September 1, 2005 
Volume 72, Number 5 www.aafp.org/afp American Family Physician 827
This article exem-
plifies the AAFP 2005
Annual Clinical Focus on
the legal, social, clinical,
and ethical issues of medi-
cal genomics.
A glossary of genomics
terms is available online at
http://www.aafp.org/afp
genglossary.xml.
P
rader-Willi syndrome (PWS), a
geneticdisorderthatusuallyinvolves
chromosome 15, is the most com-
mon form of obesity caused by a
genetic syndrome. Diagnosis often is delayed
until early childhood because the clinical
findings are relatively nonspecific, particu-
larly in infancy, and the dysmorphism often
is subtle.1,2
Epidemiology
PWS is identified in approximately one in
25,000 births.3
Because many affected per-
sons are not diagnosed at an early age, this
statistic is likely an underestimate. More real-
istic estimates of PWS prevalence range from
one in 10,000 to one in 15,000. PWS affects
both sexes equally and occurs in persons of
any race.
ClinicalPresentation
Typical findings on physical examination of
persons with PWS are shown in Figures 1
and 2 and summarized in Table 14
. Although
PWS is associated with obesity, affected chil-
dren classically present with difficulty feed-
ing and subsequent failure to thrive in the
first year of life. Newborns with PWS exhibit
nonspecific findings including hypotonia,
poor sucking reflex, diminished or absent
cry, and somnolence. Early developmental
milestones are delayed. After one year of
age, there is a transition to hyperphagia. By
school age, food-seeking behavior becomes
increasingly difficult to control.
Hypothalamic dysfunction is thought to
be the basis for many of the phenotypic
features, such as short stature and hypogo-
nadism. Hypogonadism presents as cryptor-
chidism, small testes, and decreased scrotal
rugae in males and small labia minora and
clitoris in females. Puberty typically is
delayed or incomplete.5
Learning disabilities always are present;
however, affected persons may have low-
normal intelligence to moderate mental
To complement the 2005 Annual Clinical Focus on medical genom-
ics, AFP is publishing a series of short reviews on genetic syndromes.
This series was designed to increase awareness of these diseases so
that family physicians can recognize and diagnose children with these
disorders and understand the type of care they might require in the
future. This review discusses Prader-Willi syndrome. (Am Fam Physi-
cian 2005;72:827-30. Copyright 2005 American Academy of Family
Physicians.)
Prader-Willi Syndrome
DANIEL J. WATTENDORF, MAJ, MC, USAF, and MAXIMILIAN MUENKE, M.D.,
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
annualCliniCalfoCus
figure1.Dysmorphic findings in a child with
Prader-Willi syndrome include narrowing of
the temples, almond-shaped eyes, strabismus,
and a thin upper lip.
828 American Family Physician www.aafp.org/afp Volume 72, Number 5 
September 1, 2005
retardation. Behavioral features in childhood
include temper tantrums, high pain thresh-
old, sleep disturbances, and skin picking.
Diagnosis
Although there are published consensus clini-
cal criteria for the diagnosis of PWS, genetic
testing has become the standard because it
detects nearly 100 percent of persons with
PWS, is highly specific, and can diagnose PWS
earlier than would be possible based on clini-
cal criteria.4,6
Clinical suspicion alone, even
if based on relatively nonspecific findings,
should prompt laboratory-based testing.
If an infant is hypotonic and has dif-
ficulty feeding, or if a child with this his-
tory in infancy has excessive food-seeking
behavior, obesity, and global developmental
delay, a high-resolution karyotype should
be ordered, followed by methylation studies
specific for PWS.6
Methylation analysis will
identify virtually all persons affected with
PWS. Many genetics laboratories offer both
of these tests and can coordinate sequential
testing. GeneTests, a publicly funded Web-
based resource (http://www.genetests.org),
provides an up-to-date laboratory directory
with ordering information.
GeneticsofPWs
With the exception of genes that are pres-
ent on only one of the sex chromosomes,
there are two copies of every gene--one
inherited from a person's mother and the
other from the father. For some genes,
only one copy from a chromosome pair is
active or expressed. The specific gene that is
expressed from a pair is determined by the
sex of the parent transmitting it, a process
called imprinting. The genes associated with
PWS normally are expressed only from a
region of chromosome 15 inherited from the
father (PWS critical region, Figure 3). The
genes inherited from the mother normally
are inactivated. Therefore, children affected
with PWS have a deletion or disruption of
the chromosome inherited from the father
or have inherited two copies of this chro-
mosomal region from the mother. The lat-
ter situation is called maternal uniparental
disomy.
Genetic counseling often is helpful for
parents of a child affected with PWS who
are contemplating another pregnancy. The
risk of recurrence varies widely (zero to
50 percent) depending on the underlying
genetic origin and can be determined based
on the results of genetic testing. Other fam-
ily members may be at risk for having a child
with PWS and may benefit from genetic
counseling.
Management
Treatment of a child affected with PWS
involves the primary care physician and a
figure 2. Characteristic facial features in a person with Prader-Willi
syndrome.
Narrow temple distance
and nasal bridge
Almond-shaped eyes
Mild strabismus
Thin upper lip
Downturned mouth
Overweight
Theauthors
DANIEL J. WATTENDORF, MAJ, MC, USAF, is a family physician and clinical
geneticist. He is assistant professor in the Department of Family Medicine at the
Uniformed Services University of the Health Sciences, F. Edward Hébert School of
Medicine, Bethesda, Md., and attending clinical geneticist at the National Human
Genome Research Institute, National Institutes of Health (NIH), Bethesda.
MAXIMILIAN MUENKE, M.D., is a pediatrician and clinical geneticist. He is
chief of the Medical Genetics Branch at the National Human Genome Research
Institute, NIH, and director of the medical genetics residency and fellowship
training programs at NIH.
Address correspondence to Maximilian Muenke, M.D., Medical Genetics Branch,
National Human Genome Research Institute, National Institutes of Health, 35
Convent Dr. ­ MSC 3717, Building 35, Room 1B-203, Bethesda, MD 20892-3717
(e-mail: mmuenke@nhgri.nih.gov). Reprints are not available from the authors.
ILLUSTRATIONBYDARRYLLEJA
September 1, 2005 
Volume 72, Number 5 www.aafp.org/afp American Family Physician 829
multispecialty team that includes an oph-
thalmologist to evaluate for myopia and
strabismus, a pediatric endocrinologist for
consideration of growth hormone treatment,
and a developmental pediatrician. Infants
may require supplemental tube feedings to
avoid failure to thrive. Physicians should be
vigilant for hypoventilation and subsequent
pulmonary infections secondary to hypo-
tonia, because these conditions may cause
early death.7
Early intervention for motor
skills, speech, and language is necessary, as
is an individualized education plan at the
start of school. Generally, after the first year
of life, strict dietary supervision and physical
activity plans should be initiated to reduce
complications of obesity.
Resources
Additional information about the diagnosis
and management of PWS has been pub-
lished8
and is available from the Prader-Willi
Syndrome Association (U.S.A.) (http://www.
pwsausa.org) and GeneTests (http://www.
genetests.org).
The opinions and assertions contained herein are the
private views of the authors and are not to be construed
as official or as reflecting the views of the U.S. Air Force
Medical Service, the U.S. Air Force at large, the National
Human Genome Research Institute, or the National
Institutes of Health.
Figure 1 provided by Suzanne B. Cassidy, M.D., University
of California, Irvine School of Medicine, Department of
Pediatrics.
figure3.Causes of Prader-Willi syndrome (PWS). This diagram represents
chromosomes 15 of an unaffected father (blue with PWS critical region
highlighted) and unaffected mother (pink). The children represent the
three different mechanisms for PWS: a deletion in the PWS region on
chromosome 15 that is inherited from the father (present in about
70 percent of patients) (A); both chromosomes 15 are inherited from the
mother and the PWS region from the father is missing (present in about
25 percent of patients) (B); and a defect in methylation inherited from
the father (present in less than 5 percent of patients) (C). In this case, the
genes in the PWS critical region on the chromosome 15 inherited from
the father are inactivated, similar to those of the mother.
Methylation
defect
CBA
PWS critical
region
Father Mother
Maternal
uniparental
disomy
Deletion
TABLE 1
DiagnosticCriteriaforPrader-Willisyndrome
Majorcriteria
Characteristic facial features (may include almond-shaped eyes,
down-turned mouth, narrow bifrontal diameter, strabismus,
thin upper lip; see Figures 1 and 2)
Developmental delay
Feeding problems/failure to thrive during infancy
Hypogonadism (may include cryptorchidism, hypoplastic
scrotum, and small testes in males; hypoplastic labia
minora and clitoris in females; and pubertal deficiency)
Infantile central hypotonia
Rapid weight gain between 1 and 6 years of age
NOTE: Score 1 point for each major criterion and 0.5 point for each minor criterion. A diagnosis of Prader-Willi syndrome should be suspected in
children younger than three years with a score of at least 5; and in children three years and older with a score of at least 8, with 4 points from major
criteria. Supportive criteria (no points) include high pain threshold, decreased vomiting, temperature control problems, scoliosis, kyphosis, early
adrenarche, osteoporosis, unusual skill with jigsaw puzzles, and normal neuromuscular studies.
Information from reference 4.
Minorcriteria
Decreased fetal movement and infantile lethargy
Esotropia, myopia
Hypopigmentation
Narrow hands with straight ulnar border
Short stature (compared with family members)
Skin picking
Sleep disturbance/sleep apnea
Small hands and feet
Speech articulation defects
Thick, viscous saliva
Typical behavioral problems
ILLUSTRATIONBYDARRYLLEJA
830 American Family Physician www.aafp.org/afp Volume 72, Number 5 
September 1, 2005
Figures 2 and 3 provided by Darryl Leja, National Human
Genome Research Institute, National Institutes of Health,
Bethesda, Md.
The authors thank Suzanne B. Cassidy, M.D., and
P. Suzanne Hart, Ph.D., for assistance with the prepara-
tion of the manuscript.
This article is one in a series coordinated by the National
Human Genome Research Institute, National Institutes of
Health, Bethesda, Md. Guest editor of the series is Daniel
J. Wattendorf, MAJ, MC, USAF. This series is coordinated
for AFP by Kenneth Lin, M.D.
Author disclosure: Nothing to disclose.
REfEREnCEs
1. Wigren M, Hansen S. Prader-Willi syndrome: clinical
picture, psychosocial support and current manage-
ment. Child Care Health Dev 2003;29:449-56.
2. Varela MC, Kok F, Setian N, Kim CA, Koiffmann CP.
Impact of molecular mechanisms, including deletion
size, on Prader-Willi syndrome phenotype: study of 75
patients. Clin Genet 2005;67:47-52.
3. Vogels A, Van Den Ende J, Keymolen K, Mortier G,
Devriendt K, Legius E, et al. Minimum prevalence, birth
incidence and cause of death for Prader-Willi syndrome
in Flanders. Eur J Hum Genet 2004;12:238-40.
4. Holm VA, Cassidy SB, Butler MG, Hanchett JM, Green-
swag LR, Whitman BY, et al. Prader-Willi syndrome: con-
sensus diagnostic criteria. Pediatrics 1993;91:398-402.
5. Crino A, Schiaffini R, Ciampalini P, Spera S, Beccaria L,
Benzi F, et al, and the Genetic Obesity Study Group of
Italian Society of Pediatric endocrinology and diabetol-
ogy (SIEDP). Hypogonadism and pubertal development
in Prader-Willi syndrome. Eur J Pediatr 2003;162:
327-33.
6. Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA,
Cassidy SB. The changing purpose of Prader-Willi syn-
drome clinical diagnostic criteria and proposed revised
criteria. Pediatrics 2001;108:E92.
7. Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cas-
sidy SB, Schrander JJ, Fryns JP. Prader-Willi syndrome:
causes of death in an international series of 27 cases.
Am J Med Genet A 2004;124:333-8.
8. Cassidy SB, McCandless SE. Prader-Willi syndrome.
In: Cassidy SB, Allanson JE. Management of genetic
syndromes. 2d ed. Hoboken, N.J.: Wiley and Sons,
2005:429-48.
GenomicsGlossary
Expression:Process of converting DNA into protein.
Hyperphagia:Pathologically excessive appetite or eating.
Hypoplasia:Incomplete development of a tissue or organ.
imprinting:Differential expression of a gene dependent on the sex of the parent of origin. For
example, for a maternally imprinted gene there is no expression in the offspring; expression of the
gene occurs from only the paternally inherited chromosome.
Methylation:Attachment of methyl groups (­CH3) to cytosine (C) bases. Methylation can regulate
the transcription of genes (e.g., reducing the amount of protein generated). Hypermethylation can
lead to silencing of a gene and total absence of protein production.
uniparentaldisomy:Abnormal presence of both copies of a chromosome (or part of a chromosome)
inherited from one parent.
Prader-Willisyndrome