Transcript normal stature variants

Growth Disorders
• Most children evaluated for short stature
are normal stature variants.
• The slow growth patterns of these children
reflect familial short stature and/or
constitutional delay of growth and puberty
Familial short stature
• Tend to be small at birth
• They grow approximately parallel to the
normal curve but below the 3rd percentile
from infancy
• Pubertal development and the
acceleration of growth occur normally and
they ultimately achieve a short adult
height(Father <163 cm,Mother <150 cm)
• They have no clinical or laboratory
evidence of endocrine or systemic disease
• Their annual growth rates are within
normal limits
• The bone age is appropriate for his or her
chronological age
• The diagnosis of familial short stature has
been perpetuated in families in which
impaired growth was eventually proved to
be consequence of a defined genetic
disorder.
Constitutional delay in growth and
puberty(CDGP)
• They mature at a slower than normal rate
• Height and bone age are usually delayed by 2-4
years
• Onset of pubertal maturation is understandably
delayed appropriate to the child’s bone age
• Often there is a history of delay in growth and
pubertal development of either parent or another
relative
• Final adult stature, which may not be reached
until the age of 20 or more years, is appropriate
for parental target height range
• They are usually of normal size at birth
• They grow normally for several months or years but then
deviate from the “normal” growth centiles, particularly in
the pre/peri-pubertal years
• They grow at a normal rate for their bone age
• There is a later than average adolescent “growth spurt”
• Treatment: controversial
• Synthetic steroids designed to have an increased
anabolic-androgenic ratio:oxandrolone(oral)(hepatotoxichepatic tumors!)
• No suitable equivalent for the girl
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A child’s current centile must be evaluated
in terms of:
Genetic background
Gestational or past medical history
Environment
Physical findings
Growth pattern since birth
Current growth rate(height velocity)
Causes of short stature
1- Familial or congenital conditions
• Skeletal dysplasias
• Chromosomal abnormalities
• Forms of intrauterine growth retardation which may
result in show or abnormal growth throughout later life
2- Chronic systemic disorders:
• (Due to) insufficient intake of energy and/or proteinnutritional insufficiency, malabsorption syndromes and
chronic inflammatory bowel disease)
• Insufficient oxygenation of tissues
• Electrolyte imbalance(chronic renal failure)
3-Endocrine abnormalities
• CNS or hypothalamic abnormalities which
affect regulation of the anterior pituitary
• Anterior pituitary disorders, either
developmental or acquired which can
affect synthesis or secretion of growth
hormone or the trophic
hormones(TSH,LH,FSH,ACTH)
• Primary dysfunction of the target organs
e.g. Thyroid,adrenal or gonadal disease
• Peripheral target tissue abnormalities
- a diminished or absent hormone receptor or tissue
enzyme defect
Laron type “dwarfism” – failure of IGF1 generation in
response to GH (A GH receptor defect)
- Disorders related to the interaction of the IGF’s or other
related peripheral growth factors with chondrocytes and
mucopolysaccharides in epiphyseal growth cartilage
Pygmies:genetic defect in IGF-1 responsiveness
associated with diminished IGF-1 binding
Normal human growth hormone
secretion
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In the first days of life, very high levels of GH occur.
After 2 weeks of age, lower mean levels are found.
• In pubertal children, the basal plasma GH concentration
is not significantly different from that reported for adults
but more peaks of GH may occur during the day with
greater amplitude of GH peaks during the night
• The most consistent period of GH secretion for both
children and adults occurs within one hour or so after the
onset of sleep.The initial surge of GH secretion often
correlates with the onset of stage 3 or 4 (slow wave)
sleep
Control of human growth hormone
secretion
• Positive releasing factor GHRH-Ghrelin
• Inhibitory factor:GHRIH
• Naturally occurring events that trigger GH
secretion in man are exercise, physical
and emotional stresses and high protein
intake
Normal regulation of GH
• The neurone system regulating GHRH and
GHRH release receives a variety of normal
impulses.Impulses arising in the hippocampus
are stimulatory whereas those arising in the
amygdaloid nuclei can be either stimulatory or
inhibitory. The inhibitory inputs are presumed to
activate GHRIH release via the anterior
somatostinergic pathways,the stimulatory
pathway is by way of the ventromedial(VM)
nucleus of the hypotalamus
• The GH regulatory neurone system also
recieves impulses from each of the ascending
monoaminergic neuronal systems :
dopaminergic, noradrenergic and serotonergic
- L-Dopa(converted to dopamine) in the brain
leads to a release of GH
- Sleep induced GH release is predominantly
mediated by serotonergic fibres.
- Hypoglycemia induced GH release is mediated
by noradrenergic pathways.
GH provocation tests
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Exercise
Sleep
Arginine infusion
Glucagon
Clonidine (alfa adrenergic receptor stimulant)
ITT
L-Dopa
Priming(sex hormones)??
Physiologic effects of human
growth hormone
• Anabolic-promotes protein synthesis in
muscle cells
• Catabolic effect- on fat and carbonhydrate
metabolism (short term hypoglycemic
effect) inducing lipolysis in adipoctytes
• Long term effect of high GH levels:plasma
glucose concentration increases(increased
glucose production and reduced glucose
utilization)
Evalution of height measurements
1- Growth charts
2- Parental heights- target height
3- Height SDS
4- Height velocity
5- Predicted ht
SDS:X-x*
SD
x*:mean height for age and gender
Etiology and pathogenesis of
growth failure
• Chromosomal assessment
Turner Sydrome
• FSS
• IUGR “Catch up”
• CDGP
• Skeletal dysplasia
osteochondrodysplasias(achondroplasia,
hypochondroplasia)
• Chronic systemic disorders- asthma
• Nutritional insufficiency
• Chronic gastrointestinal diseases
Coeliac disease
Crohn’s disease
Ulcerative colitis
• Chronic renal disease
• Cardiac disease
• DM
Endocrine abnormalities
• Primary hypothyrodism
• Gonadal dysgenesis
• GHD
• Glucocorticoid excess
• Growth failure to pyschosocial deprivation
Etiology of GHD
• Congenital
Acquired
• İsolated
MPHD
• Incidence 1/4000-10000 live births
• (50-60%) idiopathic
• Hereditary (aut.recessive or dominant)
Developmental defects
• Pituitary aplasia-hypoplasia
• Midline abnormalities
- Severe holoprosencephaly septooptic
dysplasia (SOD):Hypoplasia of the optic
nerves dysgenesis or agenesis of the
infundibulum and septum pellucidum +/pituitary hormone deficiency
-Cleft lip palate
-Single upper central incisor syndrome
Fizik Muayene-1:
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TY: 11 yaş 11 ay iken
Boy: 131 cm
Boy SDS: - 3.4
VA: 28 kg
BMI: 16,32 kg/m²
KY: 11-12 YAŞ
Radyoloji:
BH gene defects
• All patients with classical GH gene
deletions have complete GHD(IGHD IA,
IB,2,3(+hypogammaglobulinemic))
GH gene regulation:
• Pit1 (pituitary transcription
factor):stimulatory effect on GH gene
transcription
• Pit 1 mutations
- Severe deficiencies in GH PRI
- Often develop secondary hypothyrodism
• Prop 1 (Prophet of pit 1) mutations
combined pituitary hormone
deficiency(secondary hypogonadism)
Davis 2010
Clinical features of GHD
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Growth failure
Normal birth weight and birth length
Skeletal proportions normal for age
Somewhat overweight for height(increased subcutaneous fat)
Head circumference normal
Disparity between the size of face and the calvarium: “doll like”
“cherubic” facies most pronounced in panhypopituitarism (crowding
of the facial features to the centre of the face suggesting maxillary
hypoplasia)- frontal bossing, saddle nose
Skeletal maturity delayed
High pitched voice
Males: penis,scrotum small, hypoplastic testis
Hypoglycemia
• Radiological assessment: Skull x rays,CT,
MRI
• IGF 1 measurement, physiological tests of
GH secretion
O.E
G.Ö
B.Y
M.Ş