Accreditation Statements Physician Accreditation - This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medical Education Resources and PleXUS Communications. Medical Education Resources is accredited by the ACCME to provide continuing medical education for physicians. - Medical Education Resources designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nursing Accreditation - Medical Education Resources is an approved provider of continuing nursing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. - This CE activity provides 1.0 contact hours. Provider approval expires July 31, 2010. - Provider approved by the California Board of Registered Nursing, Provider #CEP 12299, for 1.0 contact hours. Pharmacy Accreditation - Medical Education Resources (MER) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. MER designates this continuing education activity for 1.0 contact hours (0.1 CEUs) of the Accreditation Council for Pharmacy Education. - Universal Program Number: # 816-999-07-046-H01-P - Statements of credit will be mailed within four weeks of receipt of appropriate documentation of course completion. There is no fee to participate in this activity. - Release Date: 9/24/07 - Expires: 11/31/07
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Accreditation Statements
Physician Accreditation- This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for
Continuing Medical Education through the joint sponsorship of Medical Education Resources and PleXUS Communications. Medical Education Resources is accredited by the ACCME to provide continuing medical education for physicians.
- Medical Education Resources designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Nursing Accreditation- Medical Education Resources is an approved provider of continuing nursing education by the Colorado Nurses Association, an
accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. - This CE activity provides 1.0 contact hours. Provider approval expires July 31, 2010.- Provider approved by the California Board of Registered Nursing, Provider #CEP 12299, for 1.0 contact hours.
Pharmacy Accreditation- Medical Education Resources (MER) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing
pharmacy education. MER designates this continuing education activity for 1.0 contact hours (0.1 CEUs) of the Accreditation Council for Pharmacy Education.
- Universal Program Number: # 816-999-07-046-H01-P- Statements of credit will be mailed within four weeks of receipt of appropriate documentation of course completion. There is no fee to
participate in this activity.
- Release Date: 9/24/07- Expires: 11/31/07
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
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.
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.
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:
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
– 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)
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
• 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
• 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.
• 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)
(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.
• 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
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 [email protected].