Articles
Volume 46 Number 7
Prader-Willi Syndrome: An Update
and Review for the Primary Pediatrician
Christina Chen, BS,1 Jeannie Visootsak, MD,2,3
Shelley Dills, MS,2 and John M. Graham, Jr, MD, ScD4
Prader-Willi syndrome, the first known human genomic
imprinting disorder, is one of the most common micro-
deletion syndromes. Prader-Willi syndrome is caused
by the absence of certain paternally inherited genes on
the long arm of chromosome 15, resulting in a com-
plete absence of the active copy of the genetic infor-
mation in this region. It is most commonly known for
its food-related characteristics of hyperphagia, food-
seeking behavior, and consequent obesity. Primary care
physicians play an important role in the care of children
with Prader-Willi syndrome, from recognizing the
Introduction
P
rader-Willi syndrome (PWS) was first
described in 1956 by endocrinologists Prader,
Labhart, and Willi. They reported on 9 indi-
viduals with poor feeding in infancy, underdeveloped
sexual characteristics, short stature, hypotonia,
small hands and feet, cognitive impairment, and the
onset of gross obesity after infancy.1 It was not until
1981 that PWS became the first recognized micro-
deletion syndrome identified by high-resolution
chromosome analysis.2 Prader-Willi syndrome is now
known to be one of the most common microdeletion
syndromes. It is the first known human genomic
imprinting disorder and is the leading known genetic
cause of obesity. Prader-Willi syndrome is also
associated with growth deficiency, abnormal body
From Emory University School of Medicine,1 Department of
Human Genetics,2 Department of Pediatrics,3 Emory University
School of Medicine, Atlanta, Georgia; and Medical Genetics
Institute,4 Steven Spielberg Pediatric Research Center,
Department of Pediatrics, Cedars-Sinai Medical Center, David
Geffen School of Medicine at UCLA, Los Angeles, California.
Address correspondence to: Jeannie Visootsak, MD, 2165 N
Decatur Rd, Decatur, GA 30033; e-mail: Jvisootsak@genetics
.emory.edu.
580
Clinical Pediatrics
September 2007 580-591
© 2007 Sage Publications
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presenting signs and symptoms at its various stages to
understanding their unique medical, developmental,
behavioral, and dietary issues. They can also serve as
a valuable source of support and advocacy for the
family. This article reviews the current state of knowl-
edge about Prader-Willi syndrome and discusses
up-to-date understanding of the management of this
condition.
Keywords: Prader-Willi syndrome; obesity; growth
hormone; hypotonia; developmental delay.
composition, hypogonadism, and specific behavioral
and learning issues. Thus, appropriate management
of children with PWS requires collaborative efforts
from the geneticist, endocrinologist, developmental-
behavioral pediatrician, nutritionist, psychologist,
psychiatrist, educational specialist, and the family.
History
In 1956, Prader, Labhart, and Willi published a
report describing 9 patients (5 males, 4 females),
varying in age from 5 to 23 years, with a syndrome
that first manifested with extreme neonatal hypoto-
nia. In addition, the children were motionless and
limp, unable to cry or suck, and had weak or absent
reflexes, which usually led to a diagnosis of failure to
thrive or congenital myotonia. Although the hypoto-
nia and the lack of movement improved over time,
Prader, Labhart, and Willi noted that the syndrome
progressed to obesity, which developed at about the
age of 2, along with growth deficiency, learning dis-
ability, and delayed and incomplete development
during puberty. They speculated that this was a
hypothalamic disorder with no evidence of pituitary
insufficiency. Although Prader, Labhart and Willi
were unable to discover the etiology, the accurate

description of the key features of PWS in their orig-
inal report has largely formed the basis for the cur-
rent diagnostic criteria for the disorder.1
In 1976, Hawkey and Smithies described a
patient with PWS who had an abnormal karyotype
showing a 15;15 Robertsonian translocation, lead-
ing to their speculation that loss of the short arm of
chromosome 15 caused by unbalanced translocation
might be a specific cause of PWS.3 It was not until
1981 that Ledbetter et al2 first used high-resolution
chromosome analysis to find interstitial deletions of
the proximal long arm of chromosome 15 in 4 of 5
individuals with PWS. Knoll et al4 later demon-
strated that Angelman syndrome and PWS share a
common chromosome 15 deletion but differ in
parental origin of the deletion (paternal for PWS
and maternal for Angelman syndrome).
Genetics and Etiology
The genetic findings in PWS can be explained by
a concept known as genetic imprinting, in which
certain genes or groups of neighboring genes are
expressed differently depending on the sex of the par-
ent from which they were inherited. In an unaffected
individual, the maternally derived copy of chromo-
some 15 in the critical region for PWS is inactivated,
and only the paternally derived region is expressed.
The mechanism of imprinting appears to be hyper-
methylation of the maternally contributed allele that
interferes with the translation of those genes.5
PWS syndrome results when there is an absence
of the normally active paternally inherited genes on
the proximal long arm of chromosome 15 and, con-
sequently, no active copy of this genetic informa-
tion.6 In approximately 75% of cases, the absence is
due to a de novo deletion of the paternally con-
tributed chromosome 15 between bands 15q11 and
15q13.2 Most of these cases involve the same break-
points on the chromosome, resulting in the same
4 Mb deletion.
Most remaining individuals with PWS, or
approximately 20% of the cases, have 2 maternal
copies of chromosomes 15, but no paternal chromo-
some 15, a phenomenon known as maternal uni-
parental disomy.7-9 This situation is thought to occur
due to an early embryonic trisomy 15 (2 maternal
chromosomes 15 and 1 paternal chromosome 15),
followed by loss of the paternally contributed chro-
mosome through trisomy rescue.10
Prader-Willi Syndrome / Chen et al 581
An additional 5% of individuals with PWS have
a translocation or other structural abnormality that
involves chromosome 15. Furthermore, in approxi-
mately 1% of cases, there is a microdeletion in the
imprinting center, which controls the imprinting
process within 15q11-q13.11-13 This latter group
includes virtually all cases in which there has been a
recurrence of PWS within a family.
It is of note that Angelman syndrome, a genetic
condition that is clinically distinct from PWS, is the
result of an oppositely imprinted gene in the same
region of chromosome 15.4,14,15 Approximately 60% of
individuals with Angelman syndrome have the same
15q11-q13 deletion as PWS, but it occurs in the
maternally derived chromosome.4 Paternal uniparental
disomy causes 3% to 5% of Angelman syndrome, and
10% are due to an imprinting mutation. The remain-
ing cases are thought to be due to a single gene muta-
tion, leading to absence of the gene product of the
maternally imprinted gene for UBE3A.16,17
Several genes have been identified in the PWS/
Angelman syndrome region. The best-described gene in
the region is small nuclear ribonucleoprotein N
(SNRPN). Disruption of this gene is thought to
be significant in the PWS phenotype.18 This gene, which
codes for a ribosome-associated protein that functions in
controlling gene splicing, is only expressed from the
paternally derived chromosome.19,20,21 Expression of this
gene is highest in the heart and all areas of the
brain, although detectable levels are present in most
tissues.18
Other identified imprinted genes in the
PWS/Angelman syndrome region whose functions
are unknown include a zinc finger gene MKRN3
(previously referred to as ZNF127) and a noncoding
gene IPW. Also located in the PWS deletion region
is the human necdin gene (NDN), a maternally
imprinted gene thought to be involved in cell cycle
control and apoptosis. The NDN gene is completely
absent in the brain and in fibroblasts of patients
with PWS, in contrast to its normal expression in
nonaffected individuals and patients with Angelman
syndrome.22 In the homologous mouse NDN gene,
messenger RNA expression is highest in the hypo-
thalamus, which is where the main pathology of
PWS is thought to occur.19
The nonimprinted P gene, which codes for
tyrosinase positive albinism, is also located in the
PWS region, and its deletion is the probable cause
of the hypopigmentation and albinotic fundus seen
in one third to one half of individuals with PWS.23
582 Clinical Pediatrics / Vol. 46, No. 7, September 2007
Some clinical differences exist between individ-
uals with PWS resulting from a 15q deletion and
those arising from maternal uniparental disomy.
Individuals with uniparental disomy are less likely to
have the typical facial appearance of almond-shaped
eyes and thin upper lip; hypopigmentation of skin,
hair, and eyes; skin-picking behavior, or skill with jig-
saw puzzles.24-26 They may also have a slightly higher
IQ, milder behavior problems, and delayed diagnosis
owing to more subtle physical features.27-29 Psychosis
and autism spectrum disorders, however, are more
common among PWS patients with uniparental dis-
omy.30-32 Increased maternal age is seen among
mothers who bear children with uniparental disomy,
which is consistent with the theory of an initial
maternally derived trisomy.27 The few individuals
with PWS who have microdeletions in the imprint-
ing center are phenotypically similar to those with
PWS, but without hypopigmentation.10 Furthermore,
African Americans with PWS may be of normal
height, have normal sized hands and feet, and lack
the typical facial phenotype.33,34
Incidence and Prevalence
Various epidemiologic studies generally report the
prevalence of PWS at approximately 1 in 25 000.35-38
This is likely an underestimate, since many affected
individuals are not diagnosed at an early age. More
realistic estimates of PWS incidence range from
1/10 000 to 1/15 000, and it occurs in both sexes
and all races.39
Individuals with PWS who have secondary com-
plications owing to obesity, such as cardiorespiratory
insufficiency, diabetes mellitus, and obstructive
sleep apnea, have increased morbidity and mortal-
ity.40,41 The yearly death rate for individuals with
PWS has been estimated at 3%, based on a popula-
tion study.35
Diagnosis
Prader-Willi syndrome is not commonly diagnosed
prenatally because detection of chromosomal
microdeletions is not performed in the standard
amniocentesis and chorionic villus sampling that is
used to diagnose other known maternal age-related
genetic syndromes.42 In affected fetuses, prenatal-
onset hypotonia usually results in decreased fetal
movement, abnormal fetal heart rhythm, abnormal
fetal position at delivery, and an increased incidence
of caesarean section.43 Children are usually born full
term and are of normal size, although Apgar scores
are often low.
Consensus diagnostic criteria for PWS were
developed in 1993 to aid in early recognition and
diagnosis44 and have since been confirmed using
molecular and cytogenetic techniques.45 Many of the
clinical features of PWS are believed to be secondary
to hypothalamic insufficiency.46 In infancy, the most
consistent clinical feature that should lead the pedi-
atrician to obtain a PWS methylation test for diag-
nosis is significant central hypotonia, which causes
decreased movement, lethargy with decreased arousal,
weak cry, and poor reflexes, including a poor suck
that leads to feeding difficulties and consequent fail-
ure to thrive.47 Characteristic facial features that
should also suggest PWS include narrow temporal
distance and nasal bridge, almond-shaped eyes, stra-
bismus, a thin upper lip, and hypopigmentation of
hair, eyes, and skin relative to other family mem-
bers.44,47 Problems with thermoregulation and hypog-
onadism with genital hypoplasia are also evident at
birth and throughout life.48
The uniform presence of hypotonia in infants
with PWS has led to the recommendation that all
newborns with persistent hypotonia be tested for
PWS.45 Recommended testing for PWS involves a
methylation analysis, followed by fluorescence in
situ hybridization FISH if methylation analysis is
positive, to determine if the cause is due to a dele-
tion.49 By ordering methylation analysis first, physi-
cians can provide an earlier diagnosis of PWS and
avoid other unnecessary or invasive testing such as
muscle biopsies, which are performed when neuro-
muscular disorders are first suspected as the cause
of hypotonia. Other common causes of geneti con-
genital hypotonia include myotonic dystrophy, spinal
muscular atrophy, fragile X syndrome, FG syndrome,
and a wide variety of other chromosomal disorders.
Children with PWS who have milder hypotonia
and feeding problems may not be diagnosed until
early childhood (between 1 and 6 years of age), at
which time the transition to hyperphagia occurs.
The differential diagnosis then includes conditions
in which mental retardation and developmental
delay is associated with hypogonadism and obesity,
such as Klinefelter syndrome, Bardet-Biedl syndrome,
Albright hereditary osteodystrophy, Börjeson-Forssman-
Lehman syndrome, and Cohen syndrome.50 The

change in feeding, combined with improved hypoto-
nia leading to a more active child, may give parents
a false sense of security and cause them to report to
the pediatrician that their child’s development is
improving.
The food-seeking behavior and subsequent obe-
sity usually present at 2 to 3 years of age, which in
addition to gross motor and speech delays, should
lead the pediatrician to suspect PWS. Other behav-
ioral features that are often present include temper
tantrums, obsessive-compulsive characteristics, high
pain threshold, sleep disturbances, and skin-picking.
Learning disabilities are always present, and intelli-
gence can range from low normal to moderate men-
tal retardation. Later in life, short stature, lack of
pubertal growth spurt, and small hands and feet can
be indicative of PWS, along with hypogonadism
manifested as incomplete pubertal development and
infertility.46
Specific Characteristics
Neurologic
The most significant neurologic finding in PWS is
hypotonia and hypothalamic dysfunction. Hypotonia
is prenatal in onset and results in decreased move-
ment, lethargy with decreased arousal, weak cry, and
poor suck, which leads to feeding difficulties in the
neonatal period. Failure to thrive may occur, which
necessitates feeding with a gavage tube or other spe-
cial feeding techniques.
Deep tendon reflexes may be absent or decreased.
The hypotonia is central in origin, and neuromuscu-
lar studies are normal or nonspecifically abnormal.
Motor milestones are delayed, with an average age
of sitting at 12 months and walking at 24 months.
Hypotonia may also be reflected in decreased mus-
cle bulk and tone, poor coordination, and decreased
strength. The hypotonia gradually improves over
time, but adults remain mildly hypotonic, with
decreased muscle bulk and tone, which may lead to
problems with articulation skills, scoliosis, and res-
piratory problems.
Although many of the manifestations of PWS
appear to be linked to insufficiency of the hypothal-
amus, no specific neurotransmitter or visible abnor-
malities of the hypothalamus have been identified on
postmortem neuropathologic examination.46 Abnor-
malities of the autonomic nervous system have
also been reported in PWS and may be related to
Prader-Willi Syndrome / Chen et al 583
hypothalamic dysfunction. They are manifested in
decreased salivation, increased tolerance to pain,
decreased metabolic rate, altered sleep control with
excessive daytime sleepiness, and difficulties with
thermoregulation.51 Uncontrolled obesity can also
lead to serious problems with sleep apnea and sud-
den death.
Craniofacial and Ophthalmologic
Characteristic facial features in individuals with PWS
may be subtle at birth and develop slowly over time.47
They include a thin upper lip and a downturned mouth
that is thought to be related to the prenatal and infantile
hypotonia. Other features include almond-shaped
eyes with a mild lateral up-slant, a narrow temple dis-
tance and nasal bridge, and mild strabismus (Figures
1 and 2).44,47 Hypopigmentation of hair, eyes, and skin
relative to other family members occurs in one third to
one half of affected individuals46,52,53 and may predis-
pose patients to strabismus and nystagmus due to mis-
routing of the optic fibers.54
Dental anomalies include dental crowding, delayed
eruption of teeth, carious teeth, and decreased saliva
flow. The viscous and sticky saliva may dry on the
lips and contribute to difficulties with articulation as
well as predispose individuals to cavities. Oral motor
coordination problems are also common and may be
related to the hypotonia.
Growth and Stature
Birth weight and length are usually within normal
limits, but infantile failure to thrive may cause both
weight and length to drop to below the third per-
centile. If not apparent in childhood, short stature is
almost always present by the second half of the sec-
ond decade.39 The average adult height is 155 cm for
males and 148 cm for females,46 although African
Americans tend to be taller.33,34 The short stature is
related to the lack of pubertal growth spurt and the
deficiency of growth hormone and its mediator,
insulin-like growth factor 1, that is seen in most
affected individuals. Treatment with growth hor-
mone has been shown to increase height and lean
body mass.55,56 Hands and feet also grow slowly.
Hands are often small and narrow, with a decrease
of the hypothenar bulge resulting in a straight ulnar
border and sometimes tapering fingers. Feet are
short and broad, with an average adult shoe size of
5 (22.3 cm) for men and 3 (20.3 cm) for women.57
584 Clinical Pediatrics / Vol. 46, No. 7, September 2007
Figure 1. A 1-month-old girl with Prader-Willi syndrome.
Note the almond-shaped eyes, the thin upper lip and a down-
turned mouth, and the small hands and feet.
Musculoskeletal
Scoliosis or kyphosis, or both, are common in individ-
uals with PWS. Scoliosis can occur at any age during
childhood, whereas kyphosis develops in adolescence
and early adulthood. Both are thought to be related to
muscular hypotonia. Hip dysplasia occurs in approxi-
mately 10%.58 Osteoporosis also occurs frequently,
with recent studies showing a significant decrease in
total bone and spine density and total bone mineral
content.59,60 Several factors contribute to the patho-
physiology of osteoporosis in PWS, including hypogo-
nadism, growth hormone/insulin-like growth factor 1
deficiency, hypotonia, inactivity, and low-dairy diets
resulting in decreased calcium intake.50
Hyperphagia and Obesity
Between the ages of 1 to 6 years, hyperphagia and
obesity begin. Hyperphagia is thought to be due to a
hypothalamic abnormality causing a lack of sati-
ety.61,62 Elevated levels of ghrelin, a hormone pro-
duced in the stomach that is normally found in high
Figure 2. The same girl as in Figure 1 at 2 years of age. She
has been on growth hormone therapy since 6 months of age.
levels in fasting states and in low levels during eating,
have been observed,63 although its relationship with
hyperphagia remains unclear. Food-seeking behavior
is common and includes hoarding or foraging food,
eating inedible items such as garbage, pet food, and
frozen food, and stealing food or money to buy food.
A low metabolic rate, a decreased caloric require-
ment (generally less than 1000 to 1200 kcal/day),64
and an inability to vomit also contribute to obesity,
along with reduced physical activity and low energy
expenditure.
As a consequence of growth hormone deficiency,
lean body mass is decreased which results in a high
ratio of fat to lean body mass, even in children with
normal weight-to-height ratios.65 The obesity is gen-
erally centrally distributed with relative sparing of
the distal extremities, and deposition of fat on the

abdomen, buttocks, and thighs occurs even in indi-
viduals who are not overweight. Obesity is the major
cause of morbidity and mortality and can initiate
secondary conditions, including cardiopulmonary
compromise, type II diabetes mellitus, hypertension,
thrombophlebitis, chronic leg edema, and sleep
apnea.
Endocrine
In addition to short stature caused by growth hormone
deficiency, hypogonadism, and type II diabetes mel-
litus are also associated with PWS.
Hypogonadism
Hypogonadism is hypothalamic in origin and gener-
ally characterized by a deficiency of gonadotrophins,
estrogen, and testosterone. It is prenatal in onset
and manifests as genital hypoplasia, incomplete puber-
tal development, and infertility in most affected
individuals.48,55 Genital hypoplasia is evident at birth
and throughout life. It is more obvious in boys at
birth and is characterized by unilateral or bilateral
cryptorchidism, a hypoplastic scrotum that is poorly
rugated and pigmented, and sometimes a small
penis. In girls, there is hypoplasia of the labia
minora and clitoris, although it is often overlooked
in prepubertal girls.
Hypogonadism is also evident in incomplete,
delayed, or abnormal pubertal development. Most
individuals with PWS fail to spontaneously com-
plete puberty, although precocious adrenarche is not
uncommon, and precocious puberty is rare. Pubic
and axillary hair may develop early or normally. In
girls, there is usually amenorrhea or oligomenor-
rhea, although breast development generally begins
at a normal age.
In a study by Crino et al,48 pubertal onset
occurred at 14 ± 3.2 years in boys (range, 8 to 23
years) but was incomplete in all cases. In girls,
pubertal onset was at 12.6 ± 2.7 years (range, 7.2 to
18 years), with two 18-year-old subjects still not hav-
ing entered puberty. Sexual activity and fertility are
rare, although 2 cases of reproduction in women
have been reported.66,67
Diabetes Mellitus
There is an increased frequency of type II
(noninsulin-dependent) diabetes mellitus in PWS,
particularly related to obesity. In a population-based
Prader-Willi Syndrome / Chen et al 585
study, Butler et al68 found that diabetes occurred in up
to 25% of adults, with a mean age of onset of 20 years.
This group had a higher frequency of past maximum
body weight, supporting the speculation that dia-
betes is obesity-related in PWS. Diabetes mellitus
has also been found to improve with weight loss.
Developmental Delay and
Mental Retardation
In addition to delays in gross motor skills, speech
and language milestones are also delayed, with the
first word occurring at age 18 months or as late as 6
years.69 Although verbal skills are an ultimate
strength in many cases, speech is often poorly artic-
ulated. Most individuals with PWS function in the
mild mental retardation range, with a mean IQ in
the 60s to low 70s,70,71 but it can range from low-
normal intelligence to severe levels of impairment.
Most children have multiple learning disabilities
and more challenges in academic performance rela-
tive to with their cognitive level.72
Individuals tend to have relative strengths in read-
ing, visual-spatial skills, expressive vocabulary, and
long-term memory, and weaknesses in arithmetic,
sequential processing, and short-term memory.46
Some also have an unusual skill with jigsaw puzzles25
with a strong propensity toward word search puzzles.
Behavioral
The onset of behavioral problems generally occurs at
about 4 years of age, when the insatiable appetite and
cravings for food increase.73 This behavioral profile
includes temper tantrums, stubbornness, inflexibility,
and controlling and manipulative behavior.46,70 Lying,
stealing, and aggressiveness are also common.
Individuals may seem more clever or manipulative in
obtaining food than would be suggested by their IQ
scores.
It is unclear how these maladaptive, behavioral fea-
tures change over the course of development and with
body mass index (BMI). Greenswag and Alexander74
report that behavioral problems increase in adulthood
because of increased psychosocial and physical pres-
sures. However, behavioral and emotional problems
decrease with age and older adults with PWS might be
more amenable to intervention.75 Continuing in this
paradox, Steinhauser et al76 found that the behavior
disorder increased with BMI, whereas Dykens and
Cassidy reported that thinner adults with lower BMIs
had higher maladaptive behavior scores than those
586 Clinical Pediatrics / Vol. 46, No. 7, September 2007
with higher BMIs.77 Studies have also suggested that
some behavioral issues wax and wane throughout
adulthood, possibly in association with certain psy-
chosocial stressors.77
Obsessive-compulsive characteristics are highly
prevalent, and they occur with greater severity and
frequency in individuals with PWS compared with
others with mild-to-moderate mental retardation. In
addition to food preoccupations and repetitive food-
seeking behaviors, other prominent behaviors include
skin-picking, hoarding, redoing, and needing to tell,
ask, or know.78 Psychosis occurs in 5% to 10% of
patients and is usually evident by young adult-
hood.37,79 The maladaptive features and problems
with overeating and obesity associated with PWS lead
to a poor self-image and feelings of being out of con-
trol and isolated. These behavioral profiles may pre-
dispose individuals to depression and anxiety.46
Respiratory
Many different factors predispose individuals with
PWS to breathing problems, including thoracic
muscle weakness and hypotonia, reduced muscle
tone in the pharynx and upper airways, obesity, and
scoliosis. Sleep disturbances are common owing to
upper airway obstruction and sleep apnea. Abnormal
sleep architecture unrelated to apnea or obstruction
and abnormal ventilatory responses to hypercapnia
and hypoxia when sleeping and when awake have
also been found.80 Excessive daytime sleepiness and
oxygen desaturation in rapid eye movement sleep
are particularly common, even in the absence of
obesity,81 and may be due to a combination of pri-
mary hypothalamic dysfunction and abnormal sleep
architecture.37
Management
Developmental/Education
It is recommended that children with PWS be
involved in early interventional services.. Newborn
infants should be assessed for sucking problems and
failure to thrive. Developmental assessment should
be performed routinely. Physical and occupational
therapies should begin in infancy to facilitate the
development of motor milestones. Speech therapy
is important in monitoring receptive expressive
language skills. In addition, appropriate educational
intervention throughout the school years that
addresses individual strengths and challenges as well
as behavioral issues can be effectively implemented
in both inclusion and self-contained classroom set-
tings depending on individual needs.
Dietary/Nutritional
Weight and dietary management have been major
focuses of intervention for PWS, and ongoing consul-
tation with a dietician is recommended beginning early
in life. No medication has shown long-term effective-
ness in controlling appetite; therefore, the most bene-
ficial intervention is a reduced-calorie diet and
increased physical activity. Height, weight, and BMI
should be monitored and daily food intake calculated.
The caloric needs of individuals with PWS
are lower than those of the normal population. A
low-calorie diet consisting of no more than 1000 to
1200 kcal/day is generally appropriate and should be
strictly supervised to limit weight gain and keep the
BMI below 30. The recommended level to start in tod-
dlers and young children is a diet of 800 to 900 kcal/
day, with slowly increasing increments of 100 kcal,
depending on the growth chart.39 It is important to
recognize that a well-balanced diet will be deficient
in the total amount of certain nutrients because
of the reduction in overall caloric intake, and there-
fore supplemental iron, calcium, and vitamins should
be given.
Regular physical exercise is recommended, with a
suggested daily goal of 30 minutes. Environmental
modifications, such as locking the kitchen, cupboards,
and refrigerator, in addition to close supervision
around food and spending money, are also helpful
weight management techniques. External food surveil-
lance and supervision should be maintained throughout
life, even after a patient loses weight, or if the patient
has a high IQ or behaves responsibly in non-food-
related parts of his or her life, such as maintaining a
job and functioning appropriately in social settings.
Hormone Therapy
Growth Hormone
Beginning in July 2000, the United States Food and
Drug Administration (FDA) approved growth hor-
mone for all children with PWS. Demonstration of a
specific growth hormone deficiency is not necessary
for growth hormone therapy. Controlled trials of
growth hormone therapies in individuals with PWS
have shown significant benefit from infancy through
adulthood.82 Growth hormone treatment increases

the rate of growth, allows an adolescent growth spurt,
and may normalize height. Although the appearance
of a more central distribution of fat persists, it
decreases fat mass by about 10% and increases muscle
and bone mass, thereby decreasing the fat-to-muscle
ratio. In addition, growth hormone possibly enhances
motor development in infancy83 and improves body
composition in adults who have not had previous
growth hormone treatment.84
Pulmonary function and sleep apnea are also
thought to improve in some cases, although the
mechanism may be secondary to decreased fat or
better weight owing to the growth hormone.
Growth hormone therapy can begin in infancy or
at diagnosis. Daily dose recommendations of 1.0 or
1.5 mg/m2 are reported to be effective in improving
body composition, lean body mass, growth velocity,
and resting energy expenditure.85,86 Although formal
testing of growth hormone secretion is not usually
necessary before therapy, thyroid function testing,
fasting blood glucose, bone age radiograph, liver
enzyme, renal function tests, and sleep studies
should be considered.82 Consultation with a pedi-
atric endocrinologist is highly recommended once
the diagnosis is confirmed.
Although there have been few side effects asso-
ciated with growth hormone, several deaths have
been reported after initiation of growth hormone
therapy.87-89 According to a worldwide survey of
individuals with PWS treated with growth hor-
mone through mid-2004, 13 children have died.82
However, none of the cases showed a clear associa-
tion with the use of growth hormone, and most had
preexisting respiratory or other complications.39 In
addition, the PWS cases with a known cause of
death are very similar to those reported during
growth hormone therapy.82 Although the relation-
ship between growth hormone treatment and mor-
tality in PWS continues to be a concern and remains
under intense investigation, most experts in PWS
recommend growth hormone therapy and most fam-
ilies choose to use it. Several longitudinal clinical
studies on the impact of growth hormone in indi-
viduals with PWS are currently underway as
researchers attempt to understand its benefits and
risks.
Sex Hormones
Sex hormone replacement is sometimes used
to help with the development of secondary sex charac-
teristics and may potentially increase bone mineral
Prader-Willi Syndrome / Chen et al 587
content and density. Some controversy among physi-
cians regarding several recommendations for sex hor-
mone therapy currently exist.One recommendation is
that low doses of testosterone replacement be offered
if hypogonadism prevails to the age of 17 or 18 years
in a boy with PWS,90 whereas another approach sug-
gests beginning testosterone replacement at age 13
to 14 years with a relatively low dose of 50 to 75 mg
intramuscular depo-testosterone every 3 to 4 weeks
(or a single testosterone patch daily) and then slowly
increasing dose to about 150 mg every 3 to 4 weeks.39
The administration of estrogen in girls is less fre-
quent but can be used to increase breast size if desired
and to initiate menstrual cycles. In females, it is also
suggested that bone mineral density be monitored dur-
ing and after adolescence, and estrogen therapy be
considered if bone mineral density becomes low.90
In either case, measurement of testosterone in
boys or estradiol in girls in the early pubertal years
should be taken before consideration of hormone
replacement therapy and should be monitored regu-
larly once therapy is initiated.
Behavior
Strict and consistent reinforcement of behavioral lim-
its, clear and firm establishment of behavioral expecta-
tions, and establishment of regular routines are helpful
in behavior management. Pharmacologic treatment of
behavior and psychiatric problems are often used as
well, particularly in addressing depressive or obsessive-
compulsive symptoms or severe aggression and temper
tantrums. Selective serotonin reuptake inhibitors
(SSRIs) have been reported to be particularly effective,
especially in controlling tantrums and obsessive-com-
pulsive symptoms.91 Fluoxetine is currently one of the
more popular SSRIs used among patients with PWS
and has shown good response in targeting these symp-
toms.92,93 Risperidone has been particularly effective in
treating those with psychosis.94 In all medications,
affected individuals appear to be more sensitive than
the average individual, and therefore starting with a low
dose is recommended.39
Prospects for Individuals
with Prader-Willi Syndrome
Once the diagnosis of PWS is confirmed, it is impor-
tant for the child to receive multidisciplinary care in
addition to routine preventive health care from the
588 Clinical Pediatrics / Vol. 46, No. 7, September 2007
primary care physician. Early interventional thera-
pies including physical therapy, occupational therapy,
and speech therapy are essential for children with
PWS. A comprehensive psychoeducational evalua-
tion to assess the child’s cognitive, achievement, and
adaptive profiles is essential to ascertain the child’s
strengths and challenges and will serve as a valuable
resources in designing an appropriate interventional
educational plan. Furthermore, therapeutic interven-
tions to manage growth, dietary, and behavioral con-
cerns can enhance the child’s potential and have a
significant positive impact on health, self-image, and
quality of life. Emphasis on early dietary manage-
ment and regular exercise should be included as part
of the child and his or her family’s daily lifestyle, as
individuals can have a nearly normal lifespan if mor-
bid obesity is avoided.74,95 Adults appear to live opti-
mally in a group home specifically designed for those
with PWS,95 and with ongoing parental and social
supports, individuals with PWS can live longer and
have an improved quality of life.
Acknowledgments
We appreciate the generous support of the Medical
Student Summer Research Program at Emory Univer-
sity School of Medicine (COC), SHARE’s Childhood
Disability Center, the Steven Spielberg Pediatric
Research Center, and the Cedars-Sinai Burns and Allen
Research Institute, UCLA Intercampus NIH/NIGMS
Medical Genetics Training Program Grant GM08243
and NIH/NICHD Grant HD22657 from the US
Department of Health and Human Services (JMG) and
NIH Clinical Research LRP Award L32MD000625-01
NIH/NCRR K12 RR017643, and URC of Emory
University (JV).
Resources for Primary Care Physicians and
Parents, Prader-Willi Syndrome Association (PWSA);
e-mail: national@pwsusa.org; http://www.pwsausa.org.
The Prader-Willi Foundation, Inc, e-mail: foundation@
prader-willi.org; http://www.prader-willi.org
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