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

3. Short Stature Can Be a Stigma

5. 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.

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

7. Understanding Your Child’s Growth What 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

8. Assessing Stature Current Height Growth Velocity Predicted Height

9. OK135S057 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).

10. What creates error in measurement

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

12. 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

13. Scoliosis

14. Rickets

15. 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.

16. What’s normal ?

17. Normal Growth Rates During Childhood National Center for Health Statistics Age Growth (cm/year) Birth to 1 year 17– 26 1 to 2 years 10–13 2 years to puberty 5–7 Puberty Girls Girls 7–12 Boys Boys 8–13

18. Normal Growth Rates During Childhood Growth rate (cm/y) Age (y) 2193456789101112131415161718 0 13 12 11 10 9 8 7 6 5 4 3 2 1 National Center for Health Statistics. Tanner JM, et al. J Pediatr. 1985. Girls: solid lines Boys: dashed lines Girls’ peak growth rate: 11.5 years Boys’ peak growth rate: 13.5 years Boys: dashed lines Boys’ peak growth rate: 13.5 years

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

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

21. 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..

22. 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 66” 61”

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

24. Male, 8 yearsMale, 14 years

26. BA MPH

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

28. 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!

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

30. 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.

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

32. 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

33. Examples of Feeding Problems that 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.

34. 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. Nutritional/Biologic Factors and Growth

35. 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

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

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

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

39. 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

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

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

42. 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

43. 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.

44. What Can We Do?

45. 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 DisordersRenal Endocrine DisordersCardiac Gastrointestinal Infectious HematologicPsychosocial ImmunePulmonary

46. 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

47. Endocrine Causes of Short Stature

48. 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.

50. GH Testing 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

51. Etiologies of Pediatric GHD Early NCGS Pediatric Registry (1986-1994) Later NCGS Pediatric Registry (1995-2002) N%N% Idiopathic GHD10,10672.8919081.7 Organic GHD376727.2205918.3 Other/unknown99626.4*95546.4* CNS irradiation88423.5*31715.4* Other CNS tumor79921.2*30815.0* Craniopharyngioma60015.9*21410.4* Septo-optic dysplasia41311.0*24812.0* Trauma752.0*170.8* Levy RA, et al. J Pediatr Endocrinol Metab. 2003.* Percentage of organic GHD cases

52. Pediatric Indications For Growth Hormone The FDA has approved GH for the following pediatric conditions associated with short stature: –GH deficiency (defined as on the basis of the provocative tests) –Turner Syndrome –Chronic renal insufficiency –SGA or IUGR infants that fail to demonstrate catch-up growth –Prader-Willi Syndrome –Idiopathic short stature (<2.5 SD below the mean and not expected to meet a normal adult height)

56. Cancer and GH Therapy No definitive link between GH therapy and an increased incidence of leukemia. Currently GH therapy is not recommended in patients with an active malignant condition.

57. Endocrine Abnormalities in 11q- Syndrome 9 children with Jacobsen (11q-) were studied in San Diego with the following findings: 8/9 had short stature (ht<5th%) Six with >-2SD One had IUGR Four had low IGF-1 levels 4/9 males had cryptorchidism (failure of testes to descend).

58. Endocrine Abnormalities in 11q- Syndrome Case Reports suggest an association of 11q deletions or translocations with short stature. 6 publications with 5 single case reports plus the small series from San Diego of 8 affected patients One publication of central GH and TH deficiencies. Studies suggest that genetic information encoded in 11q is important for normal growth. Insufficient data is available to suggest a mechanism for growth failure in these children.

59. Take-away Messages Growth Velocity correlates with good health Abnormal growth velocity merits evaluation A good history and exam are often diagnostic Laboratory and Imaging studies may be helpful Timing is everything

60. Resources For Patients & Families MAGIC Foundation: www.magicfoundation.org www.magicfoundation.org Human Growth Foundation: www.hgfound.org