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Manuel Fontoura Faculdade de Medicina do Porto
Centro Hospitalar de S. João Endocrinologia Pediátrica e Diabetes
Crescimento Variantes do normal e patológico
Curso Pré-graduado de Pediatria Sociedade Portuguesa de Pediatria
Braga, 19 Abril de 2013
Porque é que somos o que somos ?
Porque crescemos como crescemos ?
“… larger mammals fewer offspring…” Walker et als, 2008
Slow growing … Late reproducing … Long lived … Large brained … Extreme immaturity after birth Short duration of breast feeding Extended period of dependence of the young beyond breast feeding Multigenerational resource support by older people Menopause and long postmenopausal life Hochberg, 2012
Dilema obstétrico Washburn 1960
Brain Growth and Bipedalism … head and brain growth along with mental and motor development have
been deferred into the post natal period ( Leutenegger 1973).
High energy consuming
Growth velocity (cm/year)
0 2 4 6 8 10 years
Plagiocefalia Postural(PP) vs Craniosinostose Diagnóstico diferencial
Plagiocefalia Diagnóstico
Torcicolo
Causas: Torcicolo muscular congénito Torcicolo postural Postura durante o sono Alteração neurológica Alteração cervical Prematuridade
Início: Pré-natal Pós-natal
Plagiocefalia Postural Tratamento
Helmet treatment or DOC (Dynamic Orthotic Cranioplasty) band
Início 4 a 6 meses
The evolution of hominid life history during the first 20 years of life
Ze’ev Hochberg, 2012
Infancy
Childhood
Juvenility
Adolescence
Youth
22 18 16 14 12 10 08 06 04 02 00
Ag
e (
year
s)
Life span (yrs) 25 45 60 70
Aus afarensis H. Habilis H. erectus H. sapiens 3.2 mya 1.9 mya 670 kya 100 kya mya = millions of year ago kya = thousands of year ago
Human Growth
Ovum fertilisation Epiphyseal fusion
infancy foetal puberty
Racial Familial Age Puberty Sex Nutrition Season Diurnal Environmental Socioeconomic
Physiology of normal growth: Pediatrics and Child Health, 236-240, 2009 Manuel Fontoura, 2013
Genetics (80%)
Hundreds of variants clustered in genomic loci and biological pathways affect human height Nature 2010; 467:832-8 180 adult height loci – 21 skeletal/growth genes
Juvenility (> 6 anos)
1st molar eruption
childhood
Fetal
Infancy (1)
Puberty (3) 30%
15%
40%
15%
Nutrition Placenta
Nutrition Good Health GH-IGF1
hGH-IGF1 Thyroxine
Sexual steroids
Childhood (2)
(1) + (2)
(1) + (2) + (3)
The “Infancy-Childhood-Puberty” (ICP) growth model
Adaptado de Karlberg J, 1989
Juvenility
SDHEA
0 2 4 6 8 10 12 14 16
Age in years
10 20 30 40 2 4 6 … …24 months
IGF1
IGF2
IGFBP3
GH
hPL
Idade gestacional (sem) Idade pós natal (sem)
Co
nce
ntr
ação
pla
smát
ica Glucose
Insulin
Perinatal Growth Niklasson and Albertsson-Wikland, 2008
90 cm
33 cm
0,8 Kg
14 Kg
Leptin
+2 SD 0 SD -2 SD
LGA
AGA
SGA
Feta
l We
igh
t / L
en
gh
t
Gestational Age
SGA not IUGR SGA and
IUGR
IUGR not SGA
Nutrient demand > placental supply <
Fetal Undernutrition
Poor maternal nutrition
Low maternal fat stores
Poor placental function
Hormonal and metabolic adaptations in utero
IGF1-GH switched off Amino acid oxidation Insulin Lactate oxidation Cortisol Glucose oxidation
IUGR
Survival and brain development - Fetal programming
Predictive adaptive response Adjustments in its development and homeostatic systems for
later survival and reproductive fitness
Development plasticity and human disease Origins of health and adult disease
Development plasticity and human disease Gluckman PD & Hanson MA, J Int Med - 2007
Integrated responses to the predictive environment Likely response to a secure environment Likely response to a threatening environment
Investment for longevity (predictive response) Expenditure to survive to birth (immediate adaptive response) Commitment to repair Smaller birth size Commitment to tissue reserve (neuronal & nephron Prematurity number) Fetal sarcopenia Investment for large adult size (predictive response) Reproductive strategy (predictive response) Greater bone mass Altered time of menarche Greater muscle growth Investment to resist threatening and difficult environment
(predictive response) Altered hypothalamic-pituitary-adrenal axis Increased behaviour, altered anxiety Increased propensity to store fat Central components Increased appetite Altered food preference Reduced motor behaviour Peripheral components Altered hepatic development and function Sarcopenia Altered insulin release and action Impaired action of GH and IGF factors Leptin resistance Altered endothelial function
Mini-puberty HPG in male < 9 months and in female HPG < 24 months
3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24
Age (months) Age (months)
♀
♀
♀
♀
♂
♂
♂
♂
FSH
EE2/Testosterone Inhibin
LH
Boys
Girls
Mea
n g
row
th v
elo
city
IGF growth factors and infancy-childhood transition
Kalberg and Albertsson-Wikland (1988)
IGF1
IGFBP3
IGF1
C-onset < 10 m C-onset > 10 m
0 2 4 6 8 10 12 Age (months)
Weaning < plasma fatty acids and ketones < fatty acid oxidation < ketogenesis < gluconeogenesis Rise in fatty acid synthesis Transition from high-fat to high carbohydrate diet < GHrelin < IGF1 > Leptin
DICT Delay Infancy-Childhood Transition
DICT - delay in the rise of IGF1
Deficiência em hGH Manutenção da desaceleração do crescimento lactente
GH IGF1
IGFBP3
ALS
IGFBP3
IGF1 Bone
Hipófise Fígado Plasma Tec. Alvo
N0 infant-childhood growth transition
Transition from infancy to childhood Adaptado de Hochberg, 2012
105 100 95 90 85 80
75 70 65 60
6 – 12 months
Down syndrome
Noonan syndrome
Silver-Russell syndrome
8.8 months
9.3 months
15.2 months
+ energy balance - disease - undernutrition - gastrointestinal infection - socioeconomics <
Catch-up growth
Life-history phases Hochberg, 2009
Me
an G
row
th V
elo
city
G
row
th A
cce
lera
tio
n
Boys Girls
Boys Girls
Infa
ncy
Ch
ildh
oo
d
Juve
nili
ty
Ad
ole
sce
nce
Transição infantil - escolar Adrenarca < velocidade crescimento 1º molar > adiposidade
JUVENILITY …coincides with age children go to school
and compete with adults for food and space…
Age of adiposity rebound is inversely related to the BMI percentiles Younger age of rebound In the obese
5 6 7 8 9 10 11 12 13 14
T – Testosterone EE2 – Estradiol …… SDHEA
T
T
EE2
EE2
SDHEA
SDHEA
Adrenarche
Age (years)
Cole et als, 1995
Energy stored as abdominal fat preparing accelerating growth during adolescence
Growth of the juvenile Brain growth is complete, social adult competition (big may be a threat)
More efficient energy economy, longer lower limbs relative to BMI reduce energetic cost of walking
SDHEA – inibe crescimento condrócitos
Leg length velocity (♂)
Leg length velocity(♀)
Neurological effects preparing the CNS for Puberty 1) Social interactions + 2) Memory +, social e cognitive capacity + 3) + cortical maturation
The juvenility-adolescence transition Hochberg , 2012
…early and late transitions do not
change final height.
Mean SDS
♀ 8 anos
♂ 9 anos
♀ 13 anos
♂ 14 anos
Precocious Puberty
Delayed Puberty
Tall and short children Veldhuis, Roemmich, 2005
Tall
Short
Normal prepubertal growth Normal pubertal growth
Precocious puberty
Short prepubertal growth Normal/longer pubertal growth
Fin
al h
eig
ht
Prepubertal Growth
Adrenarche
S. Down - < 17 cm
S. Noonan - < 19 cm
S. Silver-Russell - < 26 cm
4.1 4.4 6.2
5.8
Growth failure mechanisms Height Growth Velocity
- 3
- 7
- 4
- 12
- 5,4 - 10 - 3,5
-5
-7
-1
Turner Syndrome Even L at al. J Pediatrics, 2000
Growth velocity Length
- 2
- 1 - 7
- 17
EE2
- 1.2SDs - 3SDs
Periods of adaptive plasticity in the transition between life-history stages
Predictive adaptive responses
Prenatal environment
Postnatal environment
Endocrine control
Prenatal Growth
Pubertal growth
Adult phenotype
Adult height
Body composition & metabolic adjustment
Fertility & lifespan
Infantile growth
Childhood growth
Juvenile growth Transition to
Childhood
Transition to juvenility
Transition to puberty
Prematurity
Size at birth
?
Adapted from Hochberg Z, Feil et al, 2011
Obrigado !
Nuno Milheiro
“…Live fast, remain small, reproduce early and die young…”
“… Live slow, grow much, reproduce late and die old…” Charnov EL. 1991
