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Endocrine Endocrine obesityobesity in PWS patient in PWS patient
C. Badiu, G. Madaras
National Institute of EndocrinologyBucharest
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Prader Prader--Willi Syndrome...Willi Syndrome...
first described in 1956
prevalence = 1:12,000 to 15,000 multisystemic disorder - all races, both sexes
the cause = unclear
Prader A, Labhart A, Willi H. Schweiz. Med. Wochenschr 1956; 86: 1260±1.
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Diagnosis«
Diagnosis«
Prenatal= reduced fetal movement and polyhydramnios
= genetic testing (chorionic villous sampling)
= amniocentesis
Postnatal= clinical features
= confirmed by genetic testing
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Endocrine Endocrine
obesity disordersobesity disordersin PWS in PWS
short stature p high BMI
delayed puberty & hypogonadism osteoporosis
excessive appetite morbid obesity
Low GH q lipolysis
central hypocorticism could be associated
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Etiology of Etiology of
endocrine obesityendocrine obesityin PWS in PWS
Reduced GH secretion + hypogonadotropic hypogonadism +abnormal appetite control + high pain threshold suggest
hypothalamic - pituitary dysfunction
No organic defect of the hypothalamus has been discovered on post
mortem investigation
Genetic abnormalities in chromosome 15 disrupt the normal
functioning of the hypothalamus
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CRH/ACTHCRH/ACTH -- What can go wrong?What can go wrong?
central adrenal insufficiency (CAI)
60% of PWS patients had CAI during
stressful conditions (insufficient ACTH
response during metyrapone test) elevated levels of DHEA and its sulfate
(DHEAS)
more research is required, but at this
moment, it is important to consider hydrocortisone treatment for PWS
patients during stressful conditions
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F ood intake F ood intake -- What can go wrong?What can go wrong?
Highly significant decrease inthe number of OXT neurons of the PVN nucleus which inhibitfood intake seem to be good
candidates for playing a physiological role in ingestive behavior ("satiety neurons³)
Vigorous control of the food
environment
Regular exercise is essential tomanage hyperphagia and obesity
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F rom genes to behavior F rom genes to behavior
G. Lucignani et al. / NeuroImage 22 (2004) 22±28
Del 15q11 ±13 loss of EFK SU - GABAA rec
Alterations of the G ABAergic system have a relevant role in the pathogenesis of
symptoms commonly observed in PWS.
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GHRH/GH GHRH/GH -- What can go wrong?What can go wrong?
low spontaneous GHsecretion
low peak GH response tostimulation tests
low serum IGF
-I levels
low levels of IGF-binding protein 3
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GHRH/GH GHRH/GH -- What can go wrong?What can go wrong?Clinical features support the presence of GHD in PWS:
short stature
abnormal body composition
obesity with extra fat deposits over the abdomen
reduced muscle mass
decreased bone density
retarded bone age
T he degree of GHD may vary from mild to severe
Theodoro et al. Body composition and fatness patterns in Prader-Willi syndrome:
comparison with simple obesity. Obesity (Silver Spring) 2006; 14(10):1685-1690.
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W hat we should do?W hat we should do?
starting GH treatment as early as 2 yr benefit in starting therapy between 6 and 12
months of age
recommended dose = 1.0 mg/m2/d
increases longitudinal growth
decreases in percent body fat
increases muscle mass
improves bone mineral density
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T he HypothalamicT he Hypothalamic--Pituitary Pituitary--Gonadal AxisGonadal Axis
H ypogonadism:
GnRH deficiency
(central)
primary gonadaldamage (peripheral)
retarded or incompletesexual development
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Puberty in PWS Puberty in PWS
no/delayed/incompletepuberty
almost all subjects will requirehormonal treatment for induction, promotion, or maintenance of puberty
no consensus as to the most
appropriate regimen in PWS
the chosen therapy, the dosingand timing should reflect as far as possible the process of normal puberty
precocious puberty (4%)*
* GnRH analogs is not needed (early
puberty not usually sustained)
isolated prematurepubarche (14%)*
= growth of axillary and pubic hair probably due to early maturation of
zona reticularis of the adrenal gland
* use of hydrocortisone in premature pubarche to decrease adrenal androgenswhen there is associated advancementof bone age
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Sex hormone steroid replacement in adultsSex hormone steroid replacement in adults
known benefits to bone health*
muscle mass metabolic protection
possible benefits to mental, emotional, and physical well-
being
* estrogen and androgen status should be monitored yearly during adolescence and adulthood and B MD assessed as indicated by dual-energy x-ray photon absorptiometry
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What should we do?
cryptorchidism (80%)
orchidopexy
human chorionicgonadotropin (hCG)
testosterone patches andgel preparations*
* when transdermal preparations are
not tolerated initial low dose of imtestosterone preparations (one third tohalf the recommended dose for hypogonadal adults) with incrementsas tolerated
estrogen therapy
(transdermal andnonsynthetic) should beconsidered if:
amenorrhea/oligomenorrhea
low-normal BMD
reduced estradiol levels
aware of the possible needfor contraceptives (fewreports of pregnancy inPWS women)
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E ndocrine obesity E ndocrine obesityMortality & morbidity: caused by obesity MS
(type 2 diabetes mellitus (DM2), arterial hypertension, sleep apnea, respiratory
insufficiency and cardiovascular disease)
Brambilla P et al., Metabolic syndrome in children with Prader Willi syndrome: the effect of obesity, Nutr Metab Cardiovasc Dis (2009), doi:10.1016/j.numecd.2009.10.004
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E ndocrine obesity E ndocrine obesity
Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22
mTOR
AMPK
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E ndocrine obesity E ndocrine obesity
Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22
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GhrelinGhrelinControl of food intake and energy metabolism at central as
well as peripheral levels.
PWS presents higher ghrelin levels, relative
hypoinsulinemia and normal insulin sensitivity.
F . Prodam et al. / Clinical Nutrition 28 (2009) 94±99
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Intervention Intervention Psychopharmacology: Risperidone
± Araki et al. Successful risperidone treatment for behavioral
disturbances in Prader-Willi syndrome. Pediatr Int 2010; 52(1):e1-e3.
Vigorous control of the food environment
Regular exercise is essential to manage
hyperphagia and obesity
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Bariatric surgery Bariatric surgeryBilio-pancreatic diversion
+ Sleeve gastrectomy
Papavramidis et al., J Pediatric Surgery (2006) 41, 1153± 1158
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Bariatric surgery Bariatric surgery
Pa avramidis et al., J Pediatric Sur er 2006 41, 1153± 1158
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