Update on Medical Issues in
Prader-Willi Syndrome
June 17, 2009 NM PWS Gathering
Carol Clericuzio, MD
Medical Genetics and Pediatrics
Medical Advisor New Mexico Prader-Willi
Syndrome Project
Outline for Today’s Discussion
• Brief overview of cause and diagnosis of
PWS
• Sleep disorders in PWS
• Growth hormone therapy in PWS
• Adrenal gland problems in PWS
• Questions!
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; some with
adrenal insufficiency
• Cognitive and behavioral
differences
• Cause is lack of expression of
paternal genes at 15q11-13
Prader-Willi syndrome is due to 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, apnea
oppositional behaviors,
learning problems,
short stature Rx GH and
thyroid, check adrenals
Adulthood: type 2
DM, obstructive sleep
apnea, hypogonadism
Rx hormone replacement
Sleep Disorders in PWS
Key Abnormalities of Sleep and
Arousal in Prader-Willi Syndrome
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 hypercapnia
Sleep and Breathing in Prader-Willi Syndrome
Nixon and Brouillette. Pediatric Pulmonology 34:209–217 (2002)
What is Sleep Apnea?
• Abnormally long pauses in airflow during sleep
• Obstructive sleep apnea: pause in breathing due
to blockage in the air passages; physical block to
airflow despite respiratory effort for 2 or more
breaths
• Central sleep apnea: pause in breathing due to
the brain not telling the body to breathe; lack of
respiratory effort for 20 seconds
• Complex sleep apnea: a combination of central
and obstructive sleep apnea
Sleep Apnea in PWS
• Sleep apnea is diagnosed with an
overnight sleep test called a
polysomnogram, or a "Sleep Study".
• PWS individuals may have any type, but
most often obstructive sleep apnea
• Treatment of obstructive sleep apnea
may be adenoidectomy, tonsillectomy,
oxygen and/or CPAP
CPAP
Short for "continuous positive airway pressure"
• Positive airway pressure therapy is the
most effective noninvasive treatment
for Obstructive Sleep Apnea (OSA)
How does CPAP therapy work?
• Air is pushed from the flow generator
through the tubing and mask, the air
then passes through the nose and into
the throat, where the slight pressure
keeps the upper airway open.
• The low air pressure does not
interfere with breathing - though
some people need a few nights to get
used to the sensation of positive
airflow.
GeneReviews: Prader-Willi Syndrome
• Regardless of age, evaluate respiratory status
and perform a sleep study. These studies are
specifically recommended prior to initiation of
growth hormone therapy, along with assessment
of the size of tonsils and adenoids, particularly in
the obese individual.
• Cassidy and Schwartz Updated March 24, 2008
webpage www.genetests.org
Growth Hormone in PWS
PWS:
Problems with the
Hypothalamus
• Body thermostat
• Regulation of food intake
• Controls endocrine system
– Growth hormone releasing factor
– Corticotropin releasing factor (adrenal gland)
– Pubertal hormone releasing factors
– Thyrotropin releasing factor (thyroid gland)
GeneReviews: Prader-Willi Syndrome
• Data from at least 15 studies involving more than
300 affected children (reviewed in Burman et al
2001) document reduced growth hormone
secretion in PWS. Growth hormone deficiency is
also seen in adults with PWS [Grugni et al 2006,
Hoybye 2007]
• Cassidy and Schwartz Updated March 24, 2008
webpage www.genetests.org
GH therapy in PWS
• A rational therapy to improve body
composition, growth, strength
• Approved by the FDA 2000: Those with
PWS only need to show signs of growth
failure and have a genetic diagnosis of
PWS to qualify for GH treatment under
this special Orphan Drug Act approval.
(PWSA website 6/10/09)
GH improves final adult height in
children with PWS
• 2007 US retrospective review of 21 children
with confirmed GH deficiency compared with
39 non-GH treated adults who had similar
early childhood heights
• Conclusion: administration of GH to PWS
children restores linear growth and adult
height without significant effects other than
premature adrenarche
Angulo et al., AMJG 143A:1456-61 (2007)
Concerns with GH therapy in PWS
• Sudden death in children with PWS treated with GH
has been reported, and a possible contribution of GH
to these events has not been definitively excluded.
One possible factor is the development or worsening
of obstructive sleep apnea.
• PWSA recommends a sleep study before the start of
growth hormone (GH) on infants, children and adults
with Prader-Willi syndrome, and then a follow up
study 6-8 weeks later. If there is worsening of
obstructive sleep apnea (OSA) on GH temporarily
stopping the GH is recommended until the cause is
understood. Frequently the OSA can be corrected by
removing the adenoids and tonsils or lowering the
dose of GH. We also recommend taking precautions
during bouts of upper respiratory infections.
Does GH Improve Body Composition?
• Retrospective study of the potential benefits and
adverse events during growth hormone treatment in
children with Prader-Willi syndrome
Fillion et al., J Pediatr. 2009 Feb;154(2):230-3
• Review of 23 patients with PWS (14 males, 9
females) under age 18 years, 10 of whom (5 males,
5 females) had been treated with GH for periods
between 0.1 and 5.5 years
• GH therapy in children with PWS in the clinical setting
did not lead to any discernible improvement in BMI or
body composition
• AND it appeared to be associated with OSA
• Regardless of GH therapy, parental education was
associated with better outcome
The Jury is OUT on GH risks/benefits
to body composition in PWS
• Body mass index in children with Prader-Willi
Syndrome during human growth hormone therapy:
a real world situation. Dewan and Chanoine
J Pediatr. 2009 May;154(5):777-8
• Whether GH affects body mass and composition in
patients with PWS in a clinic setting remains unclear
and may reflect yet undiscovered individual-specific
characteristics. It is, however, important to remind
parents that GH is not a cure for obesity and that
control of food access and increased physical activity
remain the most important factors in obesity control
Adrenal Gland Problems in PWS
PWS:
Problems with the
Hypothalamus
• Body thermostat
• Regulation of food intake
• 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.
Deaths in PWS
• Annual death rate is high ~3%
• Multiple causes (e.g. choking) but some
deaths are unexplained
• There are several lines of evidence
suggesting that adrenal insufficiency may
contribute to unexpected deaths
• In 2004 Clericuzio and Stevenson [with the
help of NM PWS Project] published a paper
on 10 PWS individuals with unexplained
death/critical illness and autopsy of 3
infants showed small adrenal glands
Two New Adrenal Studies in PWS
• 2008: Netherlands physicians studied 25
PWS patients and 60% had adrenal
insufficiency
– Suggested that hydrocortisone be used during
acute illness unless adrenal function studied
• 2009: Butler & Garg studied cortisol levels
in 63 subjects with PWS and found one of
four infants with PWS had a low cortisol
level
– Recommended PWS infants and children
undergo low-dose ACTH stimulation testing
before GH treatment or other interventions
considered to be stressors
Recommendations for PWS patients in
stressful situations: e.g. surgery, infections
• Our NM pediatric endocrinologists
recommend that ALL PWS individuals have
a low-dose ACTH stimulation test
• Endocrinologist should be consulted prior to
elective surgery and in case of acute illness
to consider prescribing “stress” doses of
replacement cortisol in PWS individuals who
have not been tested
• Clericuzio and Stevenson recommend that
hospitalized PWS patients be monitored
closely
Most physicians are not aware of risk of
adrenal insufficiency in PWS
• Studies have not been published in the
most widely read pediatric journals
• More studies need to be done –
including of adults
• Physicians can contact me or the
Pediatric Endocrinologists
• Carol Clericuzio, MD (505) 272-2000
UNM physician access line
Questions?