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Primary and Secondary Insensitivity to Growth Hormone in Short Children
Otto Mehls
University Hospital for Childen and Adolescents
Devision of Pediatric Nephrology
Heidelberg, Germany
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Reasons for Short Stature : Insulin-like Growth Factor Deficiency
Hypothalamic dysfunction
Pituitary GHD
GH insensitivity A. Primary GH insensitivity
1. GH receptor defect
B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease like chronic kidney disease
(CKD)
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Growth Hormone Receptor
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GH action on liver and extrahepatic tissue
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Molecular defects resulting in severe primary IGF deficiency
after Rosenfeld 2009
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Severe Primary IGF Deficiency
I. GHR abnormalities1. Mutations/deletions of the GHR affecting the extracellular domain of
the GHR and resulting in decreased GH binding
2. Mutations/deletions of the GHR affecting the ability of the GHR to dimerize
3. Mutations/deletions of the GHR affecting the transmembrane domain of the receptor and resulting in defective anchoring in the cell membrane
4. Mutations/deletions of the GHR affecting the intracellular domain and signaling
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Molecular defects resulting in severe primary IGF deficiency
after Rosenfeld 2009
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Severe Primary IGF DeficiencyContinuation
II. Post-GHR signaling defects1. Mutations of STAT5b resulting in defective or absent GH signal
transduction
III. Mutations/deletions of IGF-I1. Deletions of IGF-I
2. Mutations of the IGF-I resulting in bioinactive IGF-I
IV. Defects of IGF transport and/or clearance1. Mutations/deletions of –ALSIGF, resulting in defective IGF transport
and rapid IGF clearance
V. IGF resistance1. Mutations of the IGF1R, resulting in decreased sensitivity to IGF-I
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Secondary GH insensitivity/resistance
Example : Chronic renal failure
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Effect of Forced Feeding in Infants on PD Heidelberg Experience
27 infants, age < 2 years. 22 NG tube, 5 PEGMean energy intake 100 % RDA, protein intake 125 % RDA
BMI SDS
Months on Tube Feeding
0 3 6 9 12 15 18 21 24
SD
S
-3
-2
-1
0
Height SDS
0 3 6 9 12 15 18 21 24
SD
S
-3
-2
-1
0
Initial BMI > -2 SDS
Initial BMI < -2 SDS
Months on Tube Feeding
Initial BMI > -2 SDS
Initial BMI < -2 SDS
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Effect of Gastrostomy Feeding in ESRD ChildrenNottingham Experience
Treatment: 20 PD, 2 HD patients
Age at gastrostomy: 2.3 (0.2-10.3) years
Observation period: 14.5 (2.5 - 56) months
Mean Energy Intake: 115 % RDA (98-155%)S
DS
Coleman et al. NDT 1998
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Resistance to GH/IGF in CKD• Serum concentration of GH increased, metabolic
clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994
• GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77
• GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997
• Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001
• IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991
• IGF activity decreased by binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990
• Endorgan (postreceptor) resistance to GH and IGF-I
Mak and Pak, Kidney Int 50, 40-6, 1996
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Resistance to GH/IGF in CKD• Serum concentration of GH increased, metabolic
clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994
• GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77
• GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997
• Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001
• IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991
• IGF activity decreased by excess of binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990
• Endorgan (postreceptor) resistance to GH and IGF-I
Mak and Pak, Kidney Int 50, 40-6, 1996
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Derangements of Somatotropic Hormone Axis in CRF
Post-R Defect
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Improvement of response to GH following dayly hemodialysis
Fischbach et al ,Ped Neph 2006Fischbach et al, Pediatr Nephrol 2006
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• General clinical problem: Some short patients respond better to GH treatment than others.
• Why ? What is the reason ?
• Prediction possible ?
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First year response to daily growth hormone treatment in males with IGHD Bakker et al JCEM 93,352, 2008
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Prediction of Growth Hormone (GH)-Response
in Short Children with CKD
O. Mehls, A. Lindberg, R. Nissel, D. Haffner, A. Hokken-Koelega, M. B. Ranke
Submitted to JCEM
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Design
Data from 208 prepubertal children on conservative treatment or dialysis from a large pharmaco-epidemiological survey (KIGS)
Independent control Data from 67 similar CKD patients registered at the Dutch Growth Research Foundation
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Statistical Analysis
Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program.
Variation of response to GH was expressed in terms of Studentized residuals.
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Regression equation variables used for prediction
Parameterestimate
Rank Partial R2 Variablesignificance
Intercept (constant)
13.3
Age at start (years)
-0.38 1 0.203 < 0.001
Weight SDS at start
0.39 2 0.062 < 0.001
Hereditary renal disorder
-1.16 3 0.039 0.0008
GFR (ml/min x 1.73 m²)
0.023 4 0.039 0.0005
Log dose GH (mg/kg per week)
1.04 5 0.022 0.0090
Cumulative R² 0.37
Error SD (cm) 1.6
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Studentized Residuals
Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV
= index of responsiveness
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Individual Prediction
●
o
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Identification of Non-Responders
Dutch non responders= Dutch patients
with HV SDS < 0.0
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Summary
• Primary resistance to GH resulting in very low or defective IGF1 is explained by various molecular defects of the GH receptor and along its signaling pathway
• Secondary resistance to GH is due to functional, reversible defects of the GH-IGF axis
• Low , normal or high response to GH treatment can be seen from Bakker charts or predicted using KIGS prediction models.
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Reasons for Short Stature : Insulin-like Growth Factor Deficiency
Hypothalamic dysfunction Pituitary GHD GH insensitivity
A. Primary GH insensitivity 1. GH receptor defect
B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease
Primary defects of IGF synthesis Primary defects of IGF transport/clearance IGF resistance
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Studentized Residuals vs. predicted height velocity
KIGS Dutch Controls
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Growth Response to GH ( Height SDS) 1st YearAccording to Primary Renal Disease
Prepubertal Patients
H
eigh
t S
DS
1st
yea
r
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Growth Response to GH ( Height SDS) 0-2yearsAccording to Primary Renal Disease
Prepubertal Patients
Hei
ght
SD
S 2
yea
rs
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Short stature in children with CKD:-Variable diagnosis -Varable renal function-Variable response to GH
Aim: -Prediction of individual growth response and identify non-responders
Clinical problem
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rGH Treatment Efficacy in Prepubertal Children with CRIGerman GH in CRI Study Group
Haffner et al. J Am Soc Nephrol 1998
74 CRI, 29 dialysis patients from 27 centers, observation up to 5 years
DialysisDialysis
CRICRI
Years of Observation
Hei
ght
SD
S
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Schaefer et al. Pediatr Nephrol 1996; 10:288–93
Impact of Renal Function on Prepubertal Growth320 children with congenital CKD
Hei
gh
t (c
m)
404 100
Age (years)
150
90
100
110120
130
140
80
70
60
6 82
9075502510
50
Moderate CRFGFR > 25 ml/min/1.73 m2
404 100
Age (years)
150
90
100
110120
130
140
80
70
60
6 82
9075502510
50
Severe CRFGFR < 25 ml/min/1.73 m2
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First year response to dayly growth hormone treatment according to primary disease
Bakker et al JCEM 93,352, 2008
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Growth of uremic rats is impaired by reduced food intake and uremia ,
but reduced food intake might only be associated with poor growth
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Growth of uremic rats is impaired by reduced food intake and uremia,
but reduced food intake might only be associated with poor growth
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Studentized Residuals
Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV = index of responsiveness Patients with an observed height velocity (HV) of < 0.0 height velocity SDS were excluded to allowidentification of non-responders by the model.
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Statistical Analysis
Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program.
The hierarchy of predicting factors was derived by the all-possible regression approach as described for other prediction models.
Differences were expressed in terms of Studentized residuals.