PRADER-WILLI SYNDROME: WHAT IS THE GENERAL PEDIATRICIAN SUPPOSED TO
DO? - A REVIEW
The Prader-Willi Syndrome (PWS) is a rare genetic disorder resulting from the loss of
gene expression within the paternal chromosome 15q11-q13. PWS has a prevalence rate
of 1/10-30,000 and is characterized by endocrine abnormalities due to
hypothalamic-pituitary insufficiency and complex physical, behavioral and
intellectual difficulties. Nowadays, most developing countries can reach an early diagnosis, at around 8.6 weeks
of life, however, even in centers of mean reference of the diagnosis, it happens at
3.9 years of age. The purpose of clinical diagnostic criteria has changed in the
last decades. In 1993, when genetic tests were still very limited, a consensus was
established that served as a guideline for the diagnosis and was known as the
criteria of HOLM. Gunay-Aaygun et al., in 2001, aiming at an early diagnosis, proposed
sufficient features of PWS, which should prompt DNA testing: hypotonia with poor
sucking under 2 years of age, hypotonia with history of poor sucking and global
developmental delay between 2-6 years of age, and hyperphagia and cognitive
impairment after the age of 6 years. As the disease aspects may be non-specific or only appear over time,
clinical criteria may often fail to identify PWS cases. However, in the last
decades, molecular genetic tests became available for the definitive diagnosis of
PWS, and clinical criteria were recognized as an initial screening for the
indication of the genetic test. Three different genetic mechanisms can lead to PWS: paternal deletion within
chromosome region 15q11-q13, which occurs in approximately 70% of the cases.
Maternal uniparental disomy of chromosome 15 (UPD15), occurring in approximately 25%
of the affected individuals, whereas about 2% of PWS patients have biparental
inheritance of chromosome 15, but show abnormal methylation pattern and gene
expression. These patients have a defect in the imprinting center. The recurrence
risk in deletion and UPD cases is less than 1%, whereas for families in which the
patient presents with defect in imprinting, the risk can be as high as 50%. , Therefore, the identification of the genetic mechanism involved in each
patient is a requirement for the genetic counseling and depends on the efficiency
and reliability of the genetic test. An efficient strategy for the routine diagnosis of PWS patients consists of
methylation analysis, which allows the diagnosis of 99% of PWS patients, and does
not require parental samples. In patients with a normal methylation pattern and
normal chromosomes, a clinical reassessment is recommended to determine whether
additional DNA investigations are indicated. PWS is the main genetic cause of obesity in children, and the early approach can
improve quality of care, which may give these individuals a better perspective of
life. 

The weight, length and body mass index of infants with PWS is often in the normal
range at birth, however, they evolve with hypotonia associated with suction and
feeding impairments, besides growth impairment. According to Miller, there are seven different nutritional phases to which
individuals with PWS typically progress. At the pre-natal phase (phase 0), there are
reduced fetal movements and growth restriction. From birth up to 9 months of age
(phase 1a) the infant is hypotonic, has feeding impairment and reduced appetite.
After this period, PWS patients start gaining weight progressively. In spite of a
normal caloric intake, they gain weight due to reduced metabolism (phase 1b: 9
months-2 years/phase 2a:2-4.5 years). After 4.5 years (phase 2b), the weight
increase is associated with increased interest in food, but not hyperphagia. Around
the age of 8 years, hyperphagia is established, characterized by food seeking and
lack of satiety. Some of the individuals with PWS progress to phase 4 in adult life,
when there is some leve of satiety. During early childhood, there is delayed motor and language development, with
milestones achieved at about double the normal age. Intellectual and/or learning
disabilities are variable and generally evident by the time the child reaches school
age. 

Individuals with PWS can present with several different endocrine disorders, most of
them caused by hypothalamic-pituitary insufficiency. rhGH deficiency The insulin-like growth factor 1 (IGF1) and the insulin-like growth factor
binding protein 3 (IGFBP3) are low in PWS, and GH deficiency occurs in 40-100%
of children. Growth hormone is an anabolic agent that increases lean body mass (LBM) and
decreases fat mass in a range of conditions. It is recommended that rhGH therapy
be discussed at the time of diagnosis and GH testing is not mandatory before the
beginning of GH treatment. One of the most important reasons for treating PWS children with rhGH is
to improve their body composition, increasing LBM and reducing fat mass, once
the natural history of PWS shows increasing progressive fat mass with age. , The rhGH therapy in combination with a healthy lifestyle makes it possible to
counteract the clinical course of PWS, preventing obesity, a major threat to
these patients. Another important gain from the use of rhGH therapy is the positive effect on
markers of development, such as verbal IQs, adaptive communication, cognitive
skills and language. , Children who began treatment before 12 months of age had higher
nonverbal and higher composite IQs than children who began treatment between 1
and 5 years of age. The use of rhGH has not demonstrated any adverse effects on glucose parameters,
lipid profile, bone mineral density or blood pressure, although insulin levels,
HOMA-IR and IGF-1 may increase, as expected, during therapy. There was not a
clear correlation between rhGH therapy and the development of scoliosis, but a
close follow-up is recommended for its high prevalence in PWS, especially during
puberty. , Growth hormone replacement in children with PWS has well-defined benefits and
risks, although data are limited to adults with PWS. The reports on rhGH treatment in adults with PWS indicate improved body
composition, with increased LBM, reduced total body fat, subcutaneous adiposity
and visceral fat, but with minor increase in fasting glucose after 12 months of
treatment. Exclusion criteria for starting rhGH therapy in patients with PWS include severe
obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active
cancer, and active psychosis. Infants and children with PWS should start on a
daily dose of 0.5 mg/m 2 /day, with subsequent adjustments toward 1.0
mg/m 2 /day every 3-6 months, according to clinical response.
Adults with PWS should receive a starting dose of 0.1-0.2 mg/day. Subsequent
dose titration should be based on clinical response, age, and sex-appropriate
IGF-I levels in the 0 to +2 SDS range. Central Adrenal Insufficiency In a study with 25 randomly selected PWS children performed by van Wijingaarden
et al., 60% of the children presented with central adrenal insufficiency,
although they had normal morning salivary cortisol levels. It suggests that
adrenal insufficiency becomes apparent only during stressful conditions.
Therefore, it is recommended to monitor cortisol levels before starting the rhGH
treatment and assess them in situations of severe comorbidity. Van Wijingaarden
et al. also suggested that hydrocortisone should be used during the acute phase
of severe diseases that affect the patient ( ) . Hypothyroidism Hypothyroidism, particularly of central origin, is present in PWS. It has been
documented in up to 25% of the individuals with PWS. In general, thyroid function is normal at birth and treatment should not be
routinely prescribed to young people with PWS. It is important to perform
thyroid function screening regularly, since hypothyroidism can contribute with
delayed psychomotor development, impaired linear growth during childhood and
increasing fat mass and hypotonia. Hypogonadism Hypogonadism is highly frequent among PWS patients, and its presentation is
extremely variable. It is usually seen as genital hypoplasia, delayed puberty,
incomplete pubertal development and infertility, but early puberty and premature
pubarche may occur as well. The etiology of hypogonadism in PWS is heterogeneous and is due to a combination
of hypothalamic and gonadal primary dysfunction, besides the fact that sexual
hormones (testosterone and estradiol) are usually below normal range. Even though the benefits of sex hormone replacement in hypogonadism are well
known, there are few reports in the literature and there is still no consensus
about when or how it should be done. Obesity Obesity and its complications are the major causes of morbidity and mortality in
individuals with PWS. There is some evidence to suggest a hypothalamic basis and
an abnormal neural response to food intake. In PWS, the response os satiety is delayed, reduced or absent to
food. The etiology of obesity is mostly attributed to a low basal metabolism
and an elevated circulating ghrelin level than to the increased caloric
intake. The maximal weight in PWS patients frequently occurs in late adolescence and
early adulthood. For these patients, uncertainty and opportunity related to food
consumption are a constant source of stress. Thus, they show signs of anxiety
and other stress symptoms when they are responsible for their own food
regulation. The main implication of these findings for the management of PWS is
that the supervision of the food environment is critically important. Early
counseling, caloric restriction and dietary recommendations can help keeping
normal weight-for-height ratio. Up to now, pharmacologic intervention with appetite suppressants (sibutramine),
anti-absorption agents (orlistat), topiramate or glucagon-like peptide 1 (GLP-1)
receptor agonist have been ineffective in patients with PWS. A small series of cases reported short-term success with bariatric surgery in
PWS. The results suggest there is little justification for subjecting PWS
patients to the potential risks of surgical interventions, besides the risk of
gastric rupture. The best recommendation for weight control in cases of severe
obesity includes the use of supervised energy reduction diets with
vitamin/mineral supplementation, restricted access to food, and a daily exercise
regimen. Impaired glucose tolerance and diabetes mellitus Up to 25% of adults with PWS presented type 2 diabetes. In a multicenter study based on 274 PWS patients, altered glucose was
detected in 24.4% of the patients and was significantly correlated to age, body
mass index (BMI) and HOMA-IR. This study shows the strong correlation between
development of altered glucose metabolism, obesity and aging. 

The insulin-like growth factor 1 (IGF1) and the insulin-like growth factor
binding protein 3 (IGFBP3) are low in PWS, and GH deficiency occurs in 40-100%
of children. Growth hormone is an anabolic agent that increases lean body mass (LBM) and
decreases fat mass in a range of conditions. It is recommended that rhGH therapy
be discussed at the time of diagnosis and GH testing is not mandatory before the
beginning of GH treatment. One of the most important reasons for treating PWS children with rhGH is
to improve their body composition, increasing LBM and reducing fat mass, once
the natural history of PWS shows increasing progressive fat mass with age. , The rhGH therapy in combination with a healthy lifestyle makes it possible to
counteract the clinical course of PWS, preventing obesity, a major threat to
these patients. Another important gain from the use of rhGH therapy is the positive effect on
markers of development, such as verbal IQs, adaptive communication, cognitive
skills and language. , Children who began treatment before 12 months of age had higher
nonverbal and higher composite IQs than children who began treatment between 1
and 5 years of age. The use of rhGH has not demonstrated any adverse effects on glucose parameters,
lipid profile, bone mineral density or blood pressure, although insulin levels,
HOMA-IR and IGF-1 may increase, as expected, during therapy. There was not a
clear correlation between rhGH therapy and the development of scoliosis, but a
close follow-up is recommended for its high prevalence in PWS, especially during
puberty. , Growth hormone replacement in children with PWS has well-defined benefits and
risks, although data are limited to adults with PWS. The reports on rhGH treatment in adults with PWS indicate improved body
composition, with increased LBM, reduced total body fat, subcutaneous adiposity
and visceral fat, but with minor increase in fasting glucose after 12 months of
treatment. Exclusion criteria for starting rhGH therapy in patients with PWS include severe
obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active
cancer, and active psychosis. Infants and children with PWS should start on a
daily dose of 0.5 mg/m 2 /day, with subsequent adjustments toward 1.0
mg/m 2 /day every 3-6 months, according to clinical response.
Adults with PWS should receive a starting dose of 0.1-0.2 mg/day. Subsequent
dose titration should be based on clinical response, age, and sex-appropriate
IGF-I levels in the 0 to +2 SDS range. 

In a study with 25 randomly selected PWS children performed by van Wijingaarden
et al., 60% of the children presented with central adrenal insufficiency,
although they had normal morning salivary cortisol levels. It suggests that
adrenal insufficiency becomes apparent only during stressful conditions.
Therefore, it is recommended to monitor cortisol levels before starting the rhGH
treatment and assess them in situations of severe comorbidity. Van Wijingaarden
et al. also suggested that hydrocortisone should be used during the acute phase
of severe diseases that affect the patient ( ) . 

Hypothyroidism, particularly of central origin, is present in PWS. It has been
documented in up to 25% of the individuals with PWS. In general, thyroid function is normal at birth and treatment should not be
routinely prescribed to young people with PWS. It is important to perform
thyroid function screening regularly, since hypothyroidism can contribute with
delayed psychomotor development, impaired linear growth during childhood and
increasing fat mass and hypotonia. 

Hypogonadism is highly frequent among PWS patients, and its presentation is
extremely variable. It is usually seen as genital hypoplasia, delayed puberty,
incomplete pubertal development and infertility, but early puberty and premature
pubarche may occur as well. The etiology of hypogonadism in PWS is heterogeneous and is due to a combination
of hypothalamic and gonadal primary dysfunction, besides the fact that sexual
hormones (testosterone and estradiol) are usually below normal range. Even though the benefits of sex hormone replacement in hypogonadism are well
known, there are few reports in the literature and there is still no consensus
about when or how it should be done. 

Obesity and its complications are the major causes of morbidity and mortality in
individuals with PWS. There is some evidence to suggest a hypothalamic basis and
an abnormal neural response to food intake. In PWS, the response os satiety is delayed, reduced or absent to
food. The etiology of obesity is mostly attributed to a low basal metabolism
and an elevated circulating ghrelin level than to the increased caloric
intake. The maximal weight in PWS patients frequently occurs in late adolescence and
early adulthood. For these patients, uncertainty and opportunity related to food
consumption are a constant source of stress. Thus, they show signs of anxiety
and other stress symptoms when they are responsible for their own food
regulation. The main implication of these findings for the management of PWS is
that the supervision of the food environment is critically important. Early
counseling, caloric restriction and dietary recommendations can help keeping
normal weight-for-height ratio. Up to now, pharmacologic intervention with appetite suppressants (sibutramine),
anti-absorption agents (orlistat), topiramate or glucagon-like peptide 1 (GLP-1)
receptor agonist have been ineffective in patients with PWS. A small series of cases reported short-term success with bariatric surgery in
PWS. The results suggest there is little justification for subjecting PWS
patients to the potential risks of surgical interventions, besides the risk of
gastric rupture. The best recommendation for weight control in cases of severe
obesity includes the use of supervised energy reduction diets with
vitamin/mineral supplementation, restricted access to food, and a daily exercise
regimen. 

Up to 25% of adults with PWS presented type 2 diabetes. In a multicenter study based on 274 PWS patients, altered glucose was
detected in 24.4% of the patients and was significantly correlated to age, body
mass index (BMI) and HOMA-IR. This study shows the strong correlation between
development of altered glucose metabolism, obesity and aging. 

Individuals with PWS present with impaired cognitive, communication and social
skills. They may show a compulsive, manipulative and controlling behavior including
stubbornness, episodes of temper tantrums and difficulties in changing routines.
They also present a mild intellectual disability, with a mean IQ of approximately
65-70. A study comparing magnetic resonance imaging brain scan and cognitive skills showed
reduction in cortical gyrus, mainly in the frontal, temporal and parietal lobes,
irrespective of the genetic subtype. There was strong correlation between the
alterations of these brain regions and the verbal impairment and lower IQ score in
the PWS group. Frontal-parietal cortical areas are implicated in cognitive function,
such as memory, attention regulation and language. PWS carriers are prone to more severe behavior problems, and as many as 85% show
clinically elevated scores on standardized behavioral evaluation questionnaires.
They present with high rates of obsessive-compulsive symptoms, which may express as
excessive hoarding, repetitive rituals, talking too much and skin picking. Of these,
skin picking seems to be the most prevalent and starts in early childhood. Aggressive behavior is common and temper tantrums occurred in 88% of the
individuals aged between 4-16 years old, but the severity of these problems range
widely. Studies suggest a strong association between PWS and atypical psychosis. These
episodes were generally of sudden onset and often included depressive features with
good response to pharmacotherapy and hospitalization. Repetitive and ritualistic behavior found in PWS individuals may differ from that
seen in Obsessive-Compulsive Disorder, but may have similarities with the Autism
Spectrum Disorder (ASD) characteristics. , The denomination ‘autistic-like symptomatology’ may be appropriate when
referring to PWS compulsive behavior and lack of social skills. The use of intranasal oxytocin for controlling PWS behavior has come as a possibility
of treatment for these patients, but the benefits and risks are still unkown. 

Sleep Disorders Sleep disoders are frequently associated with PWS. Excessive daytime sleepiness
(EDS) is the most common condition, followed by obstructive sleep apnea and
narcolepsy-like symptoms. Obesity and hypothalamic dysfunction can, together, be
responsible for the primary abnormalities of ventilation during sleep and
determine the symptoms of EDS. In PWS individuals, unlike the general population, the EDS is not fully explained
by the obstructive sleep apnea syndrome. EDS and REM sleep disorders together are described in narcolepsy syndrome. In
PWS, these narcoleptic symptoms are mainly owed to hypothalamic dysfunction,
once the genetic traces of classic narcolepsy syndrome are not found in
PWS. Full night polysomnography studies are recommended in children with abnormal
weight gain, snoring, and appearance of daytime symptoms or poor school
performance. The follow-up of sleep issues on PWS patients can be performed by means
of well-established sleep-related questionnaires, in order to look for specific
sleep disorders. EDS can be treated with central nervous system stimulants, such as
methylphenidate or modafinil, after complete clinical evaluation. Obstructive
sleep apnea should be treated with oral appliances, continuous or bi-level
positive airway pressure devices (CPAP or BiPAP) or tonsil surgery. Scoliosis Scoliosis is frequently observed in children with PWS, with prevalence between 30
and 70%. Such high frequency may be partly explained by hypotonia and
obesity. There are two peak ages for scoliosis in children with PWS. The presence
of scoliosis under the age of 4 is most likely related to hypotonia, and the
second peak, around 10 years of age, is typically idiopathic. The earlier the change in the spinal curve is detected, the better the
possibilities of treatment with casting or surgical treatment. This is indicated
in severe early-onset scoliosis-kyphosis and in adolescents near skeletal
maturity. Surgical complications are the risk of paraplegia (20%) and other
major problems (30% of deep infections, pneumonia, hook out). Gastrointestinal Disorders There are only few studies investigating the gastrointestinal function of
individuals with PWS. Some studies have found either normal or slow gastric
emptying in PWS. Serious events with gastric rupture and necrosis followed by
death have been reported and may be attributed to slow gastric emptying and
absence of vomit. , The incidence of constipation is around 40% in adult PWS patients, which is
considerably higher than reported in the general population. They also have an
increased prevalence of palpable stool in the rectum and prolonged
gastrointestinal transit time. Coagulation Disorders Although thromboembolic events (TEs) have been recently reported in patients with
PWS, there is no specific guideline for prophylaxis of TEs in this population of
patients. We recommend that inpatients should be evaluated for risk of TE and
receive mechanical prophylaxis (early end frequent ambulation, compression
stockings, intermittent pneumatic compression devices and venous foot pumps),
because they counteract most of the components of the Virchow’s triad and are
not associated with any risk of bleeding. Combined mechanical and
pharmacological prophylaxis should be considered only in PWS patients with high
risk of TEs. Dental issues Dental problems are very common in PWS. PWS individuals have shown reduction in
salivary flow rate and increase in the amounts of salivary ions and proteins.
They present with thick saliva which sticks to the teeth and harbors bacteria
that cause tooth decay and periodontal disease. 

Sleep disoders are frequently associated with PWS. Excessive daytime sleepiness
(EDS) is the most common condition, followed by obstructive sleep apnea and
narcolepsy-like symptoms. Obesity and hypothalamic dysfunction can, together, be
responsible for the primary abnormalities of ventilation during sleep and
determine the symptoms of EDS. In PWS individuals, unlike the general population, the EDS is not fully explained
by the obstructive sleep apnea syndrome. EDS and REM sleep disorders together are described in narcolepsy syndrome. In
PWS, these narcoleptic symptoms are mainly owed to hypothalamic dysfunction,
once the genetic traces of classic narcolepsy syndrome are not found in
PWS. Full night polysomnography studies are recommended in children with abnormal
weight gain, snoring, and appearance of daytime symptoms or poor school
performance. The follow-up of sleep issues on PWS patients can be performed by means
of well-established sleep-related questionnaires, in order to look for specific
sleep disorders. EDS can be treated with central nervous system stimulants, such as
methylphenidate or modafinil, after complete clinical evaluation. Obstructive
sleep apnea should be treated with oral appliances, continuous or bi-level
positive airway pressure devices (CPAP or BiPAP) or tonsil surgery. 

Scoliosis is frequently observed in children with PWS, with prevalence between 30
and 70%. Such high frequency may be partly explained by hypotonia and
obesity. There are two peak ages for scoliosis in children with PWS. The presence
of scoliosis under the age of 4 is most likely related to hypotonia, and the
second peak, around 10 years of age, is typically idiopathic. The earlier the change in the spinal curve is detected, the better the
possibilities of treatment with casting or surgical treatment. This is indicated
in severe early-onset scoliosis-kyphosis and in adolescents near skeletal
maturity. Surgical complications are the risk of paraplegia (20%) and other
major problems (30% of deep infections, pneumonia, hook out). 

There are only few studies investigating the gastrointestinal function of
individuals with PWS. Some studies have found either normal or slow gastric
emptying in PWS. Serious events with gastric rupture and necrosis followed by
death have been reported and may be attributed to slow gastric emptying and
absence of vomit. , The incidence of constipation is around 40% in adult PWS patients, which is
considerably higher than reported in the general population. They also have an
increased prevalence of palpable stool in the rectum and prolonged
gastrointestinal transit time. 

Although thromboembolic events (TEs) have been recently reported in patients with
PWS, there is no specific guideline for prophylaxis of TEs in this population of
patients. We recommend that inpatients should be evaluated for risk of TE and
receive mechanical prophylaxis (early end frequent ambulation, compression
stockings, intermittent pneumatic compression devices and venous foot pumps),
because they counteract most of the components of the Virchow’s triad and are
not associated with any risk of bleeding. Combined mechanical and
pharmacological prophylaxis should be considered only in PWS patients with high
risk of TEs. 

Dental problems are very common in PWS. PWS individuals have shown reduction in
salivary flow rate and increase in the amounts of salivary ions and proteins.
They present with thick saliva which sticks to the teeth and harbors bacteria
that cause tooth decay and periodontal disease. 

The treatment provided in the Department of Pediatric Endocrinology of the Children’s
Institute of Universidade de São Paulo for these patients is based on a follow-up
protocol with four main pillars: diet ( ), exercise, rhGH use and behavioral and cognitive issues, highlighted on and on a health maintenance
timeline for children with PWS ( ) 

The Prader-Willi Syndrome is rare genetic disease, even though it is the main genetic
cause of obesity in children. Early diagnosis can prevent complications and improve
quality of care throughout life. The treatment focuses on four main pillars: diet,
exercise, rhGH therapy and behavioral strategies. If the general pediatrician becomes more familiar with PWS, the diagnosis will have a
higher probability to take place and, so, treatment will start earlier. This may
improve the quality of life and care for these individuals. 

