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2. Short Stature: The Long and Short of It Diagnosis, Etiology, and Treatment Jay Cohen, MD, FACE, FAAP, CEC Medical Director Endocrine Clinic Memphis, TN

3. Activity Evaluation In order to obtain credit for this activity, please listen to the entire presentation on the CD ROM provided in your invitational materials then register for one of the live Q&A/discussion webinars and complete the evaluation form on the program website (www.plexuscomm.com/shortstature), or log onto www.igfdforum.com to take the online evaluation.www.plexuscomm.com/shortstaturewww.igfdforum.com

4. Disclaimer The comments and opinions expressed herein are those of the faculty and are in no way to be considered the comments or opinions of MER, PleXUS Communications, or Tercica, Inc. Any disclosures regarding significant relationships are provided in the following 2 slides. The products discussed in this program may not be specified to be used as indicated by this presentation. Before prescribing any medication, review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse effects.

5. Faculty Disclosures In compliance with the standards for Commercial Support of Continuing Medical Education and the ACCME guidelines, it is our policy to inform participants of any relationships the faculty has with the companies whose products or services may be mentioned in their presentations, so participants may evaluate the objectivity of the presentations. The faculty reports the following relationships:

6. Faculty Disclosure: Jay Cohen, MD, FACE, FAAP, CEC Dr. Cohen has made the following disclosures: Speakers Bureau, Grants/Research Support: – Pfizer, Genentech, Eli Lilly, Tercica Inc. Medical Education Resources, Inc. requires that the learners in all of its certified activities are informed if there is any discussion regarding off-label use of a product. Dr. Cohen has disclosed there will be discussion about the use of products for non-FDA approved or investigational use. Name: Jay Cohen, MD Date: 07/04/2007

7. Educational Objectives At the end of this educational activity, participants should be able to: 1.Describe the criteria for the definition of short stature 2.Discuss the conditions that constitute idiopathic short stature (ISS) 3.Outline the methodology for determining the presence of short stature in a young child 4.Review the treatment options for short stature and when they should be used

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10. Short Stature: The Long and Short of It Diagnosis, Etiology, and Treatment Jay Cohen, MD, FACE, FAAP, CEC Medical Director Endocrine Clinic Memphis, TN

11. Short Stature Normal variants –Familial short stature* –Constitutional delay* Pathological –Primary growth abnormalities –Secondary growth disorders –Idiopathic short stature *Diagnosis of exclusion Larson P, Williams Textbook of Endocrinology, 10 th ed. 2003.

12. Primary Growth Abnormalities Osteochondrodysplasias or skeletal dysplasia (eg, osteogenesis imperfecta) Chromosomal abnormalities –Turner syndrome –Prader-Willi syndrome –Noonan syndrome –Trisomy 13,18, 21 (eg, Down syndrome) Intrauterine growth abnormalities –Small for gestational age (SGA) Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

13. Secondary Growth Abnormalities Malnutrition/nutritional insufficiency –Food allergies –Inadequate nutritional intake Emotional deprivation –Psychosocial dwarfism Chronic neglect Starvation Chronic or systemic disease Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

14. Secondary Growth Abnormalities: Systemic Conditions Hematological - anemia Cardiovascular - cardiac failure, shunting Pulmonary –Cystic fibrosis (CF), asthma, chronic corticosteroids usage (prednisone), chronic obstructive pulmonary disease (COPD), restrictive lung disease Gastrointestinal –Malabsorption, inflammatory bowel disease (IBD), celiac disease, reflux Kidney –Renal tubular acidosis (RTA), chronic renal failure, occult renal disease Liver - chronic active hepatitis Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

15. Secondary Growth Abnormalities: Endocrine Disorders Hypothyroidism/hyperthyroidism Cushing’s syndrome Pseudohypoparathyroidism Rickets (Vitamin D – rickets resistant) Chronic hypernatremia (hypothalamic adipsia, diabetes insipidus) Glucocorticoid imbalances (hypercortisolism) Poorly controlled diabetes (diabetes mellitus) IGF deficiency –Growth hormone deficiency (GHD) – hypothalamic dysfunction, pituitary GDH –GH resistance (primary vs secondary GH insensitivity) –Primary defects of IGF synthesis –Primary defects of IGF transport and clearance –IGF insensitivity (IGF-1 receptor defects vs post-receptor defects) Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

16. Idiopathic Short Stature Diagnosis of exclusion Normal size at birth Significantly below average height for age & gender –>2 standard deviations below average height –Corresponds to the shortest 2.3% of children Tempo of growth may be slow or normal Short stature of unknown origin (idiopathic) –No evidence of other medical problems, such as: Systemic disease Malnutrition Hypothyroidism Growth hormone deficiency (GHD) Ranke M. Horm Res. 1996;45:64-66.

17. Short Stature: Variations of Normal Familial (genetic) short stature –Short, but appropriate for parental height Parallels normal growth rate curves –Bone age corresponds with chronologic age –Normal onset of puberty Constitutional growth delay (“late bloomers”) –Parents of average/tall height –Normal (but short) growth rate, including body proportions –Family history of “late bloomers” At least one parent had delayed puberty –Delayed bone age and sexual maturation Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

18. Growth Curves: Measurement is Key Growth curves help distinguish normal growth from pathologic variants of short stature Below average height and weight but parallels normal curve –eg, familial short stature and constitutional growth delay Lifshitz F. Pediatric Endocrinology; 5 th ed. 2006. X X X X X X X X X X X X X X X X X X Pathological Constitutional Familial 5% 50% 95% 24681012141618 80 90 100 110 120 130 140 150 160 170 180 190 Age (years) Stature (cm)

19. Growth Curves: Points of Interest Reliability of measurement Target height or “genetic potential” Bone age –Skeletal age relative to chronologic age Upper/lower (U/L) body ratio and some chromosomal abnormalities –Abnormal in skeletal dysplasias Height velocity Weight to height relationship –Endocrine disorders: weight percentile is greater than height percentile (eg, hypothyroidism, growth hormone deficiency) –Systemic disorders: usually lose weight first and are thin by the time they are short Farber R, Kerrigan J. Pediatric Annals. 2006;35(12):926-932.

20. What’s Normal and When to Worry Short and dysmorphic (abnormal U/L body ratio) –Skeletal dysplasias Increased U/L = long bone; Decreased U/L = spine –Short stature syndromes (eg, Turner, Down, Prader- Willi) Short and thin –Usually systemic disease Short with greater than normal weight percentile –Usually an endocrine disorder (GH, thyroid, cortisol) Proportionate with greater than normal weight percentile –Congenital growth hormone deficiency (GHD), acquired GHD (tumors, trauma, post-infectious), hypothyroidism, Cushing syndrome

21. Evaluating a Child with Short Stature Short Stature Normal Variants Familial short stature Constitutional delay Pathologic Proportionate Disproportionate Skeletal dysplasia Rickets Chromosomal abnormalities Prenatal IUGR Placental disease Infections Teratogens Dysmorphic syndromes Chromosomal disorders Postnatal Endocrine disorders Psychosocial dwarfism Malnutrition Gastrointestinal diseases Cardiopulmonary diseases Chronic anemia Renal disorders IUGR, Intrauterine growth retardation. Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

22. Clinical Evaluation for Short Stature Detailed history and physical (from head to toe) Including but not limited to: –Date of onset –Perinatal birth history –Medical/surgical history –Developmental history –Nutritional history –Family/social history –Parental heights and pubertal history –Onset of puberty –Allergies –Sitting height –Limb length –Hypospadius –Absence of goiter –Cleft lip/palate; abnormal palate/teeth –Shortened 4 th metacarpal

23. Clinical Evaluation for Short Stature (cont.) Height velocity –Growth chart that depicts the child's growth over time –Allows comparison of the height or weight to other children and graphically depicts changes in growth or growth velocity Bone age determination –Left hand and wrist radiograph to estimate skeletal maturation

24. Clinical Evaluation for Short Stature (cont.) Respiratory system –Chest deformities, chronic lung disease (eg, CF, asthma) Cardiovascular system –Congenital heart disease, hypertension, cardiac failure Abdominal evaluation –Hepatomegaly, splenomegaly, masses, ascites Renal system –Urine output Central nervous system –Visual acuity/visual fields, hydrocephalus, focal signs

25. Clinical Diagnosis of Short Stature: Laboratory Testing Urinalysis and pH Thyroxine (Free T4 and TSH) –Hypothyroidism should be excluded Comprehensive metabolic profile (CMP) –Low bicarbonate level may indicate renal tubular acidosis –Abnormal electrolytes (Ca, K) may indicate renal failure, liver function tests CBC and sedimentation rate (anemia, leukopenia, etc.) –May be helpful if inflammatory bowel disease is suspected IGF-1 and IGFBP-3 –Both IGF-1 and IGFBP-3 are GH-dependent –Low values of IGF-1 and IGFBP-3 suggest GHD –IGFs are sensitive to other factors such as nutritional state and chronic systemic disease so a low value alone is not diagnostic

26. Consideration of Additional Laboratory Testing Prolactin Chromosome analysis FSH/LH levels Celiac panel Total IgA

27. Growth Hormone Pathway Hypothalamus Anterior pituitary Liver Adipose Tissue (lipolysis) Most Tissues  glucose utilization  blood glucose Cartilage & bone growth Muscle & other organs: Protein synthesis & growth Somatostatin – GHRH + GH (GH levels and effects are most pronounced during puberty) IGF-1 Somatostatin

28. Growth Hormone Deficiency (GHD) Inadequate secretion of growth hormone May result from disruption of the GH axis in the higher brain, hypothalamus, or pituitary Most instances of GHD are idiopathic Organic –Congenital malformations of hypothalamus and pituitary –Brain tumors, especially craniopharyngioma –CNS surgery, head trauma and radiation –Chronic inflammation Genetic GHD

29. GHBP IGF-I IGFBP-3 GROWTH Growth plate Liver GH receptor ALS Hypothalamus Pituitary GH Other IGFBPs GHRH Signal Transduction Type I IGF receptor ALS, acid-labile subunit. GH-IGF Axis

30. GHBP IGF-I IGFBP-3 GROWTH Growth plate Liver GH receptor ALS Hypothalamus Pituitary GH Other IGFBPs GHRH Signal Transduction Type I IGF receptor ALS, acid-labile subunit. GH-IGF Axis: GH Deficiency

31. Image obtained online and available at: www.schoolscience.co.uk. Accessed 07-17-07.www.schoolscience.co.uk GHD subject is 18 cm shorter than her sister, despite being one and a half years older What GHD Looks Like

32. Prevalence of GHD According to Utah Growth Study, 2.5% of the population is short –Largest population-based survey of growth in children –Assessed height & growth velocity in ~115,000 American children –Among 555 children with short stature (height below the third percentile) and poor growth rate (growth velocity <5 cm annually), only 5% had an endocrine disorder –48% of children with GHD or Turner syndrome (TS) had been undiagnosed or untreated An endocrine disorder (eg, GHD) is often suspected as the major cause of short stature –This study confirms that most (95%) children with poor growth (velocity <5 cm/y) do not have an endocrine disorder Lindsay R, et al. J Pediatr. Jul 1994;125(1):29-35.

33. Growth Hormone Therapy Generally, highly effective in children with unequivocal GH deficiency Responsiveness to GH in most other approved indications is highly variable and not always predictable Thus, GH therapy has clear utility but also has limitations

34. New Treatment Perspectives on ISS Despite efficacy data, a considerable amount of variability in response to GH remains, even within the same diagnostic category, such as GHD Some children with ISS have shown little or no benefit of therapy suggesting that GH therapy is suboptimal in some patients A range of growth response to GH therapy exists including GH responsiveness, GH unresponsiveness, GH insensitivity Current data suggests that up to 25-50% of children with ISS may have primary IGF-1 deficiency (based on normal GH secretion and low IGF-1 levels) Rosenthal S, et al. Pediatr Endocrinol Rev. May 2007;4(Suppl. 2):S252-S271.

35. What Is a Poor Response to GH? Height velocity data for 8442 males with IGHD during first year in NCGS Rosenfeld R, et al. Growth Hormone Research Society/IGF Society Meeting. 2006. 24 22 20 18 16 14 12 10 8 6 4 2 0 Height Velocity (cm/yr) 23 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Age at Baseline Mean HV + 1 SD Mean HV Mean HV – 1 SD

36. What Is a Poor Response to GH? (cont.) Height velocity data for females with IGHD, including mean -2 SD and mean pre-treatment height velocity Rosenfeld R, et al. Growth Hormone Research Society/IGF Society Meeting. 2006. 16 14 12 10 8 6 4 2 0 Height Velocity (cm/yr) 23 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Age at Baseline Mean HV + 1 SD Mean HV Mean HV – 1 SD Mean HV – 2 SD Mean Pretreatment HV

37. Insulin-like Growth Factor-1 (IGF-1) IGF-1 is normally secreted in response to stimulation by growth hormone IGF-1 stimulates multiple processes leading to growth including glucose uptake glycogen and protein synthesis amino acid transport Adopted from Felix F. Vajdos, et al. 2001.

38. Role of IGF-1 Growth hormone - a naturally occurring hormone –One of its major functions, among other actions, is to promote production of IGF-1 IGF-1 is normally secreted in response to stimulation by growth hormone IGF-1 is usually necessary for normal growth and metabolism, and stimulates multiple processes including: –Glucose uptake –Glycogen and protein synthesis –Amino acid transport Deficiency of, or resistance to, growth hormone can cause IGFD, which can lead to short stature in children

39. IGF-I Measurements in the Diagnosis of Short Stature Significance of basal IGF-I measurements in the diagnostics of short stature in children 95 th 50 th 5 th 95 th 50 th 5 th Ranke M, et al. J Clin Endocrinol Metab. 2000;85:4212-4218. 600 500 400 300 200 100 0 IGF-I (µg/L) 05101520 Age (Years) 600 500 400 300 200 100 0 IGF-I (µg/L) 05101520 Age (Years) GHD (Percentile) Non-GHD (Percentile) Virtually all GHD are secondary IGFD 50% of the non-GHD are also Primary IGFD

40. Measuring IGF-1 and IGF-BP3 Levels to Assess for GHD Farber R, Kerrigan J. Pediatric Annals. 2006;35(12):926-932. IGF-I and IGFBP-3 more than 2 standard deviations below the mean for age and gender strongly suggest GH insufficiency Low IGF-1: GHD or GH resistant GH levels are measured If GH levels are high, GH resistance is likely However, low levels of GH may not distinguish GHD from GH resistance –Under these circumstances, provocative (stimulation) tests of growth hormone secretion may be indicated

41. Growth Hormone Provocative (Stimulation) Testing A number of provocative agents can be used to test for GHD including arginine, clonidine, glucagon, insulin, and L-dopa GH response to insulin is the most reliable test for GHD –Great care should be exercised in using insulin or glucagon in young children Before accepting a GHD diagnosis, many insurance companies require a documented failure to demonstrate a GH response after presentation of 2 provocative stimuli However, provocative testing often has limitations: –Poor assay standardization among laboratories –Results may conflict with other growth data –No bimodal distribution of response GH Research Society. J Clin Endocrinol Metabol. 2000;85(11):3990-3993; Owens G. Am J Manag Care. 2000;6(15 Suppl):S839–S852.

42. Magnetic Resonance Imaging (MRI) of the Brain and Pituitary Gland Scott R, Hedley-Whyte E. N Eng J Med. 2002;347(20):1604-1611. Cranial imaging may be appropriate in patients found to be GHD and –IGF-1 levels are low or –IGFBP-3 levels and GH stimulation tests are low Rule out brain tumor (eg, craniopharyngioma) or other etiologies Approximately 15% of patients with GHD have an abnormality of the pituitary gland (eg, ectopic bright spot, empty or small sella)

43. Growth Axis: The Primary Pathway Growth Hormone Receptor Activation IGF-1 Gene Expression Growth Post-Receptor GH Signaling Growth Hormone Secretion Endocrine IGF-1 IGF-1 Secretion

44. Short Stature Due to Primary IGF-1 Deficiency Growth Hormone Secretion Growth Hormone Receptor IGF-1 Gene Expression Post-Receptor GH Signaling IGF-1 Deficiency Primary IGFD GHD (Secondary IGFD) Short Stature

45. Insulin-like Growth Factor-1 (IGF-1) Deficiency Primary Insulin-like Growth Factor-1 Deficiency (IGFD) refers to IGFD caused by resistance to growth hormone Short stature due to Primary IGFD – Height standard deviation score ≤–2.0 and – Basal IGF-1 standard deviation score ≤–2.0 and – Normal or elevated growth hormone Resistant to the effects of growth hormone Restoring IGF-1 levels to normal may be an appropriate treatment option

46. IGF-1 Deficiency: Short Stature but Normal Growth Rate Hwa V, et al. J Clin Endocrinol Metab. 2005;90:4260-4266. x x x x x x x x x x x x x Untreated severe Primary IGFD Height (cm, in)

47. Distribution of First Year Change in Height Median first year changes in height were +0.77 SDS in IGHD and +0.60 SDS in non-GHD ISS patients 24% of IGHD patients and 13% of ISS patients had a first-year change in height SDS between year 1 and 2 Rosenthal S, et al. Pediatr Endocrinol Rev. May 2007;4(Suppl. 2):S252-S271. Pre-pubetal IGHD & ISS Patients IGHD ISS Year 1 change in height SDS Percent of patients 0 1 2 3

48. W: Wild-type (100% of normal body weight) G: GHR KO (52% of normal body weight) I: IGF-I KO (30% of normal body weight) D: IGF-I & GHR KO (17% of normal body weight) Synergistic Effect of Growth Hormone and IGF-1 in Mouse Postnatal Growth GHR, growth hormone receptor; KO, knock-out. Lupu F, et al. Dev Biol. 2001;229(1):141-162. 35 % 34 % 17 % 14 % Non GH or IGF GH KO alone IGF-I KO GH + IGF-I KO 69 %

49. Short Stature Height <-3 SD-3< Height <-2.25 SDHeight >-2.25 SD Reassess in 6-12 months, as indicated GHST GH <10 ng/mL GHD MRI, molecular studies GH Rx GH >10 ng/mL ISS Consider GH Rx Consider no Rx GHST GH <10 ng/mL GHD MRI, molecular studies GH Rx GH >10 ng/mL IGF-I >-3SD ISS Consider GH Rx IGF-I <-3 SD Primary IGFD Consider molecular studies Consider IGF-I Rx Consider GH Rx Consider No Rx Treatment Algorithm: Severe Primary IGFD (Height <-3 SDS) Rosenthal S, et al. Pediatr Endocrinol Rev. May 2007;4(Suppl. 2):S252-S271.

50. Short Stature Poor linear growth Delayed puberty Absence of family history Height <–2.25 SDHeight >–2.25 SD Reassess in 6-12 months, as indicated GHST GH <10 ng/mL GHD MRI, molecular studies GH Rx Consider GH Rx Consider no Rx IGF-I < – 2.5 SD Primary IGFD Consider molecular studies Consider IGF–I Rx Consider GH Rx Consider No Rx Treatment Algorithm: Primary IGFD GH >10 ng/mL ISS

51. Mecasermin: Recombinant-human Insulin-like Growth Factor-1 FDA-approved for long-term treatment for growth failure in children with severe primary IGF-1 deficiency or GH gene deletions who have developed neutralizing antibodies Patients undergoing at least one year of mecasermin treatment demonstrated statistically significant improvements in growth Increlex™ Prescribing Information (Mecasermin, Tercica, N=71).

52. Mecasermin Improves Height In clinical trials, height velocity increased the first year, on average to 8.0 cm/year from a baseline of 2.8 cm/year (P<0.0001) In Years 2 through 6, height velocity was sustained at approximately 5 cm/year (P<0.005) Increlex™ Prescribing Information (Mecasermin, Tercica, N=71).

53. Important Considerations with Mecasermin Therapy Mecasermin is not a substitute for GH treatment Primary IGFD patients cannot be expected to respond adequately to exogenous GH treatment Mecasermin should not be used for growth promotion in patients with –closed epiphyses –active or suspected neoplasia –allergies to mecasermin (IGF-1) Increlex™ Prescribing Information (Mecasermin, Tercica, N=71).

54. Adverse Events with Mecasermin Treatment Hypoglycemia –Highest frequency occurred in the first month of treatment and is more frequent in younger children Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years Intracranial hypertension occurred in 3 subjects –Events resolved without interruption of treatment in 2 patients and the other patient discontinued and resumed later at a lower dose without recurrence Lipohypertrophy at injection sites noted in 24 subjects (32%) –Resolved when injections were properly rotated Increlex™ Prescribing Information (Mecasermin, Tercica, N=71).

55. Short Stature: Summary Short stature can be promptly recognized with accurate measurements of growth and critical analysis of growth data Appropriate evaluation for poor growth and endocrine consultation are crucial prior to electing therapy An individualized approach to children with short stature should be practiced, taking into consideration factors such as psychosocial concerns and must exclude alternative etiologies of poor growth prior to consideration of therapy Recent advances in the field have resulted in several successful treatment options, including GH and mecaserim

56. Appendix Supplemental Slides

57. Helpful Hints with Reimbursement: GH Stimulation Test Coding Sheet 99211 Limited office visit 99354 Prolonged attendance, 1 st hour (face-to face) 99355 Prolonged attendance each additional 30 minutes physician (face-to face) x 4 –Bill this code 4 times 99358 Prolonged attendance, 1 st hour physician not face-to-face (then 99359) –Use this instead of 99354, 99355 if no MD present 36415 Venipuncture 32912 Injection, sodium chloride 31820 Injection, insulin up to 100 units Cohen, J. Personal communication.

58. Helpful Hints with Reimbursement: GH Stimulation Test Coding Sheet 33490 Arginine 80428 Growth hormone stimulation panel –Growth hormone – 83003 x 4 80435 Growth hormone deficiency panel –Glucose – 82947 x 5; growth hormone – 83003 x 5 80434 Insulin tolerance panel –Cortisol – 82533 x 5; glucose – 82947 x 5 82533 Cortisol – each additional 82948 Glucometer – each additional 83003 Growth hormone – each additional Cohen, J. Personal communication.

59. Unique Educational Opportunity!!! Join your colleagues in a live Q&A/Discussion with a leading pediatric endocrinology expert Share your challenging cases Discuss current treatment strategies Register Online Today at www.plexuscomm.com/shortstature www.plexuscomm.com/shortstature

60. Thank You Please log onto www.plexuscomm.com/shortstature in order to complete the activity evaluation, or go to www.igfdforum.com to take the online evaluation. www.igfdforum.com Certificates will be mailed within 4 weeks of successfully completing the activity evaluation. If you have any questions, please contact shortstature@plexuscomm.com.

61. Thank You!!! Jay Cohen, MD, FACE, FAAP, CEC