1. Normal and Abnormal Growth
Nancy J. Charest, MD
Pediatric Endocrinology
Children’s Hospital at Dartmouth

2. Normal and Abnormal Growth Outline
Review the endocrine control of growth
Discuss patterns of normal growth
Outline clinical evaluation of growth disorders
Illustrate some causes of growth failure

3. Endocrine Regulation of Growth

4. Endocrine Regulation of Growth

5. Endocrine Regulation of Growth
Growth Hormone:
GRF (stimulates GH secretion)
Somatostatin (inhibits GH secretion)
Ghrelin (stimulates GH secretion)
Insulin-like growth factors (IGF-I and IGF-II)
Produced in response to growth hormone
Mediates most of the effects of growth hormone
Binds in serum to insulin-like growth factor
binding proteins (IGFBP3)
Thyroid Hormone
Gonadal steroids ( estradiol and testosterone)
Glucocorticoids

6. Endocrine Regulation of Growth
Hypothalamus
GRF
(+)
Somatostatin (-)
Pituitary
Growth Hormone
Liver, Mesenchyma
Insulin Like Growth Factor 1
Bone and Cartilage

7. GH/IGF-1 AXIS
Figure IGF-GH axis regulation. Growth hormone releasing factor (GHRH) and somatostatin (SMS) regulate pituitary GH secretion. GH binds to the circulating GH binding protein (GHBP), which is the cleaved extracellular domain of the GH receptor, as well as to the receptor itself. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) and the acid-labile subunit are produced in response to GH signal transduction. IGF mediates growth by binding to its receptor (IGF-R). In hyperinsulinemic states, serum insulin often interacts with the IGF-R and can further potentiate growth. Such growth has been observed in growth hormone deficient children who have become obese following surgery for craniopharyngioma [], [].

8. Endocrine Regulation of Growth
Thyroid hormone
Skeletal growth is exquisitely sensitive to thyroid hormone
Hypothyroidism impairs growth hormone release
Hypothyroidism delays bone maturation and limits linear growth
Hyperthyroidism accelerates linear growth and bone maturation

9. Endocrine Regulation of Growth
Gonadal steroids
Estrogen and testosterone accelerate linear growth
Both hormones work synergistically with growth hormone
Bone maturation appears to be due to estrogen (aromatized from circulating androgens in males)

10. Normal Growth

11. Stages of Human Growth
Fetal
Infancy
Childhood
Pubertal

12. Stages of Human Growth Fetal Extraordinary growth rates (120 cm/yr!)
Not dependent on fetal pituitary
(anencephalic infants are born at normal size)
IGF-1 and IGF-II play a role in fetal growth
Highly dependent on maternal/placental factors
e.g. mult. pregnancy, placental insufficiency, maternal diabetes

13. Stages of Human Growth Infancy
Rates are initially quite high, but decelerate rapidly
40 cm/yr down to 12 cm/yr
Transition towards pituitary dependent growth
IGF-I, mediated by growth hormone becomes increasingly important
May be a crossing of percentiles during 1st 2 yrs of life as genetic influences in stature manifest

14. Stages of Human Growth Childhood
Slowly progressive fall in growth rate from 8 cm/yr to 5 cm/yr just before puberty
Children generally track along percentiles
Exquisitely sensitive to growth hormone and thyroid hormone
Minimal (if any) effect of sex hormones

15. Stages of Human Growth Pubertal
Rapid rise in growth rate due to sex hormones
Sex hormones have direct effect on linear growth, and also increase the production of growth hormone and IGF-I

16. Growth Velocity-Girls

18. Growth Velocity - Boys

20. Evaluation of Growth

21. Key Issues for PCP in evaluating growth
Accurate height and weight
Plotting of height and weight for age
Growth rate
Genetic height potential: mid-parental height calculation
Pubertal status

22. Correct technique to measure infant

23. Inconsistent measuring technique

24. Correct technique for measuring child

25. Infant Growth Charts

26. Children Growth Charts

27. Longitudinal growth chart
Individual data obtained
over time and pooled
Note the sigmoid shape
during puberty

28. Expected growth rates in children
Age (years)
Growth rate (cm/year)
0-1
18-20
1-2
8-10
2-4
5-7
4-puberty
4-5
GROWTH RATE < 4 CM/YR SIGNALS NEED FOR EVALUATION!

29. Growth Failure-Crossing percentiles

30. Growth Failure- Growth Velocity under 4 cm/year

31. Mid-parental height (target height)
Evaluation of Growth
Mid-parental height (target height)
For a male, add 5 inches to mother’s height, add father’s height and divide by 2.
For a female, subtract 5 inches from father’s height, add mother’s height and divide by 2.
Children will normally fall within about 3.5 inches of the target height

32. Father=74 inches, Mother= 67 inches. MPH= (74+67+5)/2)=73in +/- 3
Father=74 inches, Mother= 67 inches. MPH= ( )/2)=73in +/- 3.5 in ( in)

33. Growth Failure and Short Stature
Short stature: height more than 2.0 SD below the mean for age and gender
Growth failure: decline in rate of linear growth (cross channels)
Short for family: (More than 3 inches below mid-parental height percentile)
Growth Hormone Research Society recommends investigation of children with the above noted definitions of growth failure/short stature
Referral to pediatric endocrinologist is usually indicated.

34. Evaluation of growth failure/short stature (usually performed by pediatric endocrinologist)
Bone age
Laboratory testing

35. Evaluating Growth-Bone Age
Skeletal maturation (“bone age”)
indirect measure of the completeness of endochondral ossification
correlates with growth potential
closely correlates with pubertal progression
mediated by estrogens

36. 6 yr M
8 yr M
10 yr M

37. Evaluating Growth Predicting adult stature based on bone age
Estimate skeletal age from radiograph
Read proportion of adult height complete from tables (Greulich and Pyle)
Divide current height by the proportion of growth complete

38. CA 8 yrs
Bone age 8 yrs
Ht. Pred. 70”

39. CA 8 yrs
Bone age 6 yrs
Ht prediction 74”

40. CA 8 yrs
Bone age 10 yrs
Ht. Prediction 67”

41. Screening labs for growth failure
IGF-1
IGF-BP3
TSH, free T4
Karyotype in female or dysmorphic child
CBC with differential
ESR
Chemistry profile
Urinalysis
Celiac screen(IgA, tTG IgA Ab)

42. Growth Disorders Normal variants of growth
Endocrine causes of growth failure
Non-endocrine causes of growth

43. Familial short stature
Consistent growth pattern at lower edge of height curve
Parents are short
Growth pattern, bone age, and puberty are appropriate for chronologic age
Calculate mid-parental height or target height:
Girl = {[Fa-5 in] + Mo}/2
Boy = {[Mo+5 in] + Fa}/2

44. Familial Short Stature

45. Constitutional growth delay
Family history of late onset puberty and slow growth until late adolescence
Normal annual growth rate for delayed bone age
Delayed puberty
Predicted height in range for family
No evidence of disease

46. Constitutional Delay of Growth

47. Growth Disorders Endocrine disorders that cause growth failure
Growth hormone deficiency
IGF-I deficiency
Hypothyroidism
Hypogonadism
Precocious puberty

48. Endocrine disorders that cause growth failure: Growth hormone deficiency
Decreased linear growth
Hypoglycemia (in infancy)
Increased adiposity (ripply abdominal fat)
Bone age typically delayed
Weight relatively well preserved (cherubic)

49. ER
Growth Hormone
Deficiency

50. Growth hormone deficiency
Figure Growth hormone (GH) deficiency occurs in approximately 1 per 10,000 children []. The severely GH-deficient child may present with hypoglycemia in the newborn period, usually indicating concomitant glucocorticoid deficiency and panhypopituitarism. After the first 6 months of life, linear growth rate slows in the GH-deficient child, resulting in downward crossing of percentiles and subsequent growth retardation. The classically GH-deficient child has a chubby appearance with increased peritruncal fat and decreased muscle mass. Skeletal age is delayed, as is pubertal development in the older child. This 5.5-year-old boy (left) with GH deficiency was significantly smaller than his fraternal twin sister (right), the discrepancy beginning in early childhood. Note his chubby immature appearance compared to that of his sibling.

51. Making the diagnosis of GH/GRF deficiency
Endocrine Disorders that cause Growth Failure: Growth Hormone Deficiency
Making the diagnosis of GH/GRF deficiency
Document a low growth velocity
Exclude non-endocrine causes (CBC, ESR, UA, Chem panel)
Exclude hypothyroidism
Determine skeletal age
Measure IGF-I and IGFBP-3 (low levels support the diagnosis, but are not necessarily diagnostic)

52. Because GH secretion is pulsatile, random values are not helpful.
Endocrine Disorders that cause Growth Failure: Growth Hormone Deficiency
Because GH secretion is pulsatile, random values are not helpful.
Most rely on provocative tests:
Insulin induced hypoglycemia (“gold standard”)
Arginine infusion
L-Dopa, clonidine, glucagon
GHRH

53. JT
Growth Homone
Deficiency

54. Endocrine Disorders that cause Growth Failure: Growth Hormone Deficiency
Causes
Idiopathic
Tumors (particularly craniopharyngioma)
Radiation
Genetic syndromes
Defects in growth hormone gene
Septo-optic dysplasia
Prop-1 mutation

55. Magnetic resonance imaging of large peri-sellar mass
Figure A, Evaluation of patients presenting with a large perisellar mass. Patients with a large pituitary or perisellar mass lesion who present to medical attention, with or without symptoms, should be thoroughly investigated, because they are likely to have some hormone deficits as well as visual manifestations. A thorough general medical evaluation is very important, to address potential causes of the mass lesions as well as tolerance to possible surgical intervention. Biochemical testing of pituitary function should be performed and correlated with clinical assessment. Evaluation by a neuro-ophthalmologist, including visual field testing, is an important aspect of this process and should be done before therapeutic intervention. In most instances, an imaging study has already been done by this time. Magnetic resonance (MR) scans are the preferred choice and should be done before treatment is begun. MR scans provide a better appreciation of the anatomy and relation to surrounding structures. Furthermore, they often eliminate the need for additional neuro-imaging studies such as angiography. B and C, Two examples of perisellar mass lesions presenting for treatment. B, MRI scan of a patient with a large intrasellar mass that proved to be a craniopharyngioma (single arrow). Double arrows show the optic chiasm. C, MRI scan of a patient with optic glioma. Lesions can be easily mistaken for a pituitary adenoma.

56. Endocrine Disorders that cause Growth Failure: IGF-I deficiency
Defects in growth hormone receptor (Laron dwarfism)
Low levels of growth hormone binding protein (extracellular domain of the GH receptor)
High levels of growth hormone
Low levels of IGFs
Resistant to growth hormone treatment
Responsive to IGF-I infusion

57. IGF-1 Deficiency (Laron Dwarfism)

58. Growth Disorders Hypothyroidism
Much more common than growth hormone deficiency
Marked decrease in growth velocity (“crossing percentiles”)
Epiphyseal fusion is delayed, preserving some growth potential
Weight is well preserved or excessive
Diagnosis can usually be suspected by associated signs/symptoms:
cold intolerance, constipation, fatigue, bradycardia, goiter.

59. JR
hypothyroidism

60. Growth Disorders Hypogonadism
Without sex hormones, the
pubertal growth spurt is
blunted.
Because epiphyseal fusion is
delayed, growth continues
well past puberty
There are disproportionately
long arms and legs -
a “eunuchoid body habitus”

61. Growth Disorders Precocious puberty
Precocious puberty results in
rapid, early growth spurt
There is rapid acceleration of
bone age, premature fusion of
growth plates, compromising
adult stature

62. Non-Endocrine Causes of Growth Failure
Osteochondrodysplasias:
- achondroplasia / hypochondroplasia
Chromosomal disorders
- Turner’s syndrome, Down’s syndrome
Malabsorption
Celiac disease; Inflammatory bowel disease
Hypoxia
Cystic fibrosis, cyanotic heart disease, anemia
Iatrogenic
high dose steroid treatment

63. TM
Turner Syndrome

64. Turner Syndrome: 45 XO / mosaic
Short stature due to SHOX mutation
Gonadal failure, female phenotype
Cubitus valgus
Madelung deformity of distal radius/wrist
Short, webbed neck
Shield chest, wide-spaced nipples, atrophic breasts
Low nuccal hairline
Nevi
Cardiac lesions: typically aortic coarctation & hypertension
Renal lesions: typically horseshoe kidney
Celiac disease
Autoimmune thyroid disease

65. Normal and Abnormal Growth Summary
Growth is mediated primarily through the action of IGF-I, which is stimulated by pituitary growth hormone secretion.
Thyroid hormone , estrogen and testosterone interact with the GH/IGF-I axis and play important roles in human growth
The timing of sex hormone secretion can have profound effects on final height, by altering the maturation of the growth plates

66. Normal and Abnormal Growth Summary
The PCP should accurately measure height and weights, plot data on growth charts, and calculate
mid-parental height.
PCP should know that from age 2 years until puberty, children should maintain their height along the same percentile.
PCP should be able to assess growth rate in context of pubertal status.

67. Normal and Abnormal Growth Summary
Children who are:
1.more than 2 SD below the mean for height, or
2. crossing height percentiles over time or
3. short compared to parents,
should be evaluated for a growth disorder
by a pediatric endocrinologist.