2013 Update on Endocrine Complications in
Prader-Willi syndrome
October 18, 2013 NM PWS Gathering
Carol Clericuzio,MDUNM Medical Genetics/PediatricsMedical Advisor NM PWS Project
Outline for Today’s Discussion Brief overview of features of
PWS Hypothalamic dysfunction in
PWS Diagnosis and management of
endocrine abnormalities
Prader-Willi Syndrome 1/15,000 births Neonatal hypotonia and
cryptorchidism Hypothalamic dysfunction:
lack of satiety and subsequent obesity; low sex hormones and growth hormone
Cognitive and behavioral differences
Cause is lack of expression of
paternal genes at 15q11-13
Prader-Willi Syndrome at Different Ages
Infancy: hypotonia,feeding problems, cryptorchidism, apnea,check adrenals
Childhood: obesity, apneaoppositional behaviors,learning problems,short stature Rx GH andthyroid, check adrenals
Adulthood: type 2DM, obstructive sleepapnea, hypogonadismRx hormone replacement
Hypothalamus – part of the brain• One of the most
important functions of the hypothalamus is to link the nervous system to the endocrine via the pituitary gland
• The endocrine system is a system of glands, each of which secretes different types of hormones directly into the bloodstream
•
PWS: Problems with
the hypothalamus
Body thermostat Regulation of appetite Regulation of sleep Controls endocrine system
Growth hormone releasing factor Corticotropin releasing factor (adrenal
gland) Pubertal hormone releasing factors Thyrotropin releasing factor (thyroid
gland)
PWS: Growth hormone deficiency in 40-100% of children
Effects of GH deficiency: Short stature Increased fat mass and
decreased lean mass (abnormal body composition) – even toddlers
Low insulin-like growth factor (IGF-1: made by the liver in response to GH)
Decreased GH secretion on provocative tests
Benefits of GH therapy in children with PWS
Lower body fat; increased muscle mass Better height Better motor function Possibly better cognition Experts recommend starting GH prior
to onset of obesity: ~ 2 yo
Benefits of GH therapy in adults with PWS
Benefits of childhood GH may persist into adulthood: lower fat Prevalence of severe GH deficiency in adults is 40-50% GH use associated with higher
glucose Currently no consensus on GH
testing in adults, but GH is recommended
Risks of GH therapy
Contraindications per pharmaceutical industry and clinical experts:
Severe obesity Untreated severe obstructive sleep
apnea Uncontrolled diabetes Active cancer Active psychosis
Risks of GH therapy Concerns have been raised
regarding: Excessive elevations of IGF-1- may
increase tonsils & theoretical risk of cancer
Sleep disordered breathing Scoliosis Alterations in glucose metabolism Sudden death
Currently recommend monitor IGF-1 levels every 6-12 months
PWS: Sleep-disordered breathing
Obstructive sleep apnea
Sleep-related hypoxemia
Hypoventilation Reduced ventilatory
response to low oxygen and high CO2
Sleep and Breathing in Prader-Willi SyndromeNixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)
Risks of GH therapy
Sleep disordered breathing may increase with GH therapy in some studies
May be improved on other studies
Current guidelines to evaluate sleep disordered breathing prior to starting GH therapy
Pulmonary evaluation and sleep studies on all patients
ENT referral if obstructive sleep apnea, snoring, enlarged tonsils/adenoids
Repeat sleep study within first 3-6 months of starting GH
PWS: Scoliosis and GH therapy Scoliosis affects 30-80% No effect of GH found on
scoliosis Consensus recommendation
is that prior to GH therapy, have spine films and orthopedic referral if necessary
After start of GH therapy, spine film and/or orthopedic assessment should be considered if scoliosis progress a concern
PWS: Alteration in glucose metabolism with GH
Concern is GH can increase insulin resistance causing high blood glucose
Pediatric: no problem with GH therapy up to 4 years
Adult: minor increase in glucose/insulin
Consensus recommendation: monitor HgbA1C, glucose, insulin and consider oral glucose tolerance test for obesity, >12 yo, family history of diabetes
PWS: Association of sudden death with GH therapy
Has received a lot of attention: 2002-2006: 20 deaths reported in children on GH but cause not been proven to be GH
Respiratory disorders are the most common cause of death in PWS
When PWS deaths are looked at however, there is no increase in those on GH hormone
PWS: Association of sudden death with GH therapy
However, 75% of deaths in GH group occurred within 9 months of start of GH
Need close surveillance for any worsening of sleep related breathing disorders during first year of GH therapy
Sudden death may also be related to central adrenal insufficiency – we published a study showing small adrenals
PWS: Problems with
the hypothalamus
Body thermostat Regulation of appetite Controls endocrine system
Growth hormone releasing factor Corticotropin releasing factor (adrenal
gland) Pubertal hormone releasing factors Thyrotropin releasing factor (thyroid
gland)
Adrenal Gland Function Adrenal glands sit on
top of the kidneys. They are chiefly responsible for regulating the stress response through the synthesis of cortisol.
Cortisol increases blood pressure and blood sugar, and reduces immune responses
Cortisol deficiency can lead to death if an individual is stressed by surgery, infection, dehydration, etc.
PWS and adrenal insufficiency
Frequency is unknown but it does occur
Due to problems with the hypothalamus
While deaths may be associated with adrenal problems, especially during an acute illness or after surgery, none of the individuals were on GH
GH interferes with cortisol production so in theory could contribute to a death
PWS and adrenal insufficiency
No consensus on appropriate evaluation and management of PWS-associated adrenal insufficiency
In New Mexico our pediatric endocrinologists have recommended low-dose ACTH stimulation testing
Some experts recommend giving families hydrocortisone to use at home in case of severe illness and for surgeries
PWS: Problems with
the hypothalamus
Body thermostat Regulation of appetite Controls endocrine system
Growth hormone releasing factor Corticotropin releasing factor (adrenal
gland) Pubertal hormone releasing factors Thyrotropin releasing factor (thyroid
gland)
PWS: Hypogonadism Decreased function of ovaries and
testes due to hypothalamic and pituitary understimulation
Underdevelopment of genitals, delayed or incomplete puberty and infertility in the vast majority
Most males have undescended testes and should have surgery by 1-2 yo
PWS: Replacement hormone treatment for hypogonadism
Many individuals require hormonal treatment for induction, promotion or maintenance of puberty
Benefits include improved bone health, muscle mass and possibly general well-being
Timing should reflect normal puberty
PWS: Replacement hormone treatment for hypogonadism
Sex hormone deficiency contributes to low bone density in adults
Female sex hormones are taken orally
Male sex hormones can be delivered by injection or patches and gels
PWS patients may have difficulty with topical treatment due to skin irritation and skin picking behaviors
PWS: Reproduction No instances of paternity Four cases of pregnancies and
therefore potential of fertility in females necessitates discussion of sexuality and birth control at the appropriate age
2 of the babies had Angelman syndrome, a severe neurologic disorder
PWS: Problems with
the hypothalamus
Body thermostat Regulation of appetite Controls endocrine system
Growth hormone releasing factor Corticotropin releasing factor (adrenal
gland) Pubertal hormone releasing factors Thyrotropin releasing factor (thyroid
gland)
PWS: Hypothyroidism Reported in 20-30% of
children Adult frequency is 2% =
general population Experts recommend that
freeT4 and TSH be screened in the first 3 months of life and annually thereafter, especially if receiving GH therapy
SUMMARY: PWS is characterized by problems with the
hypothalamus Body thermostat Regulation of appetite Regulation of sleep Controls endocrine system
Growth hormone releasing factor Corticotropin releasing factor (adrenal
gland) Pubertal hormone releasing factors Thyrotropin releasing factor (thyroid
gland)
Questions?
Endocrine manifestations and management of Prader-Willi syndrome. Emerick JE, Vogt KS. Int J Pediatr Endocrinol. 2013 Aug 21;2013(1):14.
Sleep disorders in PWS
Main feature Associated features
Excessive daytime sleepiness Increased nocturnal sleep Behavioral problems Issues related to learning and
safety Abnormalities of arousal Reduced arousal to hypoxic
and hypercapnic stimuli during
sleep Sleep-disordered breathing Obstructive sleep apnea Sleep-related hypoxemia Hypoventilation Reduced ventilatory response
to hypoxia and hypercapniaSleep and Breathing in Prader-Willi Syndrome
Nixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)