Prader-Willi syndrome

Protopopu Patriciu
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca

Abstract. Prader-Willi syndrome is a rare genetic disease affecting 1 in 25,000 people worldwide.
These patients suffer from hypotonia and feeding difficulties during early childhood, motor and language
developmental delays, low IQ with a degree of mental disability, metabolic issues such as obesity and type
2 diabetes caused by excessive food consumption, short stature due to low growth hormone levels, hy-
pogonadism and personality/behavioral problems such as temper tantrums, stubbornness and obsessive-
compulsive behavior. In this article we look at the main features of the disease, diagnostic criteria and at
how different management and treatment options can be used to improve the outcome and the quality of
life for PWS patients.
Keywords: Prader-Willi syndrome, hyperphagia, hypotonia, growth hormone deficiency, hypogonadism,
obesity, developmental delay, DNA methylation analysis.

Introduction Clincal manifestations

Prader-Willi Syndrome (PWS), also known
as Prader-Willi-Labhart syndrome, is a genetic
disorder characterized by the lack of expression
of the paternally inherited imprinted genes on
chromosome 15q11-q13. This can be caused
by a paternal deletion, a uniparental maternal
disomy or by a faulty imprinting mechanism.
The main characteristics of the syndrome are
the presence of neonatal hypotonia, early onset
of hyperphagia which leads to the development
of morbid obesity and type II diabetes, cogni-
tive and developmental delays, behavioral and
psychiatric problems, and multiple endocrine
manifestations such as growth hormone defi-
ciency, hypogonadism, hypothyroidism. The
global prevalence of PWS is approximately 1
in 15,000 to 25,000 live births [1], and both
sexes are affected equally. The majority of cases
are sporadic. The recurrence risk for siblings is
up to 25 percent.
▷ Prenatal
Prenatal hypotonia, manifesting as decreased
fetal movement, is a constant feature and can
lead to an abnormal fetal position at delivery,
which increases the incidence of assisted delivery
and might require cesarean section. While fetal
size is within the normal range, birth weight and
the body mass index are on average 15% lower
than in healthy newborns [2].
▷ Newborn and infant
This phase is characterized by severe hypo-
tonia, so profound that it can lead to asphyxia,
at which point PWS needs to be differentiated
from severe neonatal hypotonia [3]. Affected
infants often have feeding difficulties, includ-
ing poor suck, weak cry and genital hypoplasia
(e.g., cryptorchidism, scrotal hypoplasia, or cli-
toral hypoplasia). Depigmentation of the skin or
eyes may also be present. Another differential
diagnosis that should be considered is Temple
syndrome (TS), also characterized by hypotonia,

45
developmental delay and excessive weight gain
later in life. One study, consisting of 143 patients
suspected of PWS who were also tested for
Temple syndrome, found 3 patients with PWS
and 3 with TS [4]. While poor feeding and thus
poor weight gain is one of the features of this
stage, studies have documented the presence of
excessive body fat by skin fold measurements [5].
▷▷ Early childhood
Hypotonia persists into early childhood and
the patient has a positive history of poor suck.
Global development is delayed.
▷▷ Late childhood and adolescence
Patients have a positive history of hypotonia
and of poor suck. Hypotonia may persist. Physi-
cal and cognitive delays are more evident. With-
out proper dietary control, hyperphagia may
cause central obesity.
▷▷ Adulthood
Excessive eating with central obesity can be
seen in this phase, but the appetite may subside
in adulthood. Sexual maturity is not achieved
because of hypothalamic hypogonadism. Pa-
tients show cognitive impairment with mild in-
tellectual disability.
Evaluation of comorbidities
▷▷ Dysmorphism
The facial features of PWS are a narrow bi-
frontal diameter, fair hair, almond shaped pal-
pebral fissures, hypopigmentation of the eyes,
a narrow nasal bridge, thin upper lip and down
turned mouth. Individuals with this syndrome
have small hands, with narrow palms and hy-
poplasia of the hypothenar bulges, and small
feet. Hypopigmentation of the hair and eyes
is more frequent among individuals with dele-
tion-type PWS.
▷▷ Nutrition, hyperphagia and obesity
While in the first stage there is poor feeding
and a delay in development, later in childhood,
around 5-8 years of age, is the onset of hyper-
phagia. This transition is complex and follows
multiple stages (Table I.) [6]
Food seeking behaviors may include eating ▷▷ Growth hormone deficiency
garbage, eating frozen food and stealing resourc-
es to obtain food. Studies show decreased satiety nor­ma­lity of PWS, rather than a consequence
46 47
and increased reward feedback in response to
food [7]. High levels of ghrelin, the “hunger hor-
mone” that regulates satiety and the metabolic
rate, can be observed even before the onset of
hyperphagia. Hyperghrelinemia was more strik-
ing in PWS females than males, which may con-
tribute to hyperphagia and excessive weight gain,
but adiponectin levels were higher in females,
maintaining insulin sensitivity [8]. Decreasing
ghrelin levels with somatostatin analogs does
improve eating habits. The intense food seek-
ing behavior and the decreased lean body mass
index and thus decreased metabolic rate, with-
out external control of dietary input, will lead to
the onset of obesity. This can result in multiple
health problems such as cardiorespiratory failure,
cor pulmonale, sleep apnea and severe infections
[9]. Respiratory failure is the most common
cause of death reported for PWS patients [10].
Patients may develop abnormal glucose metabo-
lism with increased insulin resistance; therefore
early and strict dietary intervention with proper
monitoring of nutrition has shown good results.
▷▷ Type 2 diabetes
In a study aimed at determining the health prob-
lems affecting patients with PWS, type 2 diabe-
tes was present in 25% of the cases and the mean
age of onset was 20 years of age. The mean body
mass index of these patients was 37 kg/m2 [11].
Among children suffering from PWS, type 2
diabetes is not common, but impaired glucose
tolerance can be present [12]. Another study
conducted on an Italian Cohort shows a high
prevalence of abnormal glucose metabolism in
adults and in obese patients (regardless of age),
further emphasizing the importance of early nu-
tritional intervention [13]. The introduction of
hGH replacement therapy can also increase the
risk of developing type 2 diabetes, since it in-
creases glucose levels and negatively impacts in-
sulin sensitivity, and screening is recommended
before and during treatment.
Endocrinopathies
Low growth hormone levels are a primary ab­
Table I. Nutritional phases in PWS [6]
phase Median age Clinical characteristics
Decreased fetal movements and
0 Prenatal - birth
lower birth weight than sibs
Hypotonia with difficulty feeding and
1a 0-9 months
decreased appetite
Improved feeding and appetite;
1b 9-25 months
growing appropriately
Weight increasing without appetite increase or
2a 2.1-4.5 years
excess calories
2b 4.5-8 years Increased appetite and calories, but can feel full
3 8 years - adulthood Hyperphagic, rarely feels full
4 Adulthood Appetite no longer insatiable for some
of obesity. Small stature is first noticed at the be found in the literature, but pregnancies have
age of 2, being further exacerbated by the lack been reported [17]. Hypogonadism is both pe-
of growth spurts during puberty. Low levels of ripheral and hypothalamic in origin, therefore
IGF-1 and low basal and stimulated hGH lev- low testosterone and estrogen levels are associ-
els are present, especially in obese patients [14]. ated with low FSH and LH values.
The average height is 1.62 m for male patients ▷▷ Osteoporosis
and 1.49 for females [15]. Treatment should be- The late onset or the lack of pubertal devel-
gin before the onset of obesity, which is usually opment associated with hypogonadism and low
around the age of 2. Early introduction of hGH levels of growth hormone are a major risk factor
replacement therapy shows positive effects on for the development of osteopenia or osteoporo-
physical and cognitive development. sis. This can lead to multiple bone fractures and
▷▷ Hypogonadism spine deformities. With proper GH replacement
It is a constant feature in PWS patients and therapy, bone development and density remain
manifests as hypogonadism throughout life, ab- stable until the age of puberty, when they start
sent or incomplete pubertal development and to decline in the absence of proper sex hormone
infertility. The scrotum is poorly rugated and secretion [18]. Therefore proper initialization of
hypopigmented, unilateral or bilateral cryptor- sex hormone replacement therapy in hypogo-
chidism can be present. In females, the labia ma- nadal patients, together with GH replacement
jor is hypoplastic, a sign that is often overlooked, therapy is critical in preventing the decline of
and while the onset of puberty is the same as bone density in PWS patients [19].
in the general population, progression is delayed
and menstrual cycles tend to be irregular [16].
Among PWS patients, no case of paternity can
Developmental and cognitive delays in these patients is both central and obstruc-
▷▷ Growth hormone deficiency
Motor developmental delay is present in 90-
100% of children with Prader-Willi syndrome,
with early milestones achieved at double the
normal age (e.g., sitting at 12 months, walking
at 24 months). Language development is also
delayed. By the time the child reaches preschool
age, intellectual disabilities become evident. The
mean IQ of patients with PWS is in the 60s to
70s, with 40% having borderline disability and
around 20% having moderate disability [2]. In
the absence of proper behavioral guidance, aca-
demic achievements can be lesser than predicted
by the IQ score [20].
▷▷ Behavioral and psychiatric disturbances
Behavioral problems are a frequent manifesta-
tion of the disease, with the first symptoms ap-
pearing in early childhood in 70-90% of the cases.
It is characterized by temper tantrums, stub-
bornness, obsessive-compulsive behavior, skin
picking which causes skin lesions, and other self-
mutilating acts. Patients with attention problems
responded well to stimulants, which might be
caused by the presence of ADHD, even if hyper-
activity was not observed in these patients [21].
When studying autism spectrum disorder symp-
toms, there was a marked discrepancy between
direct observational assessment and parental as-
sessment [22], and the variable results were possi-
bly related to sex differences and genetic subtype
composition [23]. Compulsivity and insistence
on sameness in routine or events were seen in
76-100% of children and were highly correlated
with lower adaptive functioning [22]. One study
observed the role of rigid routines in the behav-
ior of PWS patients, showing that during early
primary school years there is a higher response to
lower rigidity in routines, results that could also
be observed later in life. However, the presence
of a balance between low rigidity and high ri-
gidity routines is also recognized, the latter being
beneficial for the patients’ current behavior [24].
▷▷ Sleep abnormalities
Throughout childhood, PWS patients mostly
experience typical sleep patterns and only later
in life does sleep apnea occur [25]. Sleep apnea
48 49
tive, and obesity can worsen the symptoms. One
study reports that the prevalence of OSA among
PWS patients is around 79.91% and that among
children, mild OSA was more frequent [26].
Abnormal circadian rhythms, abnormal arousal
response and excessive daytime sleepiness are
characteristic. The literature suggests that ad-
enotonsillectomy is an effective treatment in 60-
85% of the cases; therefore, alternative strategies
should be considered [27].
Diagnosis
In individuals with typical clinical findings
or with cytogenetic findings, Prader-Willi syn-
drome should be suspected, but diagnosis must
be confirmed by genetic testing [28]. The pres-
ence of all age-specific clinical manifestations is
sufficient to justify DNA methylation analysis.
Approximately 70% of patients with PWS have a
15q11.2-q13 deletion on one of the chromosomes.
DNA methylation analysis is very important in
confirming diagnosis for all suspected individu-
als, and even more so in patients with atypical
clinical manifestations. This method detects ab-
normal imprinting in the Prader-Willi critical
region on chromosome 15 (e.g., if the paternally
inherited gene is absent) and can differentiate
between PWS and Angelman syndrome (when
deletion on chromosome 15 is present). It detects
more than 99% of the affected individuals [2].
Complications and prognosis
PWS is a disease with many complications and
comorbidities, among which respiratory failure
is the most prevalent and the most dangerous.
Hyperphagia presents a high risk for developing
metabolic abnormalities such as obesity, high
cholesterol, type 2 diabetes, leading to obstruc-
tive sleep apnea, cardiorespiratory failure, cor
pulmonale. Fast paced eating and lack of sati-
ety in response to food frequently lead to chok-
ing episodes, food poisoning and sometimes to
acute gastric dilation and gastric necrosis. Due
to the lack of proper bone ossification caused by
the early onset of hypogonadism, patients often
develop scoliosis, osteoporosis and pathological
fractures. A study from 2015 reveals that a total
of 486 deaths were reported between 1973 and
2015 (263 males, 217 females, 6 unknown), with
a mean age of 29.5 ± 16 years (2mo–67yrs), 70%
occurring in adulthood. Respiratory failure was
the most common cause, accounting for 31% of
all deaths [10]. Recently, the number of acciden-
tal deaths in males has increased, possibly due
to enhanced weight management and mobility,
while the overall risk of death from respiratory
failure has remained unchanged [30].
Table II. Diagnostic criteria for Prader-Willi
syndrome [29]
Birth to age two years
Hypotonia with poor suck (neonatal period)
Age two to six years
Hypotonia with history of poor suck,
global developmental delay
Age six to 12 years:
History of hypotonia with poor suck
(hypotonia often persists), global
developmental delay, excessive eating
with central obesity if uncontrolled
Age 13 years to adulthood
Cognitive impairment, usually mild
intellectual disability, excessive eating with
central obesity if uncontrolled,
hypothalamic hypogonadism and/or
typical behavior problems
Conclusions
In conclusion, Prader-Willi syndrome is a
complex disease with multiple comorbidities that
require thorough examination and early inter-
vention, such as metabolic problems, endocrine
abnormalities, mental disability and behavioral
problems. PWS should be suspected in any pa-
tient with typical clinical findings, and diagnosis
should be confirmed by DNA methylation anal-
ysis. Hormone replacement therapy and proper
nutritional and behavioral guidance are necessary
to improve the quality of life of PWS patients.
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