1. Endocrinology of Growth Laura K. Bachrach, M.D. Stanford Medical School

2. Why Discuss Growth? Major parental/social concern

3. Growth makes headlines

4. Why Discuss Growth? Major parental/social concern Barometer of health in children Variability of normal is challenging Underscore interaction of genetic, endocrine, & non-endocrine factors

5. There’s more to growth than growth hormone

8. Goals of Growth Talk Review tempo of growth & puberty Discuss normal variants Review causes of short & tall stature

9. Expected Growth Rates Age Cm (inches)/yr 0-1 25 (10) 1-2 12 (5) 2-4 8 (3) 5-12 5 (2) Puberty 7.5 (3) females 10 (4) males

10. Growth Velocity is Key Normal growth tracks along curve “Catch up” or “catch down” growth before age 2 may be normal Crossing percentiles after 2 years suggests slow or accelerated growth

11. Worrisome!

12. Puberty & Growth Puberty modifies growth rates

13. Growth Hormone & Puberty Williams

14. Puberty & Growth Puberty modifies growth rates What’s normal? What determines variability?

15. Tanner Stages

16. Puberty in Girls Breast bud at 10 Pubic hair soon after Menarche at 12.7 Growth spurt early in puberty

17. Puberty in Boys Testes start to enlarge at 11.5 Pubic hair 1-2 yrs later Testes mature at 15 Growth spurt later in puberty

18. Puberty & Growth FemalesMales

20. Puberty & Growth

21. What Determines Timing? Secular trend?

22. Is Puberty Happening Earlier?

23. Ethnic Differences in Puberty in Girls Breasts HairMenses Blacks 9.5 9.5 12.1 Hispanics 9.8 10.3 12.2 Whites 10.3 10.5 12.7 Wu et al. Pediatrics 2002; 110: 752-757

24. Earlier Puberty? Early start linked to BMI in white females African American female Age at menarche essentially unchanged in past 40 years

25. What Determines Timing? Secular trend? Ethnicity/race Tempo of puberty in parents Nutrition Illness

26. Growth Regulation Varies In Infancy & Childhood

27. Growth Regulation - The Fetus Maternal factors/Placenta Insulin-like growth factors Insulin Thyroid hormone - essential for brain Growth hormone - not essential

28. Placenta & Fetal Growth Post natal catch up 10% stay small

29. Insulin – A Potent Growth Factor Expect “catch down” growth

30. Infant of a Diabetic Mother Increased maternal glucose & amino acids Fetal hyperinsulinemia Manifestations in fetus macrosomia polycythemia delayed lung maturation neonatal hypoglycemia

31. Growth Regulation in Childhood Hormonal Growth hormone/IGFs Thyroid hormone Glucocorticoids - inhibitory effect Metabolic, nutritional

32. Growth Regulation - Puberty Hormonal Growth hormone/IGFs Thyroid hormone Sex steroids Glucocorticoids – inhibitory Metabolic, nutritional

33. Short Stature “Short” Population stds (<-2 SD) Family standards (<mid-parental ht) Growing too slowly – decrease ht %

34. Causes of Short Stature Normal variants – most common Familial (genetic) – Short parents – Nl birth and growth – Will be short as adult Constitutional Delay of Growth – Parents not short – Delayed growth & puberty (after 2) – Normal adult height

35. Constitutional Delay – “Late Bloomer”

36. Causes of Short Stature Non-endocrine skeletal abnormalities genetic/chromosomal disorders intrauterine growth retardation chronic disease

37. Achondroplasia & Hypoplasia

38. Hypochondroplasia Disproportionate short stature

39. Turner Syndrome

41. Common: 1 in 2,000 females Clinical features vary short stature100% gonadal failure 96% cardiac 55% renal anomalies 39% cubitus valgus 47% webbed neck 25%

42. Endocrine Short Stature Hypothyroidism Growth hormone deficiency Glucocorticoid excess

43. Hypothyroidism

44. Signs of Acquired Hypothyroidism growth failure puberty - delayed, rarely precocious constipation dry skin weight gain bradycardia fatigue feeling cold

45. Before & After Thyroxine

46. Risks of Prolonged Hypothyroidism Incomplete “catch-up” growth Pseudo tumor cerebri Altered mental status –decline in school performance –attention-deficit-like symptoms –emotional lability/psychosis

47. Incomplete Catch Up Growth

48. Endocrine Causes of Short Stature Growth hormone deficiency isolated panhypopituitarism

49. GH Deficiency

50. Endocrine Causes of Short Stature Growth hormone deficiency isolated panhypopituitarism Growth hormone resistance – rare abnormal GH receptor post-receptor signaling defect defect IGF-1 or IGF-1 receptor

51. GH-IGF-I Axis

52. GH Receptor Deficiency (Laron) Rosenbloom AL. JCEM 1994; 79: 695 Father with GHRD Sons (7, 10 yr) Daughter (5 yr)

53. Growth Curves – GH-IGF Axis Defects X Laron syndrome Del IGF-I Stat5b defect Hwa V. JCEM 2005; 90: 4260-6

54. Glucocorticoid Excess

55. Growth Increased weight Slowed height Causes Iatrogenic Endogenous

56. Tall Stature

57. Growth rates Normal Accelerated

58. Tall Without Accelerated Growth Familial (genetic) tall stature Syndromes – Marfan syndrome – Klinefelter syndrome – Homocystinuria

59. Marfan Syndrome Autosomal dominant Tall stature Ectopia lentis Arachnodactyly Aortic abnormalities

60. Tall WITH Accelerated Growth Exogenous obesity Precocious puberty Congenital adrenal hyperplasia Hyperthyroidism GH excess – RARE Cerebral gigantism

61. Exogenous Obesity Rapid growth Weight > height %iles Tall & fat Normal adult stature

62. Exogenous Obesity Tall for age when young Earlier puberty Reach genetic potential..........

63. Precocious Puberty Rapid growth Signs of sex maturity Short as adult if untreated

64. Tall adult if untreated Gigantism – GH Excess

65. Investigating Growth Problems

66. Growth Evaluation History – Birth weight & length – Growth patterns – Illness & meds Family history – Heights – Timing of puberty Exam – height, weight, trends, puberty

67. Lab Studies Endocrine T4, TSH IGF-1 & IGF binding protein 3 Sex steroids (if appropriate) Rarely cortisol Non-endocrine CBC, ESR celiac screen renal, hepatic function karyotype

68. Questions ?