Le Recours au Pédiatre-Endocrinologue

Pierre CHATELAIN MD

Professeur de Pédiatrie

Université Claude Bernard Lyon - France

Pierre CHATELAIN MD

Professeur de Pédiatrie

Université Claude Bernard Lyon - France

Le Recours au Pédiatre-Endocrinologue

Le Recours au Pédiatre-Endocrinologue

Quand faut-il activer l’Endocrino-Pédiatre ?

■

En anté-Natal

• Anomalie de croissance fœtale

• Anomalie des OGE

■

A la Naissance

• SGA / RCIU

• Anomalie des OGE

• Hyoglycémie (+ Micropénis)

• Dépistage de l’Hypothyroïdie

■

Dans l’Enfance

• Absence de rattrapage ( 2 ans)

• Mauvaise prise pondérale

• Anomalie des OGE

A

B C

1200

400

Usher R, McLean F. J Pediatr. 1969;74:901. GA (wk)

25 27 29 31 33 35 37 39 41 43

4400

4000

3600

3200

2800

2400

2000

1600

800

+ 2 SD ( 97.7%)

Birth weight (g)†

Mean (50%)

- 2 SD ( -2.5%)

Prems

AGA

SGA VLBW

The 3 typical postnatal growth patterns of SGA:

–3,5 –3,0 –2,5 –2,0 –1,5 –1,0 –0,5 0,0 0,5 1,0 1,5

0 20 40 60 80 100 120

Mean post-natal age (months)

Height SDS

Boys Girls

1 - Catch Up 2- No Catch Up 3- Catch Down

Consider GHD+ SGA

The Lyon SGA series : 92% catch up Literature : 85% to 92% catch up

The Lyon SGA Series : Postnatal Growth Pattern .

Postnatal Growth Data (until 8 years) of 179 (out of more than 700 ) well characterized SGA newborns were

collected retrospectively at the outpatient clinic

Analysis generated SGA spontaneous Postnatal Growth curves for Boys & Girls.

Birth data of the 179 did not differ from the 700.

Results (1)

Catch Up: n = 136

Non Catch Up : n = 9 ( 8 %)

Undetermined when as to age of Catch Up: n = 34 Mean Age at Catch Up : the – 1 DS SGA/IUGR

Curve crosses the –2 DS French Standards:

Girls: 29 month Boys: 22 month

Results (2)

The Lyon SGA Series : Postnatal Growth Pattern .

The Lyon SGA Series : Postnatal Growth Pattern

.

Mean Postnatal Height SD in Girls and Boys **

-4 -2 0 2

0 10 20 30 40 50 60 70 80 90 100 110 120 Mean Postnatal Age (month )

S D S c o re

Boys Girls

** not corrected for parental height

30 40 50 60 70 80 90 100 110 120 130

0 10 20 30 40 50 60 70 80 90 100 110 120

Postnatal Age in month

Height(cm )

Normal French Sempe

Standard -1 & -2 DS

Mean Age at Catch Up = 29 Month

(arbitrarily defined as the - 1SD SGA line crosses the – 2SD of normal i.e ~75% back to normal range)

SGA – 1 SD & -2 SD

Catch Up in Girls

20 40 60 80 100 120 140

0 4 9 16 22 27 34 40 46 54 66 77 90 103

SGA / IUGR -1 SD & -2 DS Normal French -1 & -2 DS

Postnatal Catch Up In Boys born SGA

Postnatal Age in Month Height cm

Mean Age at Catch Up = 22 Month (arbitrarily defined as the - 1SD SGA line crosses the – 2SD

of normal i.e ~75% back to normal range)

“Low birth weight, short birth length, small head circumference at birth, and preterm birth increased the risk of subnormal intellectual and psychological performance”.

“Among SGA-born males, the most important predictor was the absence of catch-up growth”.

“Being born SGA is associated with increased risk of subnormal intellectual and psychological performance”.

Intellectual and Psychological Performance in Males Born Small for Gestational Age With and Without Catch-Up Growth.

E. LUNDGREN, S. CNATTINGIUS, B. JONSSON and T. TUVEMO Pediatrics Research 2001;50:91-98.

GH Treatment in Short Children born SGA.

Change in Height SDS over Time of Genotropin

Treatment.

0 0.5 1 1.5 2 2.5 3

0 12 24 36 48 60 72

Cont. 0.033 mg/kg/day 0-72 mo

Cont. 0.067 mg/kg/day 0- 72 mo

Cont. 0-24 mo 0.067mg/kg/d + Disc. 24-72 moCon 0-24

0.1mg/kg/day + Stop 24-72

Month of Rx Ht SDS

0 10 20 30 40 50 60 70 80 90 100

0 6 12 18 24 30 36

0.033mg / kg/ day 0.067 mg / kg / day

Y= %

X= month of Rx Mean Time and Percent of Patient Achieving

Catch Up to –2 SD:

Condition # 1: Height SDS at start < -2 and > -3

0 10 20 30 40 50 60 70 80 90 100

0 6 12 18 24 30 36

0.033mg / kg/ day 0.067 mg / kg / day

Mean Time and Percent of Patient Achieving Catch Up to –2 SD:

Mean Height SDS at start : -3 / -3.5 / -4 / <-4 sd

0 10 20 30 40 50 60 70 80 90 100

0 6 12 18 24 30 36

0.033mg / kg/ day 0.067 mg / kg / day

0 10 20 30 40 50 60 70 80 90 100

0 6 12 18 24 30 36

0.033mg / kg/ day 0.067 mg / kg / day

0 10 20 30 40 50 60 70 80 90 100

0 6 12 18 24 30 36

0.033mg / kg/ day 0.067 mg / kg / day

Mean at –3 sd

Mean at –3.5 sd

Mean at –4 sd Mean < –4 sd

Y = %

X =month

6/14/2011

SGA: Change in HT SDS by Age at Start All Patients; 2 Years Treatment

~ 0.5 SD

Children Born SGA Reach

Target Height After GH Treatment

2 4 6 8 10 12 14 16 18 20

Height (cm) Boys

Chronological Age (Year)

2 4 6 8 10 12 14 16 18 20

Height (cm) Girls

Chronological Age (Year)

40 200

120

80 180

140

100

60 160

40 200

120

80 180

140

100

60 160

After 5 Year of GH Treatment Study Start

Source: Sas T et al. J Clin Endocrinol Metab 1999;84:3064

Participants who Consent to Enter the Study and were Randomization (between February, 1993 and January 1995) : n = 168

Treatment Group n = 112 Untreated Control Group n = 56

Treatment group, n = 102

refused treatment but agreed to participate in the follow-up study, n = 6

participated in the follow-up study, n = 41

refused to participate in the follow-up study, n = 15 Follow-up untreated control group, n = 47 patients with major

exclusion criteria excluded from analysis,

n =4

Followed until Final (or near) Height n = 91 (89%)

Followed until Final (or near) Height n = 33 (70%)

The French Short IUGR/SGA GH Treated until Final Height : a Randomized Controlled Pubertal Study.

Carel J Cl, Chatelain P, Rocchicioli P & JL Chaussain 2003 JCEM

Cl ini ca l R ese arc h

Untreated Controls

n = 33

Treated * n = 91

A: At Baseline

Height SDS

-2 0 +2

-3

-4

-6

-2.1 SD

-2.7 SD

-3.2 SD

+/-0.6

-3.2 SD

+/-0.6

Treated * n = 91

-6 -4 -2 0

treatment duration (years)

1 2 3

Height SDS

B: At Final Height

Untreated Controls

n = 33

GH dose = 67 mcg/kg/day

= 0.2 I.U./kg/day

The French Short IUGR/SGA GH Treated until Final Height : a Randomized Controlled Pubertal Study.

Carel J Cl, Chatelain P, Rocchicioli P & JL Chaussain. 2003 JCEM

1. In the absence of treatment, Short SGA, despite of marked delay in Bone Age, start puberty at a normal age, display an

abnormally low total pubertal growth, and display very limited spontaneous Catch Up.

2. GH treatment significantly increase Final Height in Short SGA 3. Bone Age is not reliable in predicting the residual growth

potential in Short SGA and should not be used for this purpose.

Conclusions from the French Study:

JC Carel, P Chatelain , P Rocchicioli, JL Chaussain JCEM 2003

-5-5 -5-5 -4 -4 -4 -4 -3 -3 -3 -3 -2 -2 -2 -2 -1 -1 -1 -1 0000

33 3333

33 67676767 Disc.Disc.Disc.Disc.

Ht SDS Ht SDS Ht SDS Ht SDS Baseline Baseline Baseline Baseline Ht SDS Ht SDS Ht SDS Ht SDS Final Final Final Final

Change in Final Height SDS

0000 2222 4444 6666 8888 1010 1010 12 12 12 12 1414 1414 16 16 16 16 1818 1818

33 3333

33 67676767 Disc.Disc.Disc.Disc.

Change in Change in Change in Change in Final Ht SDS Final Ht SDS Final Ht SDS Final Ht SDS Change in Change in Change in Change in FH cmst FH cmst FH cmst FH cmst

Final Height Gain Centimeter

Effect on Final Height

n = 16

n = 8

n = 26

SGA et Syndrome Métabolique:

- Obésité

- Hypertension Artérielle

- Diabète de Type 2

From Claire Lévy-Marchal in

Small for Gestational Age: Issues in 2008 CME

Anita Hokken-Koelega, MD; Ken Ong, MD; Claire Lévy-Marchal, MD

< 2500 2500 > 4500 / 4500

15 25 35 45 55 65 75 85 95 105 115 125 135

16 17 18 19 20 21 22 23 24 25 16 27 28

Weight at one year (pound) Standardized Mortality (normal =100)

Barker Lancet 1989

0 30

19 17

12

6 6

0 0 5 10 15 20 25 30 35

0 < 2475 2475- 2925

2925- 3375

3375- 3825

3825- 4274

>4275 Syndrome X (%)

Birth Weight (g)

2500 > 4500

3500/4000

3000/3500

2500/3000

1179 Pima Indians 20-39 Yr Mc Cance BMJ 1994 7086 Finns

Glycemia at 120 minutes(OGTT) according to Weight at 1 Year and Adult BMI .

David BARKER & al. Acta Paed Scan SUPPL 1993; 391:93-99.

1,19 1,21

1,39

1,1

1,24

1,33

1,04 1,06

1,19

1,00 1,11 1,22 1,33 1,44

<25.5 25.5 - 28 > 28 Adult BMI

Glycemia (g/L) OGTT at 120 min Weight at 1 Year < 9675g

Weight at 1 Year 9675 - 10575 g Weight at 1 Year > 10575 g

Copyright ©2008 The Endocrine Society

Ibanez, L. et al. J Clin Endocrinol Metab 2008;93:2079-2083

Fig. 2. Effects of birth weight and gender in 6-yr-old children matched for height, weight, and BMI (n = 64) who were born either AGA (n = 32, 16 boys and 16 girls) or SGA (n = 32, 16

boys and 16 girls)

Small for Gestational Age: 6 Key Messages to Parents

The majority (85-92%) of SGA newborn Catch-Up in both height and weight by 2 years of age with simple normal care.

The SGA condition is associated to an increase risk in Metabolic

Syndrome during adulthood (Obesity+Hyertension+ Type 2 Diabetes).

SGA should not be overfed since Catch Up further increase the risk of altered body composition & Metabolic Syndrome.

Children born SGA present as a group with a lower cognitive ability in mathematics and in reading comprehension. Awareness & support is needed.

SGA without Catch-Up growth by age 2 have a growth failure. Early examination in a growth clinic is needed.

GH treatment benefits to short SGA, inducing Catch Up to normal range & normalizing adult height when applied young & long enough.

Mont-Blanc

Avril 1974

Glucose Homeostasis in GH Treated Short SGA:

The Experience in Lyon – France *

(Pr P. Chatelain -Universite Claude Bernard ).

* SGA approved in France

OGTT : Insulin/Glucose Ratios

SGA (n=32) & Turner (n=13) before and at 1 year of GH;

Obese Controls (basal – n=10).

18

0 2 4 6 8 10 12 14 16

0 30 60 90 120 150 180

minutes

Insulin/Glucose SGA : Turner : Obese :

GH Treatment in Short SGA & TS is associated with an increase in Insulin secretion, sign of decrease in Insulin Sensitivity.

This increase compares to the one observed during puberty when both GH and Insulin secretion increase.This decrease in Insulin

Sensitivity appears as a compensatory phenomenon.

This phenomenon seems less in GH-Treated SGA than in GH- Treated Turner

In case of family history positive for Type 2 Diabetes and/or

Obesity, surveillance of Glucose Homeostasis seems recommended.

Conclusion on Glucose Homeostasis in Short SGA GH-treated Children (applies strictly to countries where approvals are granted).

Prediction of Growth Response in SGA (Ranke 2003)

4. Predicted Bad Responders:

Increased dose at start ?

3. Predicted Good Responders:

Standard dose at start

1. Great variability of response Of Short SGA at the US SGA dose 2. Comparable variability of response

Of Short SGA at the EU SGA dose

3 Phenotypes are expressed through the SGA Condition

■ A Fetal Phenotype: the SGA Newborn

■ A Post-Natal Phenotypes: Catch Up vs Non Catch Up

■ An Adult Phenotype:

A subgroup of the Metabolic Syndrome

Lesson from The Short SGA Child:

The SGA Phenotypes through Life Span.

Question:

Are these human variants driven by the GH / IGF-I / Insulin Genes’ Specificities?

Thank You very much indeed

Thank You very much indeed

The Obesity «Epidemy» !

Evolution of Body Mass Index (1962 / 1994) : US Population (Men & Women).

Wickelgren & al. Science 1998:280:1364-1367.

2 3 2 3 2 4 4 5

31 32 31

34

15

9 10 10

0 20 40

1960-62 1971-74 1976-80 1988-94

BMI 25-29.9

BMI 30 - 34.9

BMI > 40

%

P o p u l a t i o n

Years