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Short Stature: The Long and Short of It

Diagnosis, Etiology, and Treatment

Jay Cohen, MD, FACE, FAAP, CECMedical Director

Endocrine Clinic

Memphis, TN

Activity Evaluation

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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.

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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:

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

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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This activity is supported through an unrestricted educational grant provided by Tercica, Inc.

Short Stature: The Long and Short of It

Diagnosis, Etiology, and Treatment

Jay Cohen, MD, FACE, FAAP, CECMedical Director

Endocrine Clinic

Memphis, TN

Short Stature

• Normal variants– Familial short stature*– Constitutional delay*

• Pathological – Primary growth abnormalities– Secondary growth disorders– Idiopathic short stature

*Diagnosis of exclusionLarson P, Williams Textbook of Endocrinology, 10th ed. 2003.

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.

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.

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 hepatitisLarson P, Williams Textbook of Endocrinology, 10th ed. 2003.

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.

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.

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.

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; 5th ed. 2006.

X

X

X

X

X

X

X

X

X

X

X

XX

XX

X

X X

Pathological

Constitutional

Familial

5%

50%

95%

2 4 6 8 10 12 14 16 1880

90

100

110

120

130

140

150

160

170

180

190

Age (years)

Sta

ture

(cm

)

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.

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

Evaluating a Child with Short Stature

Short Stature

Normal VariantsFamilial short statureConstitutional delay

Pathologic

Proportionate DisproportionateSkeletal dysplasiaRicketsChromosomal abnormalities

PrenatalIUGR

Placental diseaseInfectionsTeratogens

Dysmorphic syndromesChromosomal disorders

PostnatalEndocrine disordersPsychosocial dwarfismMalnutritionGastrointestinal diseasesCardiopulmonary diseasesChronic anemiaRenal disorders

IUGR, Intrauterine growth retardation.Larson P, Williams Textbook of Endocrinology, 10th ed. 2003.

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 4th metacarpal

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

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

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

Consideration of Additional Laboratory Testing• Prolactin

• Chromosome analysis

• FSH/LH levels

• Celiac panel

• Total IgA

Growth Hormone Pathway

Hypothalamus

Anterior pituitary

Liver Adipose Tissue (lipolysis)Most Tissues glucose utilization blood glucoseCartilage & bone growth

Muscle & other organs:• Protein synthesis & growth

Somatostatin – GHRH +

GH (GH levels and effects aremost pronounced during puberty)

IGF-1Somatostatin

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

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

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

Image obtained online and available at: www.schoolscience.co.uk. Accessed 07-17-07.

• GHD subject is 18 cm shorter than her sister, despite being one and a half years older

What GHD Looks Like

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.

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

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.

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.

2422201816141210

86420

Hei

gh

t V

elo

city

(cm

/yr)

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Age at Baseline

Mean HV + 1 SDMean HV

Mean HV – 1 SD

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

Hei

gh

t V

elo

city

(cm

/yr)

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Age at Baseline

Mean HV + 1 SD

Mean HV

Mean HV – 1 SD

Mean HV – 2 SDMean Pretreatment HV

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.

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

IGF-I Measurements in the Diagnosis of Short Stature

Significance of basal IGF-I measurements in the diagnostics of

short stature in children

95th

50th

5th

95th

50th

5th

Ranke M, et al. J Clin Endocrinol Metab. 2000;85:4212-4218.

600

500

400

300

200

100

0

IGF

-I (

µg

/L)

0 5 10 15 20Age (Years)

600

500

400

300

200

100

0

IGF

-I (

µg

/L)

0 5 10 15 20Age (Years)

GHD(Percentile)

Non-GHD(Percentile)

• Virtually all GHD are secondary IGFD• 50% of the non-GHD are also Primary IGFD

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

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.

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)

Growth Axis:The Primary Pathway

Growth HormoneReceptor Activation

IGF-1 GeneExpression

Growth

Post-ReceptorGH Signaling

Growth HormoneSecretion

Endocrine IGF-1

IGF-1 Secretion

Short Stature Due to Primary IGF-1 Deficiency

Growth HormoneSecretion

Growth HormoneReceptor

IGF-1 GeneExpression

Post-ReceptorGH Signaling

IGF-1 Deficiency

PrimaryIGFD

GHD(Secondary

IGFD)

Short Stature

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

IGF-1 Deficiency: Short Stature but Normal Growth Rate

Hwa V, et al. J Clin Endocrinol Metab. 2005;90:4260-4266.

xx

x xx

x xx x x

xx x Untreated severe

Primary IGFD

Hei

gh

t (c

m,

in)

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

IGHDISS

Year 1 change in height SDS

Per

cen

t o

f p

atie

nts

-1 0 1 2 3

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 IGFGH KO aloneIGF-I KOGH + IGF-I KO

69 %

Short Stature

Height <-3 SD -3< Height <-2.25 SD Height >-2.25 SD

Reassess in 6-12months, as indicatedGHST

GH <10 ng/mLGHD

MRI, molecular studiesGH Rx

GH >10 ng/mLISS

Consider GH Rx

Consider no Rx

GHST

GH <10 ng/mLGHD

MRI, molecular studiesGH Rx

GH >10 ng/mL

IGF-I >-3SDISS

Consider GH Rx

IGF-I <-3 SDPrimary 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.

Short StaturePoor linear growthDelayed puberty

Absence of family history

Height <–2.25 SD Height >–2.25 SD

Reassess in 6-12months, as indicated

GHST

GH <10 ng/mLGHD

MRI, molecular studiesGH Rx

Consider GH Rx

Consider no Rx

IGF-I <–2.5 SDPrimary IGFD

Consider molecular studies

Consider IGF–I Rx

Consider GH Rx

Consider No Rx

Treatment Algorithm: Primary IGFD

GH >10 ng/mLISS

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).

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).

Important Considerationswith 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).

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).

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

Appendix

Supplemental Slides

Helpful Hints with Reimbursement:GH Stimulation Test Coding Sheet

• 99211 Limited office visit• 99354 Prolonged attendance, 1st 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, 1st 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.

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.

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

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.

Certificates will be mailed within 4 weeks of successfully completing the activity evaluation. If you have any questions, please contact shortstature@plexuscomm.com.

Thank You!!!

Jay Cohen, MD, FACE, FAAP, CEC