Prader Willi

S P E C I A L F E A T U R E
C l i n i c a l P r a c t i c e G u i d e l i n e
Recommendations for the Diagnosis and

Management of Prader-Willi Syndrome
A. P. Goldstone, A. J. Holland, B. P. Hauffa, A. C. Hokken-Koelega, and M. Tauber, on behalf of

speakers and contributors at the Second Expert Meeting of the Comprehensive Care of Patients
with PWS
Department of Investigative Medicine (A.P.G.), Medical Research Center Clinical Sciences Centre and Endocrine Unit, Hammersmith
Hospital, Imperial College London W12 ONN, United Kingdom; Department of Psychiatry (A.J.H.), Section of Developmental Psychiatry,
University of Cambridge, Cambridge CB2 8AH, United Kingdom; Department of Endocrinology (B.P.H.), University Childrens Hospital,
45122 Essen, Germany; Department of Pediatric Endocrinology (A.C.H.-K.), Erasmus University Medical Centre and Sophia Childrens
Hospital, 3000 DR Rotterdam, The Netherlands; and Department of Endocrinology (M.T.), Hopital des Enfants and Paul Sabatier
Universite, 31059 Toulouse, France
Objective: The objective of the study was to provide recommendations for the diagnosis and
management of Prader-Willi syndrome throughout the life span to guide clinical practice.
Participants: An open international multidisciplinary expert meeting was held in October 2006 in
Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85
additional registered participants. The meeting was supported by an unrestricted educational
grant from Pfizer.
Evidence: Invited participants with particular expertise reviewed the published evidence base for
their specialist topic and unpublished data from personal experience, previous national and in-
ternational PWS conferences, and PWS Association clinical advisory groups. Sessions covered ep-
idemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics;
endocrinology; and management in infancy, childhood, transition, and adulthood.
Consensus Process: This included group meetings including open discussion after each session. The
guidelines were written by the Scientific Committee (authors), using the conclusions provided by
the sessions chairs and summary provided by each speaker, including incorporation of changes
suggested after review by selected meeting participants (see Acknowledgments).
Conclusions: The diagnosis and management of this complex disorder requires a multidisciplinary
approach with particular emphasis on the importance of early diagnosis using accredited genetic
testing, use and monitoring of GH therapy from early childhood, control of the food environment
and regular exercise, appropriate management of transition, consideration of group home place-
ment in adulthood, and distinction of behavioral problems from psychiatric illness. (J Clin Endo-
crinol Metab 93: 4183 4197, 2008)
P rader-Willi syndrome (PWS) is a complex multisystem genetic

disorder that arises from lack of expression of paternally in-
herited imprinted genes on chromosome 15q11-q13 (15). The
disabilities, behavioral problems, and psychiatric phenotypes
with severe consequences and difficult management issues for
patients, families, and care givers (6 10). Whereas earlier prev-
syndrome has characteristic phenotypes (6, 7) including severe alence estimates in the United States were in the range of 1 in
neonatal hypotonia; early onset of hyperphagia; and develop- 8,000 20,000, recent epidemiological surveys in Europe and
ment of morbid obesity, short stature, hypogonadism, learning Australia have estimated the lower limit of birth incidence at
0021-972X/08/$15.00/0 Abbreviations: AHI, Apnea-hypopnea index; BMD, bone mineral density; BMI, body mass
Printed in U.S.A. index; FISH, fluorescence in situ hybridization; FTT, failure to thrive; ID, imprinting defect;
OSAS, obstructive sleep apnea syndrome; PWS, Prader-Willi syndrome; SDS, SD score;
Copyright 2008 by The Endocrine Society SRBD, sleep-related breathing disorders; UPD, uniparental disomy.
doi: 10.1210/jc.2008-0649 Received March 20, 2008. Accepted August 1, 2008.
First Published Online August 12, 2008
J Clin Endocrinol Metab, November 2008, 93(11):4183 4197 jcem.endojournals.org 4183
Downloaded from jcem.endojournals.org at Bibl Sante Univ Paul Sabatier on March 6, 2009
4184 Goldstone et al. Recommendations for PWS J Clin Endocrinol Metab, November 2008, 93(11):4183 4197
around 1 in 30,000, and population prevalence at about 1 in ylation analysis shows only a maternal pattern, then PWS is
50,000 (5, 1113). Recent surveys have highlighted the high confirmed. Further methods may then be performed to deter-
rates and varied causes of morbidity and mortality throughout mine the genetic subtype and allow appropriate genetic coun-
the natural history of the disease (14 16). There is a clear need seling, in particular the recurrence risk.
for an integrated multidisciplinary approach to facilitate early Fluorescence in situ hybridization (FISH) analysis has the ad-
diagnosis and optimize management to improve quality of life, vantage of needing only a sample from the proband to detect
prevent complications, and prolong life expectancy (17). chromosome 15q11-q13 deletions in PWS (30). High-resolution
As the outcome of the recent expert meeting on the compre- chromosome analysis will detect only 60% of interstitial chro-
hensive care of patients with PWS, this paper summarizes clinical mosome deletions (30). Chromosomal translocations or rear-
practice guidelines, with emphasis on medical and behavioral/ rangements may also be detected using this method. Negative
psychiatric management, adding to earlier publications also FISH or karyotype analysis does not exclude the diagnosis and
based on accumulated expert opinion (18, 19). Due to space so if done first should be followed by DNA methylation analysis.
limitations, discussion about education, employment, and social Furthermore, Angelman syndrome can present with neonatal
and sexual issues in the management of children and adults with hypotonia, and FISH alone may therefore result in misdiagnosis
PWS is out of the scope of these current recommendations. Read- because it will detect maternal 15q11-q13 deletions.
ers are referred to other sources (19). If subsequent DNA methylation analysis is positive for PWS,
then DNA polymorphism analysis should be performed on the
Diagnostic issues proband and parents to distinguish a maternal UPD from an
Although the diagnosis can easily be suspected from well- imprinting defect (26, 31). Patients with an imprinting defect
defined clinical diagnostic criteria, even in the neonatal period, (ID) warrant further investigation in a specialized laboratory to
the increasing availability and application of molecular tech- determine whether an imprinting center deletion is present (32,
niques means that genetic testing by an appropriately licensed 33). Those families with a child with an imprinting center dele-
laboratory is mandatory to confirm the diagnosis. tion have a recurrence risk of up to 50% if the father of the child
Over the last 10 yr, the age of diagnosis has fallen significantly is a carrier for the imprinting center deletion (32, 33). The risk of
and the majority of cases are now diagnosed during the first recurrence in case of chromosomal translocations is evaluated up
months of life (17, 20, 21). This should allow the earlier intro- to 10%. In the other groups, the risk of recurrence is the same as
duction of therapies to reduce the morbidity in particular by the general population.
preventing obesity. This will not only increase the quality of life In the future the new method, methylation-specific multiplex
for patients but also reduce the burden on the family and care ligation PCR amplification, may be more widely used because it
givers. has the advantage of combining dosing and DNA methylation
analysis in one assay, thus distinguishing PWS deletions from
Definition UPDs and IDs as well as providing an approximate size of the
PWS arises from the lack of expression of genes on the pa- deletion (34).
ternally derived chromosome 15q11-q13. Candidate genes for
PWS in this region are physiologically imprinted and silenced on Genotype-phenotype correlations
the maternally inherited chromosome (4, 10). PWS develops if There are also several biallelic and maternally expressed, pa-
the paternal alleles are defective, missing, or silenced. In 75% of ternally imprinted genes throughout the PWS chromosomal re-
cases, there is paternal deletion of chromosome 15q11-q13 (type gion. Their relative under- or overexpression may explain the
I or II, depending on the proximal breakpoint) (22, 23), maternal increasingly recognized genotype-phenotype correlations, such
uniparental disomy (UPD) in 24%, and imprinting errors in 1% as differences between type I and II deletions, and between de-
[due in 15% of cases to either a sporadic or inherited microde- letion and UPD. In particular hypopigmentation is seen primarily
letion in the imprinting center (for review see Ref. 24)], whereas in those with deletion. Patients with UPD have less consistent
there is a paternal chromosomal translocation in less than 1% of presence of the characteristic facial phenotype and an increased
cases. risk of psychosis (35, 36) but higher verbal intelligence scores and
less maladaptive behaviors (37 40), compared with patients
Genetic testing methods with deletions. Intellectual ability, academic achievement, and
There are different methods for confirming the diagnosis and behavioral and psychological problems appear to be worse in
identifying the genetic subtype using peripheral blood lympho- subjects with the larger type I deletion than in type II deletion or
cytes (25). Because imprinted genes demonstrate differential UPD (41 45). More work will be needed before we can consider
DNA methylation dependent on parental origin (3, 26), patients whether and how to translate these differences to individualize
with PWS have a maternal-only imprint because they are lacking the management of patients according to their genotype.
a paternal contribution. DNA methylation analysis is the only
technique, which can both confirm and reject the diagnosis of Prenatal diagnosis
PWS, and therefore should typically be the initial investigation of A prenatal diagnosis is rarely made, but theoretically it could
choice. This is most commonly done using DNA methylation- be suspected in cases of reduced fetal movement and polyhy-
specific techniques at the SNURF-SNRPN locus (2729). Pa- dramnios (46). Genetic testing on samples obtained from cho-
rental samples are not required for this analysis. If DNA meth- rionic villous sampling and amniocentesis can be performed (47).
FISH analysis can easily pick up deletions from such tissue, but Differential diagnosis
DNA methylation analysis would be necessary for cases of UPD Patients with negative testing for PWS should be investigated
and IDs. However, the few clinical laboratories doing DNA for other chromosomal deletions and duplications and possible
methylation analysis in a prenatal setting are reluctant to use monogenic defects that are associated with PWS or PWS-like
such chorionic villous sampling samples due to the relevant hy- features (50 54). Other genetic obesity syndromes, such as Bar-
pomethylation of this tissue. In the future the introduction of det-Biedel and fragile X syndrome, associated with cognitive
techniques such as comparative array genomic hybridization impairment, can sometimes cause clinical confusion (55). In Bar-
might be transferred to prenatal diagnosis of PWS due to dele- det-Biedel syndrome, although visual impairment does not usu-
tions with resulting ethical implications. ally emerge until 6 8 yr, other phenotypes such as polydactyly
(two in three cases), brachydactyly and high arched palate can
Postnatal diagnosis assist in early diagnosis.
There is a marked clinical variability throughout life. The
evolving phenotype from birth to adulthood means that the clin- Management of infants
ical features that should lead to a suspicion of the diagnosis
depend on the age of the patient (Table 1). A diagnosis of PWS Tube feeding
is particularly helpful during the first months of life and should Historically many neonates and infants were tube fed for more
be thought of in all infants with severe and unexplained hypo- than 2 months because of severe hypotonia and poor suckling re-
tonia (48). In addition, the presence of a thin upper lip, almond- sulting in FTT, defined as descent across the centiles of weight or
shaped eyes, acromicria (short hands and feet), and genital body mass index (BMI). There is no consensus to date on the op-
hypoplasia adds to the clinical diagnosis, which should be timal feeding regimen, whether the use of tube feeding is mandatory
confirmed by genetic testing. During childhood, a genetic test or should be used only after intensive and persistent nursing has
for PWS should not be performed in every obese child with learn- failed, given the theoretical possibility that it could worsen speech
ing disabilities, but a reduced growth velocity, specific dysmor- problems. Concerns about the potentially long-term deleterious
phic features, and history of neonatal hypotonia are strong metabolic and cardiovascular effects of excessive weight gain dur-
pointers to initiate testing. Finally, genetic testing should also be ing the first 2 yr of life in non-PWS infants prompt caution against
considered in adolescents and adults with a less marked pheno- overfeeding in PWS with FTT (56, 57).
type but behavioral and psychological problems in addition to
obesity and delayed or incomplete gonadal maturation. Of note Cryptorchidism
is the fact that the absence of any of the core features of the early Cryptorchidism is present in over 80% of boys from birth
phenotype: hypotonia, failure to thrive (FTT) and, in boys, un- (58, 59). As with non-PWS boys, orchidopexy should be per-
descended testes, has been found to be associated with negative formed ideally during the first or the second year, particularly
genetics for PWS (49). because there is evidence of both primary and central hypogo-
nadism (58, 59), and rare cases of testicular cancer have been
reported in PWS (60). Scrotal hypoplasia and the development of
TABLE 1. Indications for DNA testing obesity can make surgery difficult if delayed until a later age and
Features sufficient to prompt could require repeated surgical interventions.
Age at assessment DNA testing
Birth to 2 yr Hypotonia with poor suck Motor program
2 6 yr Hypotonia with a history of poor suck Children with PWS have muscular hypotonia, decreased mus-
Global developmental delay cle mass, psychomotor delay, and reduced motor activity (61) as
Short stature and/or growth failure
well as increased variability in the size of both type I and II muscle
associated with accelerated weight
gaina fibers, and atrophy of activity-dependent type II fibers has been
6 12 yr Hypotonia with a history of poor suck seen on biopsy (62). Training programs, initiated and supervised
(hypotonia often persists) by physiotherapists and maintained by parents, have been used
Global developmental delay for many years without any evidence base (e.g. earlier onset of
Excessive eating (hyperphagia,
walking) but would seem sensible particularly in combination
obsession with food) with central
obesity if uncontrolled with GH treatment (see section below). Specific programs may
13 yr through adulthood Cognitive impairment, usually mild be necessary to counteract the inability of the hypotonic PWS
mental retardation infant to overcome gravity while moving during the early years
Excessive eating (hyperphagia, of life. These years may be a particularly sensitive period for motor
obsession with food) with central
development and skill acquisition, which have consequences for
obesity if uncontrolled
Hypothalamic hypogonadism and/or cognitive and social development. Although hypotonia improves
typical behavior problems with age, it does persist into adulthood together with reduced mus-
(including temper tantrums and cle mass, so exercise should be a regular part of daily life.
obsessive-compulsive features) Speech and language therapy are also important during child-
Adapted from Gunay-Aygun et al. (7). hood to help with the impaired articulation and delay in devel-
a
This feature has been added by the authors. opment milestones seen in language acquisition (63, 64).
Parental guidance intake (7579). Although somatostatin acutely suppresses

Early diagnosis offers the opportunity for education of parents, plasma ghrelin concentrations in PWS patients, appetite is not
families, caregivers, and other health care professionals to receive reduced (80), whereas a recent study found no benefit of chronic
and give social, psychological, and educational support (17, 18). In administration of a long-acting somatostatin analog on weight
addition, support from patient and family associations is increas- or appetite in PWS (81). Furthermore, levels of the anorexigenic
ingly available around the world (www.ipwso.org). gut hormone pancreatic polypeptide are reduced in PWS (10).
Obesity management involves environmental control with
Management of hyperphagia, obesity, and its early institution of a low-calorie, well-balanced diet, with regular
complications exercise, rigorous supervision, restriction of access to food and
PWS has been classically described as having two phases: money with appreciation of legal and ethical obligations, and
1) poor feeding and frequent FTT and 2) onset of hyperphagia appropriate psychological and behavioral counseling of the pa-
leading to obesity (8, 65). Phase 1 occurs from birth to early tient and family (82 84) (see later discussion under Ethical is-
infancy when infants with PWS have central hypotonia and a sues). Early discussion with parents about the inevitability of
poor ability to suck and often require tube feeding. Phase 2 is hyperphagia, even during infancy, is essential for attempts to
described as beginning between age 1 and 6 yr, usually between prevent obesity through their ability to set limits and the strict
2 and 4 yr (65). Recent examination of the natural history sug- control of the food environment. This should be reemphasized at
gests a more complex progression leading to four main nutri- each visit.
tional phases with subphases in the first two (66). Not all PWS Anecdotally, pharmacological treatment, including available
individuals necessarily go through all the phases and subphases, anorexigenic agents, has not been of benefit in treating hy-
which may be further altered by the use of GH. perphagia, although there are few published placebo-controlled
In the first phase, the infant is hypotonic and not obese. Sub- studies (8, 10, 82, 85). Study of any potential benefits of newer
phase 1a consists of feeding difficulties with or without FTT. In agents such as endocannabinoid antagonists are awaited in PWS,
subphase 1b, the infant is growing steadily along a growth curve but recent concerns about psychiatric side effects will need care-
at a normal rate. ful monitoring in this group of patients. Restrictive bariatric
In the second phase, body weight starts to increase. This gen- surgery, such as gastric banding or bypass, have not been shown
erally occurs between 18 and 36 months of age. In subphase 2a, to reduce hyperphagia or achieve long-term weight reduction
the childs weight increases such that it crosses one, two or more and are associated with unacceptable morbidity and mortality
weight percentiles without a significant increase in calorie intake (for review see Refs. 86, 87). Whereas some of the reports using
or increased interest in food. In subphase 2b, the child increases biliopancreatic diversion have reported successful weight loss,
its daily calorie intake and becomes overweight or obese, with an there were frequent complications from the resulting intestinal
abnormally increased interest in food, but the appetite is not malabsorption (86, 87). Importantly, it is unknown whether
insatiable and unrelenting as in phase 3. changes in the food environment might contribute to the out-
The onset of phase 3 is quite variable, appearing as early as 3 comes after surgery.
yr of age or as late as 15 yr. This is the classical phase that most Type 2 diabetes mellitus has been reported in about 25% of
people typically associate with PWS, with aggressive food seek- adults with PWS with a mean age of onset about 20 yr (88).
ing and a markedly reduced satiety. PWS patients in phase 3 have Although there are no data, it seems logical to approach diabetes
delayed meal termination and require significantly greater cal- management including weight loss and increased exercise, using
orie intake, compared with those without PWS, to result in loss similar pharmacological agents as with non-PWS obesity-related
of hunger. There is also an early return of hunger after the pre- diabetes, e.g. initially insulin-sensitizing agents, such as met-
vious meal with early meal initiation (67). Given free access to formin or thiazolidinediones, with the introduction of insulin as
food, patients will consume approximately 3 times that of con- required.
trol subjects (68). This occurs despite delayed gastric emptying Body composition studies show both increased body fat and
(69). Abnormalities in the satiety response to food intake in sev- reduced muscle in PWS from infancy to adulthood (89 94). In-
eral corticolimbic regions are supported by observations from terestingly, magnetic resonance imaging has found a selective
recent functional neuroimaging studies (70 72). relative reduction in visceral adiposity in nondiabetic PWS adults
In phase 4, an individual may still have an increased appetite, of both sexes (95). This may explain the relative hypoinsulinemia
but it is not as aggressive and unrelenting as previously observed and normal triglyceride levels with preservation of insulin sen-
and seems to occur only in a subset of individuals in adulthood, sitivity and protective elevation in adiponectin levels in patients
typically after 30 yr of age. with PWS, given their overall obesity (79, 95101). Use of lipid-
Neuroanatomical abnormalities have been found in the post- lowering therapy may therefore be required less than might be
mortem hypothalamus from patients with PWS that may under- expected. Hypertension may be present in up to 38% in adults
lie the hyperphagia, particularly low oxytocin cell number (10), (102) but is uncommon in children. There are no data on the
and structural brain defects are increasingly being recognized in advantages of particular drugs.
imaging studies that may also contribute to cognitive and be- Physical activity in PWS is significantly reduced (103), related
havioral problems (73, 74). In addition, fasting and postprandial to obesity, hypersomnolence, and persistent poor muscle tone.
plasma levels of the orexigenic stomach-derived hormone ghre- There is a reduced resting metabolic rate relative to body size,
lin are greatly elevated in PWS, although they do fall after food related to the abnormal body composition, which further con-
tributes to a reduction in 24-h energy expenditure (104, 105). GH treatment in children

Increased physical activity and exercise programs are beneficial The aims of GH treatment in children with PWS are to im-
in improving body composition in PWS (106). prove growth during childhood, adult height, and body compo-
Deaths in PWS adults are most often obesity related due to sition (for review see Ref. 122). In randomized controlled studies
cardiorespiratory failure, cor pulmonale exacerbated by ob- using the currently recommended dose of 1.0 mg/m2/d, there is
structive and central apnea, septicemia due to skin infections, a significant increase in height, growth velocity and a decrease in
and pneumonia and are seen from the teenage years into the 20s, percent body fat during the first year of GH treatment followed
30s, and beyond (16, 21, 107, 108). Appropriate consultation by stabilization during the second year. Lean body mass in-
with cardiologists and pneumologists in severely obese individ- creased significantly during the first two years of GH treatment
uals is essential. Use of continuous positive air pressure and nasal compared with untreated PWS children (126, 127). After the
intermittent positive pressure ventilation may be beneficial, but initial 2 yr, GH therapy for two additional years had continued
oxygen should be used cautiously because of the risk of hypoven- beneficial effects on body composition when doses of 1.0 and 1.5
tilation with reversal of chronic hypoxia (109). Early introduc- mg/m2d were administered but not with a dose reduction to 0.3
tion of graded exercise appears to be a vital part of cardiorespi- mg/m2d (126). This indicates that maintenance of improved body
ratory rehabilitation (110). composition requires at least GH dose of 1.0 mg/m2d. Bone mineral
Recent epidemiological surveys have also emphasized the density continued to improve at all doses of GH. Only a few studies
risks of choking (8% of deaths) due to rapid consumption of have reported data on adult height. In the Kabi International
food, particularly in patients who are temporarily unsupervised Growth Study database, 33 patients (21 boys and 12 girls) reached
(111), and gastric necrosis and rupture (2% of deaths) from adult height, and two thirds of them were above 2 SDS; the me-
overeating (13, 112, 113). The latter may be present despite the dian adult height was 1 SDS for height after a mean duration of
absence of usual clinical signs. Symptoms such as abdominal 8.4 yr (114). In a recent report including 21 adults (13 boys, eight
pain, vomiting, or anorexia warrant detailed and rapid assess- girls), the mean adult height was 0.3 SDS for height after a mean
duration of 7.9 yr of GH treatment (128). Prior improvements in
ment with a low threshold for urgent imaging and surgical
strength and agility that occurred during the initial 2 yr were sus-
exploration.
tained, regardless of the GH dose. These improvements during GH
treatment might contribute to the higher quality of life and reduced
Growth and GH treatment depression (129).
Hypothyroidism has been reported in children with PWS
Growth and GH status
(130, 132133). It may be of central or peripheral origin, re-
Mild prenatal growth retardation is common with median
quiring screening with TSH, free T4, and free T3 measurements
birth weight SD score (SDS) of 1.37 (range 2.81 to 0.15),
before and on GH treatment. Replacement therapy is recom-
with 20% having SDS less than 2.0, and median birth length
mended if measurements dictate.
SDS of 0.46 (range 2.14 to 1.40) (114). Both premature
The benefits of starting GH treatment as early as 2 yr are well
and postterm deliveries are frequently observed, with delivery
established, but there is increasing evidence of additional benefit
more than 3 wk early or late reported in some studies in around in starting therapy between 6 and 12 months of age, particularly
one third of cases each (46, 115). in terms of motor development, muscle, head circumference, and
After birth, short stature is almost always present, especially possibly cognition (94, 134). Starting GH treatment early could
during the second year, because of GH insufficiency exacerbated be difficult in the United States where GH treatment is labeled for
by the lack of a pubertal growth spurt. In a large multinational short stature. In Europe, growth retardation is not required in
cohort of 1135 children with PWS starting GH treatment, me- children with PWS for initiation of GH treatment.
dian height SDS was 2.2 SDS (4.1 to 0.3) at a median age Since October 2002, several reports of unexpected death in
of 6.4 yr (1.312.9 yr) (115). The serum levels of IGF-I are re- infants and children with PWS have been published (for review
duced in the majority of children (116 119) and many adults see Ref. 16). Most of them, whether in patients with or without
(120, 121). Spontaneous GH secretion is reduced and GH peak GH treatment, were related to a complicated course of a rela-
during pharmacological stimulation test is less than 10 g/liter in tively mild respiratory tract infection, sleep apnea, adenoid
70% of children (122). Adults with PWS have lower stimulated and/or tonsil hypertrophy, hypoventilation, and aspiration or
GH secretion than obese controls, but the precise prevalence of related to obesity. A recent review including 64 children (42 boys
severe GH deficiency is unclear because reference ranges are un- and 22 girls, 28 on GH treatment) suggested a high-risk period
available in severe obesity (121, 123). The experts agreed on the of death during the first 9 months of GH treatment (16). For this
potential importance of knowing the GH status to evaluate dif- reason it has been advised that GH treatment should be started at
ferential effects, depending on GH status. In our experience, a low dose, such as 0.25 0.30 mg/m2d or 0.009 0.012 mg/kgd,
height velocity does not reflect GH status in children with PWS, increasing during the first weeks and months to reach a standard
particularly when they are obese. Therefore, we agree that prior replacement GH dosage of around 1.0 mg/m2d or 0.035 mg/kgd,
GH testing is not required before GH treatment but if available monitoring clinical effects, particularly sleep apnea (Table 2), and
may be helpful. Mean spontaneous adult height has been re- avoiding high IGF-I levels, particularly if there is a clinical suspicion
ported as 162 cm in boys and 150 cm in girls (124) and 159 cm of overtreatment (edema, worsening or new development of snor-
in boys and 149 cm in girls (125) in German cohorts. ing, headache, acromegalic clinical features).
TABLE 2. Management of GH treatment
Management monitoring
Before starting GH treatment Genetic confirmation of PWS
Evaluation of IGF-I status and, if possible, GH status
Nutritional evaluation and advice and body composition if available (DEXA)
Prior control of food environment is vital, especially in obese children
Complete clinical evaluation including sleep and breathing studies if available. If
sleep-disordered breathing, snoring, or enlarged tonsils and adenoids are present,
ENT assessment and polysomnography are mandatory
OGTT, particularly if obese and/or older than 2 yr and family history of diabetes
Family instruction on GH treatment including benefits and risks of the treatment and
importance of careful monitoring
Scoliosis evaluation including x-ray
Evaluation of hypothyroidism (TSH, free T4, free T3) and commencement of
replacement if appropriate
On GH treatment Regular clinical assessment of height, weight, BMI, body composition, pubertal
status, scoliosis, IGF-I, and side effects every 3 6 months
OGTT if previous impaired glucose tolerance, obese, or family history of diabetes
Ideally ENT assessment and polysomnography within the first 6 months
If development or worsening of sleep-disordered breathing, snoring, or enlargement
of tonsils and adenoids, ENT assessment, polysomnography, and IGF-I
measurement are mandatory
X-ray orthopedic assessment if concern or doubt about scoliosis
Regular bone age determination, particularly during pubertal age range
Monitoring for hypothyroidism
Cessation of GH treatment Uncontrolled progression of obesity
Continued worsening of glycemic control despite weight control, diabetic
medication, and normal IGF-I
Continued worsening of sleep-disordered breathing despite weight control,
tonsillectomy, and adenoidectomy and normal IGF-I
Attainment of final height (but because there are potential benefits in adults on
body composition, peak bone mass, cognition, and quality of life, reassessment of
persistent GH deficiency, and replacement with adult doses may be warranted)
DEXA, Dual-energy x-ray photon absorptiometry; ENT, ear, nose, and throat; OGTT, oral glucose tolerance test.
Sleep-related breathing disorders (SRBD) population. In the general population, associations between
A variety of SRBDs has been reported in PWS. Obstructive SRBD and cognition, school performance, and psychiatric and
sleep apnea syndrome (OSAS) may be caused by obesity, sticky behavioral comorbidities are consistently reported. In individu-
saliva, kyphoscoliosis, or adenotonsillar hypertrophy in combi- als with PWS, OSAS is associated with behavioral disturbances,
nation with the narrow upper airways in PWS. Hypotonia of the such as autistic-related behavior and impulsiveness (138). A re-
respiratory muscles may also play a role. Recently, however, it cent study in young PWS infants found that OSAS was associated
has been demonstrated that nonobese prepubertal PWS children with lower mental development (139).
have mainly central sleep apnea and only rarely OSAS during the Five prospective studies evaluated the effects of treatment
night (135). The number of central apnea/hypopnea was in- with GH on breathing disorders in PWS (136, 140 143). CO2
creased (mean number of five per hour) and did not correlate responsiveness, resting ventilation, and airway occlusion pres-
with BMI. Central sleep apnea indicates a primary disturbance of sure improved during 6 9 months of GH treatment (140), and
the central respiratory control mechanism. When children with the inspiratory and expiratory muscle strength improved during
PWS are overweight, however, half of them have signs of OSAS 12 months of GH treatment, compared with controls (141). In a
(136). Arousal and cardiorespiratory responses to rapidly de- double-blind, placebo-controlled, cross-over study, a decrease in
veloping hypoxia and hypercapnia are also absent, decreased, apnea-hypopnea index (AHI) was found after 6 months of GH
and/or delayed in PWS compared with control subjects of similar in 12 PWS children, although the difference, compared with con-
age, sex, and BMI (137). trols, was not statistically significant (142). Another study re-
OSAS may lead to several complications, such as systemic ported a decrease in AHI after 6 wk of GH in most subjects of a
hypertension, cardiovascular disease, and cor pulmonale. Cor mixed group of adults and children (143). A subset of patients
pulmonale plays an important role in the morbidity and mor- had an increased AHI with more obstructive events after 6 wk of
tality of patients with PWS. Rapid eye movement sleep abnor- GH, but most of these patients had upper respiratory tract in-
malities and excessive daytime sleepiness are common in PWS fections and adenoid/tonsil hypertrophy during the second eval-
and are considered a primary disorder. However, it cannot be uation and two among six had high IGF-I levels. Recently a study
excluded that sleep-related breathing disorders disrupt sleep and in 35 prepubertal PWS children showed that the AHI did not
induce excessive daytime sleepiness as is also found in the general significantly change during 6 months of GH therapy (135). How-
ever, four children had a marked increase in obstructive apneas adrenal androgens when there is associated advancement of bone
during an upper respiratory disease. They continued with GH age. Because early puberty is not usually sustained, treatment
treatment, and when polysomnography was repeated after re- with GnRH analogs is not needed.
covery, the obstructive apneas had disappeared. In light of these At some stage almost all subjects will require hormonal treat-
findings, it is suggested that close attention be made to obesity ment for induction, promotion, or maintenance of puberty.
and sleep and breathing problems both before and after com- Mental retardation should not be a contraindication to allow
mencement of GH treatment, with a low threshold for ear, nose, normal pubertal development or preclude sex hormone replace-
and throat assessment and polysomnography (Table 2). Due to ment at any age. Nevertheless, management of hygiene issues in
the high prevalence of sleep-related breathing disorders, sleep females whose menses are induced should be discussed with the
studies and ear, nose, and throat evaluation should be performed family. There is no consensus as to the most appropriate regimen
whenever necessary in these children, regardless of plans for GH in PWS. This will be dictated by local availability and experience
treatment. of different sex steroid preparations, and some investigators have
also supported the use of human chorionic gonadotropin in boys
Orthopedic treatment (59, 155). Whatever the chosen therapy, the dosing and timing
Scoliosis is a frequent feature observed in children with PWS should reflect as far as possible the process of normal puberty.
with a prevalence of between 30 and 70% (88, 128, 144 146). The prevalence of obesity in PWS provides further justification
This high frequency may be explained partly by hypotonia and for the use of transdermal and nonsynthetic estrogen prepara-
obesity. Unlike idiopathic scoliosis, young children are often af- tions, which are usually well tolerated despite skin picking. It
fected with no gender bias. In a report of 139 children (mean age remains to be seen whether concerns about aggressive behavior
10 yr), the prevalence was 43%, and particularly high in young during testosterone replacement are justified and could be better
ages (15% before 5 yr and 22% between 5 and 10 yr) (146). controlled with transdermal testosterone. However, it would
Scoliosis is frequently associated with kyphosis, particularly in seem sensible to initiate and escalate therapy cautiously in boys.
obesity, and both appear to be bad prognostic factors. Weight Initial low dose of im testosterone preparations (one third to half
control is a vital part of its prevention and management. Due to the recommended dose for hypogonadal adults) with increments
the high frequency of scoliosis, even in infants, spinal x-ray and, as tolerated should be considered when transdermal prepara-
if appropriate, orthopedic assessment are mandatory before GH tions are not tolerated.
treatment at any age. Regular clinical assessment is required at
each visit, whether or not they are receiving GH. Reports of Sex steroids replacement in adults
scoliosis worsening during GH treatment may simply reflect its Hypogonadism is a common but not necessarily universal
natural history rather than a side effect of treatment in most finding in adults with PWS (58, 59, 121). Primary arguments for
cases. Cessation of GH is not justified in this situation. using sex steroid replacement in adults with PWS are known
Indications for bracing or surgery are the same as in idiopathic benefits to bone health; muscle mass metabolic protection; and
scoliosis. Surgical treatment is indicated in severe early-onset possible benefits to mental, emotional, and physical well-being.
scoliosis-kyphosis and in adolescents near skeletal maturity. Estrogen levels in women with PWS may not be as low as post-
Complications are more frequent and severe than in idiopathic menopausal levels, perhaps related to aromatization of andro-
scoliosis with a high risk of paraplegia (20%) and of major com- gens from excess adipose tissue (95, 156). Testosterone levels in
plications (30%, deep infections, pneumonia, hook out) (147 men are often subnormal, although low SHBG levels related to
149). Surgical treatment requires a multidisciplinary team with obesity may mean that free testosterone levels are higher than
expertise in the management of scoliosis associated with neuro- total testosterone levels might indicate (95).
muscular disease and PWS. Patients with PWS have low bone mineral density (BMD) and
are at risk of osteoporosis, related to deficiencies of sex steroids
Induction of puberty and GH, and low muscular activity, with elevated biochemical
Hypogonadism is a consistent feature in both males and females markers of bone turnover (89, 121, 156 159). Reduced BMD in
with PWS, and hypogenitalism is present, even at birth. There is PWS is associated with high risk of fracture in the long bones as
increasing evidence to implicate both central and peripheral origins well as in the small bones of the hands and feet, with some pa-
for hypogonadism, at least in males (59). Primate- and testis-specific tients sustaining multiple fractures (88, 148). These findings sup-
gene expression has recently been discovered in the PWS chromo- port the need for hormone therapy, particularly sex steroids re-
somal region (150, 151). Surprisingly, minipuberty, described as placement, during adolescence. However, neither standardized
gonadotrophin-dependent sex steroid secretion during the first protocols for the prevention of osteoporosis nor systematic studies
months of life, seems to be present in males (152). of sex hormones treatment in adolescents or adults with PWS are
Most individuals will have no or delayed and incomplete pu- actually available. Estrogen and androgen status should be moni-
berty. Isolated premature pubarche (probably due to early mat- tored yearly during adolescence and adulthood and BMD assessed
uration of zona reticularis of the adrenal gland) has been re- as indicated by dual-energy x-ray photon absorptiometry.
ported in 14% and precocious puberty in 4% of males and There are few case reports of pregnancy in females with PWS
females (58, 153, 154). There is no consensus as to management (160, 162). Their cognitive dysfunction, social and emotional
of either of these conditions. Some investigators have suggested immaturity, and the risk of Angelman syndrome in offspring of
the use of hydrocortisone in premature pubarche to decrease PWS deletion mothers prompt us to advice against pregnancy.
Sexual counseling and contraceptive treatment should be used as lower conventional GH dosage (0.53 mg/d) (120). However,
appropriate. In females with PWS, the use of gonadal hormone such studies may not reflect the outcomes of cessation studies at
replacement should be considered if there is amenorrhea/oligo- adolescence. i.e. because of differences in baseline phenotype.
menorrhea or BMD becomes low-normal in the presence of re- Reports of other potential benefits of GH in either circumstance
duced estradiol levels (158). Administration of testosterone are awaited.
should be considered in men with PWS as for any other hypogo- Use of transition clinics for chronic endocrine disease may be
nadal subject. Androgen therapy can be more physiologically particularly helpful in the management of adolescents with PWS
administered using the new delivery systems of testosterone in this particular period, such as those developed for type 1 di-
patches and gel preparations. This avoids the peaks and troughs abetes mellitus, Turner syndrome, and childhood-onset GH
of injections, which may be of particular interest in PWS because deficiency.
of historical concerns about aggressive behavior with testoster-
one treatment. Although normal sperm development has been Management of behavior and psychiatric problems
reported in some orchidectomy specimens, there are no reports Before considering the treatment and management of behav-
of paternity in PWS (Klockaert K, Bogaert G, Moerman P, Fryns ioral and psychiatric problems in PWS, it is important to consider
JP, Vogels A, oral communication, 6th Annual Meeting of the what is known about such disorders and specifically the under-
International Prader-Willi Syndrome Organization Conference, lying biological and psychological mechanisms. Recent research
Cluj, Romania, 2007). suggests that the propensity to overeating, repetitive and ritual-
In conclusion, sex steroid therapy should be ideally mini- istic behaviors, and mood disorder may have different etiologies
mized and titrated based on individual assessment, BMD, quality and by implication respond to different treatment approaches
of life, sexual and psychosocial issues, acceptability of menstru- and management strategies. The increased propensity to a pat-
ation, and potential side effects. tern of behavioral and psychiatric problems that appears specific
to PWS cannot be accounted for by some other nonspecific factor
Transition into adult life such as the presence of intellectual disabilities (165167). In ad-
As with other chronic diseases and disabilities, adolescents dition to the universal presence of the propensity to overeating,
with PWS struggle with the move from childhood to adulthood compulsive and ritualistic behaviors (82, 168), a predisposition
(163). New health care settings and providers, concerns about to temper outbursts (169), and skin picking are also very com-
autonomy, and the changing sexual, psychological, social, and mon, although not universal. More recently studies of affective
financial environment produce challenges, particularly if disrup- disorders and psychiatric illness in people with PWS has found
tion of comprehensive care is to be avoided. Furthermore, the that such disorders (including bipolar disorder) are common in
behavioral and psychiatric problems and pervasive food seeking PWS, regardless of genetic subtype, but that prevalence rates of
specific to PWS add an even higher level of complexity. Never- affective psychotic disorder are significantly greater in those with
theless, health professionals, care givers, patients, and their fam- UPD (170). In the population-based study that first reported this
ilies should be encouraged that the earlier diagnosis, multidisci- (35), all five people with UPD 28 yr old or older had had a
plinary care, and use of GH has had significant benefit in psychotic illness, whereas only one of nine with the deletion form
reducing morbidity and altering the disease profile at adoles- of PWS had had a similar illness. Whereas affective disorder in
cence. It is hoped that in the future, the prevalence of morbid and general in PWS is characterized by various degrees of mood fluc-
life-threatening obesity at adolescence will continue to decrease tuation, which may vary from brief and rapid changes in mood
from that seen in historical cohorts. Continuing these benefits to more prolonged changes in affective state, the psychotic illness
into adulthood will require extension of comprehensive care to is characterized by both auditory hallucinations and persecutory
now involve adult endocrinologists in conjunction with pediatric delusions.
colleagues, psychiatrists, and medical doctors specialized in per-
sons with intellectual disabilities. Management of temper outbursts and repetitive and
The potential benefits of continuing, starting, or restarting ritualistic behaviors
GH treatment after completion of growth are achievement of a The increased propensity to these behaviors in people with
normal peak bone mass, continued improvement of muscle mass PWS may be as a consequence of developmental arrest (167). The
and strength, reduction of body fat, prevention of cardiovascular approach is one of management rather than treatment in that the
morbidity, and improvement in well-being and quality of life interventions are primarily behavioral with the identification of
(164). National circumstances often dictate cessation of GH those factors that predispose, precipitate, or maintain such be-
treatment and reevaluation of GH status at final height. Personal haviors. Interventions are then based on the strategies that min-
experience is that body composition can rapidly worsen upon imizes the occurrence of such behaviors and most effectively
stopping GH at that time, emphasizing the need for formal GH manages them when they do occur. Inconsistent approaches or
cessation studies. Persistence of GH deficiency (70% partial, managements strategies that positively reinforce the unwanted
38% severe) and low IGF-I have been reported in many adults behaviors will only increase the chance that they will occur again
with PWS (119, 120). in the future. Families and those with PWS therefore need sup-
Modest benefits in body composition, improved cognition, port from psychologists and other professionals to: 1) identify
motor performance, and social status have been reported with those individual and environmental factors that are associated
short-term GH treatment of GH nave PWS adults using the with an increased risk of or the occurrence of temper outbursts
or repetitive behaviors; 2) develop management strategies that activities using the hands) and/or medication to stabilize mood as
are informed by these observations; and 3) guide how such strat- well as other established behavioral techniques. Topiramate has
egies can be implemented by family members and others in a been reported to reduce skin picking in one small open-label
consistent and acceptable manner. study (85). Infections or irritations from any skin lesion them-
selves will require treatment because such problems may aggra-
Management of affective disorder including affective vate the skin picking. Crucial to management is the identification
psychosis of those environmental or individual factors that are associated
The development of abnormal mood states results from a with skin picking, i.e. being unoccupied and bored, an abnormal
complex interaction between the biological predisposition and mood state, or the presence of a preexisting skin lesion.
past and present environmental factors that add to such a pre-
disposition and may precipitate its manifestation. Their presen- Other issues
tation may not be immediately obvious. A deterioration in the
pattern of existing behavior or the onset of new problem behav- Eyes
iors may be markers for an underlying abnormal mood state. Early screening and correction for myopia, hypermetropia, or
This eventually becomes apparent with evidence of fluctuating other eye problems is recommended. Strabismus is also frequent
mood, suicidal thoughts, loss of interest, a deterioration in the and may require surgery.
ability to concentrate, change in sleep pattern, under- or over- Poor salivary production is often observed, which requires
activity, and/or abnormal mental beliefs or experiences. All of parents and child education. Products designed to increase saliva
these may be of sufficient severity to impact on the persons flow (special toothpaste, mouthwash, and sugarless gum) are
functional abilities and quality of life. Management and treat- helpful. Individuals with PWS are less sensitive to thirst and are
ment will critically depend both on the diagnosis or not of a mood particularly at risk of dehydration in warm temperatures. Edu-
disorder and on the understanding of the circumstances that have cation for regular daily drinking is necessary and could prevent
led to the problem developing. The interventions need to con- dental complications.
sider: 1) factors in the immediate environment (e.g. high level of
demand, changes in routine) that might have precipitated a Teeth
change in mood state; 2) the use of medication known to be Abnormal enamel and frequent caries have been previously
effective in the treatment of mood disorders and/or psychotic reported, but in a recent survey (131), PWS patients presented
illness; and 3) any other factors that are potentially relevant, such with a more favorable oral health status than those in previous
as the effects of any additional medical illness, other phenotypes studies. Orthodontic treatment is often needed and the timing of
(e.g. sleep disorders), other medications, and/or the impact of life orthodontia can be complicated by the prolonged growth period.
events (such as bereavement) on his/her mental state. In terms of
the use of medication, the precise medication or combination of Ethical issues
medications that might be used will depend on the comorbid The support of people who may be vulnerable, whether in
diagnoses made. Where depression is severe, then antidepressant childhood or adult life, requires a careful balance between re-
medication may be indicated, and if psychotic symptoms are also specting individual wishes and autonomy, especially in adult life,
present, antipsychotic medication may also be required. There is on the one hand, and on the other, protection from harm, ex-
only limited research available in PWS about the benefits of psy- ploitation, or abuse. This is true for many people with intellectual
chiatric medications for the treatment of psychiatric illness in disabilities. However, for people with PWS, there are specific
PWS, but antidepressants and antipsychotic medication may be concerns predominantly around the risks associated with over-
better than mood-stabilizing medication (161). However, fur- eating and resultant obesity. How these are managed will sub-
ther research is required. Such medications must be given with stantially depend on the cultural context and the laws of any
care, starting on lower-than-normal doses with careful monitor- given country.
ing for adverse events. Whereas medication can help to return a In childhood once the diagnosis is made and the parents have
person to a normal mental state and reduce the risk of relapse, it been helped to understand the particular problem of overeating
is also important to look to how a predictable, low-stress envi- associated with the syndrome, there is a duty to act in their childs
ronment can be maintained and, when the person is able to do so, best interests. This will include managing the food environment
how any particular issues that may be important in his/her life and limiting access to food. Whereas this may not always be easy,
can be addressed (e.g. bereavement, relationships, etc.). particularly when the wishes of siblings have to be considered,
controlling access to food outside the home environment (e.g.
Skin picking school) is even more problematic. This becomes even more dif-
Whereas research might indicate that the spectrum of behav- ficult with increasing age and greater levels of independence, and
ioral problems observed in people with PWS have discrete eti- in adult life, there is a tension between respect for an adults
ologies, there are overlaps. The reason for skin picking in PWS autonomy to make decisions for him/herself and the severe obe-
is unclear, but it has been proposed that it is associated with sity that is likely to follow with all the health and social
serotoninergic dysfunction and mood. However, approaches to consequences.
its management will include the use of distraction techniques or There is no easy solution to this. However, the following need
the use of activities that are incompatible with skin picking (e.g. to be considered. First, those with PWS undoubtedly have an
TABLE 3. Ideal multidisciplinary team for children and adults plan for the possibility of greater independence that comes with
with PWS adult life and seek to establish support that balances respect for
choice and autonomy but still controls access to food and limits
For children For adults and monitors the spending of money. Ideally these strategies
Neonatologist have the agreement of the person with PWS and can then be
Medical geneticista Medical geneticista justified on the grounds of consent and the fact that such an
Pediatric endocrinologista Endocrinologist/diabetologista
approach is clearly in the best interests of the person with PWS.
Neuropediatrician Gynecologist/urologista
Speech and language specialist Cardiologist The problems arise when someone, who is now an adult, refuses
ENT specialist to agree to such a support package and to limitation on his/her
Psychiatrista Psychiatrista access to food and/or money and decides he/she wants to live
Orthopedista Orthopedista independently. In most countries it is for adults to make such
Surgeon (for orchidopexy)
decisions for themselves, even if there are likely to be adverse
Pneumologist Pneumologist
Sleep disorder specialist Sleep disorder specialist consequences. Should the same general principle of respect for an
Dentist adults autonomy apply to people with PWS? One argument
Ophthalmologist against such a view is that people with PWS lack the capacity to
Gastroenterologist Gastroenterologist make choices about food. Through no fault of their own, the
Dietitiana Dietitiana
majority of people with PWS do not have the ability to make
Speech therapist
Physical therapist Physical therapist judgments about when they have eaten enough, and because they
Psychologista Psychologista remain hungry, even after eating, they are unable to prevent
Social workera Social workera themselves from continuing to eat. If this general principle is
The coordinator of the multidisciplinary team has traditionally been a specialist in accepted, then it can be argued that there is a duty of care, and
genetics, pediatrics, endocrinology, or learning disabilities. However, the specific the task is to work with the person concerned to persuade them
individual should reflect the person with the best experience, motivation, team to accept living in an appropriately managed environment and if
working, and managerial skills, depending on local circumstances. ENT, Ear,
nose, and throat. they refused to consider whether there are lawful means whereby
a
Those particularly involved in transition. the person can be made to live in such an environment. Again,
anecdotal evidence is that, once living as such, people with PWS
abnormality of satiety consequent upon their genetic abnormal- accept it and come to prefer living in a food-controlled environ-
ity. The result of this is that they have very limited control over ment, even though they may resist such a course of action in the
their eating behavior. Second, the nature and severity of this first instance.
likely abnormality of the feeding pathways is greater than that
observed in those with normal obesity. Third, the consequence of
uncontrolled access to food is a level of obesity that results not Conclusion and future developments
only in very poor health (e.g. sleep and respiratory disorders,
diabetes mellitus, severe edema, and cellulitis) but also to restric- The complex genetics, etiology, multiple phenotypes, and
tions on movement and a marked impairment on quality of life. evolving natural history of PWS means that a multidisciplinary
Early death is likely. Fourth, there is emerging evidence that professional, parental, societal, and environmental approach to
people with PWS benefit from a food-controlled environment in the management is required with many challenges to reducing
ways that go beyond simply the prevention of obesity. When the morbidity and mortality and improving quality of life (Table 3).
food environment is controlled by others and mealtimes and However, over recent years, an increasing appreciation and
snacks are carefully managed, people with PWS accept this and availability of important management strategies have already
are then able to focus on different issues in their lives, other than made significant improvements in the life of those with PWS, e.g.
just food. early diagnosis, use of multidisciplinary teams, introduction of
The main task for families and those providing support is to GH treatment, control of the food environment, and better un-
TABLE 4. Major recommendations for the management of PWS
Recommendations
Early diagnosis in infancy using accredited genetic testing should be sought and allows early intervention
Multidisciplinary teams with experience in the management of PWS can provide best practice (Table 3)
Family education and support, early intervention, and individually directed education is vital
Vigorous control of the food environment and regular exercise is essential to manage hyperphagia and obesity
GH therapy should be started early in childhood, taking into account cautions and relative contraindications (Table 2)
Appropriate monitoring of GH replacement is essential (Table 2)
Management of the transition from adolescence to adulthood requires specific attention and care, particularly with regard to patient autonomy and
endocrinological issues
Increased availability of group homes with experience in the management of PWS is needed to help placement, quality of life, and health issues in
adulthood
Recognition of the distinction between the underlying behavioural problems seen in PWS and acute psychiatric illness is essential
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Acknowledgments
13. Whittington JE, Holland AJ, Webb T, Butler J, Clarke D, Boer H 2001
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We thank Catherine Molinas Cazals for her strong involvement in the people with Prader-Willi syndrome in one U.K. Health Region. J Med Genet
meeting organization and the writing of the manuscript. We also thank 38:792798
Gwenaelle Diene, Melanie Glattard, and Denise Thuilleaux for their 14. Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cassidy SB, Schrander JJ,
assistance; Daniel Driscoll for his comments on the manuscript; and Fryns JP 2004 Prader-Willi syndrome: causes of death in an international
Pfizer for their provision of an unrestricted educational grant for the series of 27 cases. Am J Med Genet A 124:333338
Meeting. Speakers and contributors at the Second Expert Meeting of 15. Eiholzer U 2005 Deaths in children with Prader-Willi syndrome. A contri-
Comprehensive Care of Patients with PWS: Consensus, Questions and bution to the debate about the safety of growth hormone treatment in children
Future Directions, October 2006, Toulouse, France, included: F. Ac- with PWS. Horm Res 63:3339
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cadbled, J. Cavaille, B. Roge, J. Sales de Gauzy (Toulouse, France); S.
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Schrander-Stumpel (Maastricht, The Netherlands); D. J. Driscoll, J. L. diagnosis and multidisciplinary care reduce the hospitalisation time and du-
Miller (Gainesville, FL); D. A. M. Festen (Rotterdam, The Netherlands); ration of tube feeding and prevent early obesity in PWS infants. Horm Res
L. M. Gourash, R. D. Nicholls (Pittsburgh, PA); G. Grugni (Piancavallo 69:4552
di Verbania, Italy); J. Heinemann (Sarasota, FL); B. Horsthemke (Es- 18. Eiholzer U, lAllemand D, Zipf WB 2003 Prader-Willi syndrome as a model
sen, Germany); C. Hoybye, A. C. Lindgren, M. Ritzen (Stockholm, of obesity. Basel, Switzerland: S. Karger
Sweden); F. Muscatelli (Marseille, France); T. Nagai (Saitama, Japan); 19. Butler MG, Lee PDK, Whitman BY 2006 Management of Prader-Willi syn-
M. W. G. Nijhuijs (Nijmegen, The Netherlands); T. Odent (Paris, drome. 3rd ed. New York: Springer
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France); B. Schluter (Datteln, Germany); S. Soni, J. Whittington
Jesuran-Perelroizen M, Lienhardt A, Mas JC, Moncla A, Nicolino M, Puel O,
(Cambridge, UK); D. F. Swaab (Amsterdam, The Netherlands); D.
Simonin G, Wagner K, Tauber M 2006 The French reference centre of PWS
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Address all correspondence and requests for reprints to: Professor 21. McManus B, Heinemann J 2006 PWSA (USA) database. The Gathered View,
Mathe Tauber, Equipe dEndocrinologie, Hopital des Enfants, 330 Av- Sarasota, Florida
enue de Grande Bretagne, TSA 70034, 31059 Toulouse cedex 9, France. 22. Amos-Landgraf JM, Ji Y, Gottlieb W, Depinet T, Wandstrat AE, Cassidy SB,
E-mail: tauber.mt@chu-toulouse.fr. Driscoll DJ, Rogan PK, Schwartz S, Nicholls RD 1999 Chromosome break-
Disclosure Statement: A.P.G., A.C.H.-K., and A.J.H. have nothing to age in the Prader-Willi and Angelman syndromes involves recombination
between large, transcribed repeats at proximal and distal breakpoints. Am J
disclose. M.T. received lecture fees from Pfizer and is on a Pfizer and
Hum Genet 65:370 386
Ipsen advisory board. B.P.H. consults for Pfizer and Novo Nordisk 23. Chai JH, Locke DP, Greally JM, Knoll JH, Ohta T, Dunai J, Yavor A, Eichler
Corp., has received lecture fees from Lilly, Novo Nordisk, and Pfizer EE, Nicholls RD 2003 Identification of four highly conserved genes between
Corp., and received grant support from Pfizer Corp. from November breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes
2005 to present. deletion region that have undergone evolutionary transposition mediated by
flanking duplicons. Am J Hum Genet 73:898 925
24. Horsthemke B, Buiting K 2006 Imprinting defects on human chromosome
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The 52es Journees internationales dendocrinologie clinique Henri-Pierre Klotz

will be held in Paris on May 14 and 15, 2009.
Symposium. Adrenal Tumours & Hormone Excess
Information: http://www.klotzendocrino.org

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S P E C I A L F E A T U R E

Recommendations for the Diagnosis and

A. P. Goldstone, A. J. Holland, B. P. Hauffa, A. C. Hokken-Koelega, and M. Tauber, on behalf of

P rader-Willi syndrome (PWS) is a complex multisystem genetic

J Clin Endocrinol Metab, November 2008, 93(11):4183 4197 jcem.endojournals.org 4183

Parental guidance intake (7579). Although somatostatin acutely suppresses

tributes to a reduction in 24-h energy expenditure (104, 105). GH treatment in children

TABLE 2. Management of GH treatment

TABLE 4. Major recommendations for the management of PWS

The 52es Journees internationales dendocrinologie clinique Henri-Pierre Klotz

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