Endocrine Aspects of 11q Is there a role for GH? …no issue

1. Endocrine Aspects of 11qIs there a role for GH?…no issue small Thomas G. Kelly, MD, FAAP Pediatric Endocrinology UC San Diego / Rady Children’s Hospital San Diego

2. Short Stature Can Be a Stigma

4. Goals • Review the process of growth • Promote an understanding of factors that are critical to this process. • Discuss examples of growth failure and discuss how they are treated. • Discuss 11q syndrome and what is known about growth and growth hormone.

5. Overview • Introduction with Basic Growth Vocabulary • How Do We Grow? • What can go wrong? • How do we fix it?

6. Understanding Your Child’s GrowthWhat you need to know • Height and Height % - an assessment of stature and its comparison to the general population • Growth Velocity - an assessment of the rate of growth • Mid parental height - a calculation of predicted height based on parental heights • Bone age - An assessment of the degree of growth plate closure

7. Assessing Stature • Current Height • Growth Velocity • Predicted Height

8. Height • Evaluation of height must be done in the context of normal standards • Charts compare child’s height with the 3rd-97th% of normal American kids • Plotting height and weight provides a useful and objective assessment of the adequacy of growth. • SDS score (Ht-mean HT/SD) describes the location of those whose Ht is >97th +2SD and<3rd % (-2SD).  OK135S057

9. What creates error in measurement

10. Good Technique = Good Data • Method of measurement • Staff with different techniques • Standing vs lying • The “birthday plot”

11. Incorrect Height Measuring Techniques • Line of sight not at eye level • Using floppy arm device • Child’s back not against board • Child’s hairpiece not removed • Child’s socks still on

12. Scoliosis

13. Rickets

14. Height Velocity • Invaluable in assessing a child with growth abnormalities. • Kids grow with remarkable fidelity relative to the growth curves from 2yrs to puberty. • Any crossing of Ht %’s is a concern. • Velocity should be calculated over at least a 6 month period.   

15. What’s normal ?

16. Normal Growth Rates During Childhood National Center for Health Statistics

17. 13 12 11 10 9 8 7 6 Growth rate (cm/y) 5 4 3 2 1 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Age (y) Normal Growth Rates During Childhood Girls: solid lines Boys: dashed lines Boys: dashed lines Girls’ peak growth rate: 11.5 years Boys’ peak growth rate: 13.5 years Boys’ peak growth rate: 13.5 years National Center for Health Statistics. Tanner JM, et al. J Pediatr. 1985.

18. How tall will I be when I grow up?

19. Height Prediction • Midparental height • Boys: [(M+F) + 5 inches]/2 • Girls: [(M+F) – 5 inches]/2 • Bone Age

20. Mid-Parental Height-An Assessment of Genetic Potential • The “mid-parental height” or MPH is a calculation based on parental heights of the expected final height of the child. • A useful tool in the assessment of whether a child’s current height percentile is appropriate. • MPH is adjusted ± 5 inches to account for the difference between the male and female heights on the growth curve. .

21. Examples of Mid-Parental Height • Dad = 66”; • Mom = 61” • MPH for a girl = Dad’s ht -5 or 66-5= 61” + Mom’s ht = 61 Divided by 2 (61+61)/2 = 61” MPH for a boy = Dad’s Ht + Mom’s Ht +5 2 61” 66” 61”

22. A bone age demonstrates growth potential Phalanges (Finger Bones) Epiphysis (Growth Plate) Metacarpal (Hand Bones) Carpal (Wrist Bones) Epiphysis (Growth Plate)

23. Male, 8 years Male, 14 years

25. MPH BA

26. Factors Affecting Growth Genes Environmental Influences Economic Factors Growth Nutrition Biological Factors

27. Genes • Although length and weight at birth depend on the intrauterine environment the final height achieved by a child is largely dependent on their genetic endowment. • Height is highly heritable!

28. Although this achievable height is limited by genetic factors … up to this limit height potential depends on environmental factors

29. Environment • Normal interaction between infants and children and their environment is necessary for normal growth and development. • Syndrome of growth failure and weight loss is long recognized in infants separated from their mothers or socially isolated, subject to cruelty, neglect, or institutional upbringing.

30. Economics • Socioeconomic Deprivation -Poverty leads to Stunting from: • Poor nutrition • Increased susceptibility to infections • Limited access to health care • Recurrent and/or chronic infections

31. Nutrition • Adequate Nutrition is essential for good linear growth. • Growth Failure may be the direct result of inadequate protein or other essential nutrients. • Alternatively, biologic influences such as disturbances of bowel endocrine, or metabolic function may play a role

32. Examples of Feeding Problemsthat can lead to impaired Nutrition • Problems with gastroesophageal reflux (GER) can contribute to problems with feeding. Many children with neurodevelopmental problems have GER • Tactile sensitivity or sensory defensiveness, common among children with cerebral palsy, autism, and spina bifida may cause a child to avoid putting things in his/her mouth. • Children with feeding problems as a result of behavioral or emotional issues. Or, the result of complex perinatal medical interventions that center around feeding or around the mouth, making subsequent oral experiences, including feeding, unpleasant.

33. Nutritional/Biologic Factors and Growth Low Birth Weight • Intrauterine Growth Retardation (IUGR) is a fetus with an estimated weight < 10th % for gestational age. • Small for gestational age (SGA) is an infant with a birthweight <10th%. • Depending on the timing, duration and severity of the insult, and success of postnatal intervention, the growth potential of IUGR/SGA children may be permanently adversely affected. • IUGR leading to SGA is an approved indication for Growth Hormone if growth deficit is not overcome in the first 3 yrs of life.

34. Generalizations About Growth • Despite all the factors mentioned • Genes • Environment • Nutrition • Economics • Children normally grow at a remarkably predictable rate. • The sequence of growth is usually uncomplicated and orderly, but variations exist and individual growth patterns may be confused with problems of hormonal regulation

35. Normal Growth Patterns associated with Short Stature Two Common Conditions • Genetic Short Stature • Late Bloomer (Constitutional Delay)

36. Diagnosis Growth chart pattern Family history (with accurate family heights) Normal bone age Normal growth velocity Familial Short Stature

37. Constitutional Delay • Late Bloomers • Generally refers to a delay in growth as well as pubertal development • More common in boys • Possibly related to nutrition

38. The Late Bloomer(AKA Constitutional Delay) • Not associated with growth failure • Adolescents channeled to a curve that may be short for the population and/or family • Family history of late puberty with catch-up growth at puberty

39. Pubertal Delay • Growth Velocity: prepubertal • BA<CA • May intervene to initiate puberty

40. What Can Go Wrong? Genetic/Chromosomal Abnormalities Environmental stressors Economic Stressors Growth Malnutrition And Disease

41. Genetic and Chromosomal Abnormalities • A genetic disorder is any disorder caused by faults in inherited genetic material within a persons cells. • In these conditions there is the potential for altered growth because the affected metabolic pathways disturb energy production and/or the building of body tissue. Examples: Genetic abnormalities of bone, cartilage

42. Genetic and Chromosomal Abnormalities • A Chromosomal Abnormality is any change in the normal structure or number of chromosomes. • It can be associated with growth patterns that differ from those of children without chromosomal abnormalities. • It is assumed that these differing growth patterns represent altered growth potential related to the underlying chromosomal abnormality. • Turner’s Syndrome missing an X chromosome or parts of an X. • Down’s Syndrome has an extra chromosome.

43. What Can We Do?

44. Evaluate For: • Conditions that alter growth Known or suspected Chromosomal disorders. History of IUGR/SGA Genetic Syndrome • Conditions that have the potential to alter growth. Metabolic Disorders Renal Endocrine Disorders Cardiac Gastrointestinal Infectious Hematologic Psychosocial Immune Pulmonary

45. Endocrine Causes of Short Stature • Low Thyroid Function • Decreased appetite • Constipation • Lethargy • Dry skin and hair • GROWTH FAILURE • Growth Hormone Deficiency • GROWTH FAILURE • Decreased lean body mass, increased fat mass • Decreased bone mineral content

46. Endocrine Causes of Short Stature

47. Growth Hormone Deficiency • Prevalence is 1/4000-1/80000 • Diagnosis is suspected by poor growth, history of brain irradiation or trauma • Since growth hormone secretion is pulsatile so random growth hormone measures are useless. • IGF-1 and IGFBP-3 are surrogate markers of GH sufficiency • Note that IGF-1 is significantly affected by nutritional status.

49. GH deficiency is confirmed using stimulatory tests Arginine, clonidine, L Dopa and insulin Some agents (arginine and clonidine) may act as GHRH agonists in the pituitary Stimulatory tests are not perfect: May miss partially deficient patients GH Testing

50. Etiologies of Pediatric GHD * Percentage of organic GHD cases Levy RA, et al. J PediatrEndocrinol Metab. 2003.