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Disorder of Chromosome 15

Prevalence: 1:12,000- 15,000 (both sexes, all races)

Major characteristics: hypotonia, hypogonadism,
hyperphagia, cognitive impairment, difficult
behaviors. Major medical concern: morbid obesity

Appetite Disorder

Hypothalamic dysfunction is thought
to be the cause of the disordered appetite/satiety
function characteristic of PWS. Compulsive eating and
obsession with food usually begin before age 6. The
urge to eat is physiological and overwhelming; it is
difficult to control and requires constant vigilance.
Cause and Diagnosis of PWS

The genetic cause is loss of yet unidentified
genes normally contributed by the father. Occurs
from three main genetic errors: Approximately
70% of cases have a non-inherited deletion in the
paternally contributed chromosome 15;
approximately 25% have maternal uniparental
disomy (UPD)—two maternal 15s and no
paternal chromosome 15; and 2–5 % have an
error in the "imprinting" process that renders the
paternal contribution nonfunctional.
Weight Management Challenge

Compounding the pressure of excessive appetite is a
decreased calorie utilization in those with PWS
(typically 1,000-1,200 kcal per day for adults), due to
low muscle mass and inactivity.
A balanced, low-calorie diet with vitamin and
calcium supplementation is essential as is daily
rigorous exercise and activity. Regular weigh-ins and
periodic diet review are needed. The best meal and
snack plan is one the family or caregiver is able to
apply routinely and consistently. Weight control
depends on external food restriction and may
require locking the kitchen and food storage areas.

To date, no medication or surgical intervention has
been found that would eliminate the need for strict
dieting and supervision around food. Growth
Hormone Therapy (GH) treatment, because it
increases muscle mass and function, may allow a
higher daily calorie level.
Behavior Issues

Infants and young children with PWS are
typically happy and loving, and exhibit few
behavior problems. Most older children and adults
with PWS, however, do have difficulties with
behavior regulation, manifested as difficulties with
transitions and unanticipated changes. Onset of
behavioral symptoms usually coincides with onset
of hyperphagia (although not all problem behaviors
are food-related), and difficulties peak in adolescence
or early adulthood. Daily routines and structure,
firm rules and limits, "time out," and positive
rewards work best for behavior management.
Psychotropic medications—particularly serotonin
reuptake inhibitors, such as fluoxetine and
sertroline—are beneficial in treating
obsessive-compulsive (OCD) symptoms,
perseveration, and mood swings. Depression in
adults is not uncommon. Psychotic episodes occur
rarely.
Cognition

IQ scores are variable and can range from 40 to 115.
Those with normal IQs typically have learning
disabilities. Problem areas may include attention,
short-term auditory memory, and abstract thinking.
Common strengths include long-term memory,
reading ability, and receptive language. Early infant
stimulation should be encouraged and the need for
special education services and supports assessed in
preschool and beyond.
Motor Skills

GH Therapy for young children with PWS will
eliminate most motor skill problems. Prior to 2000,
when the FDA approved the use of GH Therapy for
all children diagnosed with PWS, deficits with
coordination, balance, and motor planning was a
universal part of the syndrome. Today, many adults
with PWS are also on growth hormone therapy to
improve their motor skills. Exercise and sports
activities should be encouraged and a part of the
daily life of a child with PWS. The ability to play
sports and exercise is vastly improved with GH
Therapy. Physical and occupational therapies also
help promote skill development and proper function.
Oral Motor and Speech

As with physical motor skills, oral motor skills are
improved and in some cases are normalized with
early childhood GH Therapy. Even with GH
Therapy the need for speech therapy may also be
needed. The need for speech therapy should be
assessed in infancy. Products to increase saliva may
help articulation problems. Social skills training can
improve pragmatic language use. Even with delays,
verbal ability often becomes an area of strength for
children with PWS. In rare cases, speech is severely
affected.
Growth

Failure to thrive in infancy may necessitate tube
feeding. Infants should be closely monitored for
adequate calorie intake and appropriate weight gain.
Growth hormone is typically deficient, causing short
stature, lack of pubertal growth spurt, and a high
body fat ratio, even in those with normal weight. The
need for GH therapy should be assessed in both
children and adults.
Sexual Development

Sex hormone levels (testosterone and estrogen) are
typically low. Cryptorchidism in male infants may
require surgery. Both sexes have good response to
treatment for hormone deficiencies, although side
effects have been reported. Early pubic hair is
common, but puberty is usually late in onset and
incomplete.

Although it is often assumed that individuals with
PWS are infertile, several pregnancies have been
confirmed. Sexually active individuals should be
counseled regarding risk of pregnancy and of genetic
error in offspring (50%, except for those with PWS
due to UPD). Basic sex education is important in all
cases to promote good health and protect against
abuse
Other Common Concerns

Strabismus—esotropia is common; requires early
intervention, possibly surgery

Scoliosis—can occur unusually early; may be
difficult to detect without X-ray; curve may
progress with GH Therapy. Kyphosis is also
common in teens and adults

Osteoporosis—can occur much earlier than usual
and may cause fractures; ensure adequate
calcium, vitamin D, and weight-bearing exercise;
bone density test recommended

Diabetes mellitus, type II—secondary to obesity;
responds well to weight loss; screen obese patients
regularly

Other obesity-related problems—include
hypoventilation, hypertension, right-sided heart
failure, stasis ulcers, cellulitis, and skin problems
in fat folds

Sleep disturbances—hypoventilation and
desaturation during sleep are common, as is
daytime sleepiness; sleep apnea may develop
with or without obesity; sleep studies may be
needed

Nighttime enuresis—common at all ages;
desmopressin acetate should be used in lower
than normal doses

Skin picking—a common, sometimes severe habit;
usually in response to an existing lesion or itch on
face, arms, legs, or rectum. Best managed by
ignoring behavior, treating and bandaging sores,
and providing substitute activities for the hands.

Dental problems—may include soft tooth enamel,
thick sticky saliva, poor oral hygiene, teeth
grinding, and infrequently rumination. Special
toothbrushes can improve hygiene. Products to
increase saliva flow are helpful.
Major Clinical Findings

The following common characteristics of
individuals with PWS raise suspicion of the
diagnosis. Published diagnostic criteria include
supportive findings and a scoring system
(Holm et al, Pediatrics 91, 2, 1993).

Neonatal and infantile central hypotonia,
improving with age

Feeding problems and poor weight gain in infancy

Excessive or rapid weight gain between 1 and 6
years of age; central obesity in the absence of
intervention

Distinctive facial features—dolichocephaly in
infants, narrow face/bifrontal diameter,
almond-shaped eyes, small-appearing mouth with
thin upper lip and down-turned corners of mouth

Hypogonadism—genital hypoplasia, including
undescended testes
and small penis in males; delayed or incomplete
gonadal maturation
and delayed pubertal signs after age 16, including
scant or no
menses in women

Global developmental delay before age 6; mild to
moderate mental
retardation or learning problems in older children

Hyperphagia/food foraging/obsession with food
Minor Clinical Findings

Decreased fetal movement, infantile lethargy,
weak cry

Characteristic behavior problems—temper
tantrums, violent outbursts,
obsessive/compulsive behavior; tendency to be
argumentative, oppositional, rigid, manipulative,
possessive, and stubborn; perseverating, stealing,
lying

* Sleep disturbance or sleep apnea
* Short stature for genetic background by age 15
* Hypopigmentation—fair skin and hair
compared with family
* Small hands and/or feet for height age
* Narrow hands with straight ulnar border
* Eye abnormalities (esotropia, myopia)
* Thick, viscous saliva with crusting at corners of
the mouth
* Speech articulation defects
* Skin picking
Quality of Life Issues

General health is usually good in individuals with
PWS. If weight is controlled, life expectancy may
be normal, and the individual’s health and
functioning can be maximized.

The constant need for food restriction and
behavior management may be stressful for family
members. PWSA (USA) can provide information
and support. Family counseling may also be
needed.

Adolescents and adults with PWS can function
well in group and supported living programs, if
the necessary diet control and structured
environment are provided. Employment in
sheltered workshops and other highly structured
and supervised settings is successful for many.
Residential and vocational providers must be fully
informed regarding management of PWS.
Health Care Guidelines for Individuals with PWS
and the book Management of Prader-Willi
Syndrome are available from PWSA (USA), as are
other publications for professionals and parents.

For a more comprehensive medical description of
PWS, see the University of Washington School of
Medicine, Seattle, GeneClinics: Medical Genetics
Knowledge Base

The Foundation for Prader-Willi Research was
established in 2003 by parents of children with
Prader-Willi syndrome (PWS). Today, FPWR is
composed of parents, family members, researchers,
and others who are interested in addressing the
many issues related to PWS, including childhood
obesity and autism spectrum disorders.
Resources for Health Care Providers
Research
Diagnostic testing: Individuals who have a
number of the clinical findings should be referred
for genetic testing. DNA methylation analysis
confirms diagnosis of PWS. FISH and DNA
techniques can identify the specific genetic cause
and associated recurrence risk. (See
ASHG/ACMG Report, Am J Hum Genet 58:
1085, 1996.) Patients who had negative or
inconclusive tests with older techniques should
be retested.
Recurrence risk: Significant only for rare cases
with imprinting mutations, translocations, or
inversions. All families should receive genetic
counseling.