich J.J., Jasper H.G. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004; 350: 570-577.

43. Okubo Y., Siddle K., Firth H., O'Rahilly S., Wilson L.C., Willatt L., Fukushima T., Takahashi S.I., Petry C.J., Saukkonen T., Stanhope R., Dunger D.B. Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab 2003; 88: 5981-5988.

44. Abuzzahab M.J., Schneider A., Goddard A., Grigorescu F., Lautier C., Keller E., Kiess W., Klammt J., Kratzsch J., Osgood D., Pfaffle R., Raile K., Seidel B., Smith R.J., Chernausek S.D. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349: 2211-2222.

45. Walenkamp M.J., Van der Kamp H.J., Pereira A.M., Kant S.G., van Duyvenvoorde H.A., Kruithof M.F., Breuning M.H., Romijn J.A., Karperien M., Wit J.M. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the IGF-I receptor. J Clin Endocrinol Metab 2006; 91: 3062-3070.

46. Kawashima Y., Kanzaki S., Yang F., Kinoshita T., Hanaki K., Nagaishi Ji., Ohtsuka Y., Hisatome I., Ninomoya H., Nanba E., Fukushima T., Takahashi S.I. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab 2005; 90: 4679-4687.

47. Kawashima Y., Yang F., Miura M., Kinoshita T., Nagaishi J.I., Hanaki K., Kanzaki S. A family with short stature born intrauterine growth retardation bearing a new missense mutation at a subunit of IGF-I receptor (R431L). The Endocrine Society's 88th. Ann Meeting 2006; 2-117: 426.

48. Choi J.H., Kang M., Kim G.H., Hong M., Jin H.Y., Lee B.H., Park J.Y., Lee S.M., Seo E.J., Yoo H.W. Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. J Clin Endocrinol Metab 2011; 96: 1: E130-E134.

49. Tiulpakov A., Rubtsov P., Sverdlova P., Peterkova V., LeRoith D. A familial case of pre-and postnatal growth failure associated with a novel heterozygous missense mutation affecting the N-terminal fibronectin type III domain of IGF-IR. Horm Res 2005; 64: Suppl 1: 32.

50. Veenma D.C., Eussen H.J., Govaerts L.C., de Kort S.W., Odink R.J., Wouters C.H., Hokken-Koelega A.C., de Klein A. Phenotype-genotype correlation in a familial IGF1R microdeletion case. J Med Genet 2010; 47: 7: 492-498.

51. Rao E., Weiss B., Fukami M., Rump A., Niesler B., Mertz A., Muroya K., Binder G., Kirsch S., Winkelmann M., Nordsiek G., Heinrich U., Breuning M.H., Ranke M.B., Rosenthal A., Ogata T., Rappold G.A. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet 1997; 16: 54-63.

52. Blaschke R.J., Rappold G.A. SHOX in short stature syndromes. Horm Res 2001; 55: Suppl 1: 21-23.

53. Rappold G.A., Ross J.L., Blaschke R.J., Blum W.F. Understanding SHOX deficiency and its role in growth disorders. Ref Guide 2002; 122.

54. Rao E., Blanschke R.J., Marchini A., Niesler B., Burnett M., Rappold G.A. The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum Mol Genet 2001; 10: 26: 3083-3091.

55. Shears D.J., Vassal H.J., Goodman F.R., Palmer R.W., Reardon W., Superti-Furga A., Scambler P.J., Winter R.M. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nature Genet 1998; 19: 70-73.

56. Rao E., Weiss B., Fukami M., Rump A., Niesler B., Mertz A., Muroya K., Binder G., Kirsch S., Winkelmann M., Nordsiek G., Heinrich U., Breuning M.H., Ranke M.B., Rosenthal A., Ogata T., Rappold G.A. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet 1997; 16: 54-63.

57. Rappold G. SHOX mutations in patients with idiopathic short stature and Leri-Weill Syndrome. Topical Endocrinology 1999; Suppl 6: 8-9.

58. Rappold G.A., Fukami M., Niesler B., Shiller S., Zumkeller W., Bettendorf M., Heinrich U., Vlachopapadoupoulou E., Reinehr T., Onigata K., Ogata T. Deletions of the homeobox gene SHOX are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab 2002; 87: 1384-1388.

59. Blum W.F., Schweizer R. Insulin-like growth factors and their binding proteins. In: Diagnostics of endocrine function in children and adolescents. Ed. M.B. Ranke. Basel (Switzerland): Karger 2003; 166-199.

60. Rosenfeld R.G., Buckway C., Selva K., Pratt K.L., Guevara-Aguirre. Insulin-like growth factor (IGF) parameters and tools for efficacy: the IGF-I generation test in children. Horm Res 2004; 62: Suppl 1: 37-43.