J Clin Endocrin Metab. First published ahead of print March 29, 2013 as doi:10.1210/jc.2012-3888 Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome
Cheri L Deal,1 Michèle Tony2, Charlotte Höybye3, David B. Allen4,Maïthé Tauber5, Jens Sandahl Christiansen6, andthe 2011 GH in PWS Clinical Care Guidelines Workshop Participants.a
Research Center and Department of Pediatrics1, CHU-Sainte-Justine and Department of Public Health2,Université de Montréal, Montréal, Canada; Department of Endocrinology, Metabolism and Diabetes3,Karolinska University Hospital, Stockholm, Sweden; Department of Pediatrics, University of WisconsinSchool of Medicine and Public Health4, Madison, WI; Department of Endocrinology, Hôpital des Enfantsand Université Paul Sabatier5, Toulouse, France; Department of Endocrinology and Diabetes6, AarhusUniversity Hospital, Aarhus, Denmark
Context: rhGH therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the US in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge which includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: To formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: A systematic review of the clinical evidence in the pediatric population, including ran- domized controlled trials (RCTs), comparative observational studies and long term studies (Ͼ3.5 years). Adult studies included RCTs of rhGH treatment for [mteq] 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guide- line development recommendations outlined by the AGREE Collaboration Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM)
Conclusions: Following a multi-disciplinary evaluation preferably by experts, rhGH treatment should be considered for patients with genetically-confirmed PWS in conjunction with dietary, environmental and lifestyle interventions. Cognitive impairment should not be a barrier to treat- ment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks. Prader-Willisyndrome(PWS)isararegeneticdisorder sity,hypogonadism,decreasedadultheight,andcognitive
(OMIM: #176270) characterized by hypotonia,
poor feeding in infancy, hyperphagia with evolving obe-
The birth incidence of PWS is difficult to ascertain, but
data from several studies suggest that it is at least 1 in
Copyright (C) 2013 by The Endocrine Society
25,000 live births. PWS is genetically heterogeneous; in
principle for rhGH use in PWS (i.e., provision of care and
approximately 65%–70% of patients PWS results from a
protection of patients who do not have autonomy).
deletion of the paternally inherited chromosomal
The objective of the workshop was to evaluate the ef-
15q11.2– q13 region (DEL15), 25- 30% from maternal
fects of rhGH therapy in pediatric and adult patients with
uniparental disomy for chromosome 15 (UPD15), while
PWS and provide evidence-based guidelines for its use,
ϳ1% have imprinting defects (ID) or translocations in-
The therapeutic rationale for use of recombinant hu-
man growth hormone (hGH) (rhGH) is derived from our
Forty-three experts (pediatric and adult endocrinolo-
understanding of the comorbidities seen in PWS, which
gists, clinical and basic geneticists, epidemiologists, a nu-
resemble those seen in association with growth hormone
trition specialist, an orthopedic surgeon, a psychiatrist,
(GH) deficiency (GHD) (e.g., reduced muscle strength,
health technology assessment (HTA) specialists, a bioethi-
altered body composition, low energy expenditure and
cist, health economist, and a patient advocate) partici-
reduced growth even in the presence of obesity). Although
pated by invitation from the scientific committee (see au-
the etiology of impaired GH secretion in PWS remains
thor list). Clinical representatives from 5 manufacturers of
controversial due to the common occurrence of obesity,
rhGH also submitted their PWS-specific safety data.
the serum levels of IGF-I are reduced in most children
Prior to the workshop, an extensive literature review
(4 – 6) and adults (7) with PWS, and excess body fat is seen
based on a multicriteria methodology (30, 31) was per-
in even nonobese affected children (8, 9). Reduced GH
formed to identify relevant available data concerning
responses to a variety of GH secretagogues, as well as
rhGH treatment for patients with PWS. For clinical evi-
decreased 24-h spontaneous GH release, have been doc-
dence in the pediatric population, RCTs, (20 –26, 33– 41)
umented in 58%–100% of affected children (10). Infor-
comparative observational studies (42– 48) and long term
mation regarding GH secretory pattern in adult patients
studies (Ͼ3.5 y) (5, 49 –58) were included. Adult studies
with PWS is more limited, and suggests more variability,
included RCTs of rhGH treatment for [mteq] 6 mo (7, 29,
with many potential explanations (7, 11–13).
59, 60) and uncontrolled trials, (61– 64) since data were
Short-term rhGH treatment of children with PWS was
more limited. Safety data from pharmaceutical registries
first reported in 1987 (14). It has been used by many mem-
(phase 4 trials) (1) and sponsored clinical trials (phase 3)
bers of the international medical community and advo-
were reviewed. Data on disease, therapeutic context, and
cated by parental support groups since its FDA approval
economic, ethical and societal aspects were also included
in 2000 for use in children with PWS, based on short term
to reflect a broad international context. Details on ap-
growth data and subsequently for its effects on body com-
proach, evidence tables and data summaries are available
position. However, the use of rhGH therapy for this con-
in Supp Table 1a,b and on the workshop website (65).
dition represents a unique therapeutic challenge which in-
Level of evidence was evaluated using the scoring pro-
cludes treating individuals with cognitive disability, varied
cedure based on the Oxford Centre for Evidence-based
therapeutic goals that are not focused exclusively on in-
Medicine (CEBM) Level of Evidence scale (66). (Supp Ta-
creased height, (15), and concerns about potential life-
ble 1c) Strength of evidence was graded independently by
two of the authors (CD and MT) using the EVIDEM Qual-
Prior expert consensus documents discuss the general
ity Assessment (QA) instrument, (30, 67) and a quality
care of patients with PWS, including some discussion of
grade on a 4-point scale (low to excellent) was then as-
rhGH therapy in children and adults with PWS, (17, 18)
signed to each publication. In the rare cases of disagree-
although many questions remained, particularly the ef-
ment, the study was re-examined jointly.
fects on functional outcome and on long-term body com-
Synthesized information by criteria was then provided
position changes. Recent pertinent publications have since
to workshop participants prior to the workshop discus-
appeared, (19 –29) and the Growth Hormone Research
sions for i) validation of content, and ii) to provide back-
Society therefore held a Consensus Workshop in order to
ground information to answer relevant questions concern-
systematically review the literature and grade the available
ing GH and PWS (Supp Table 2).
evidence (30, 31) and provide concise recommendations
Based on 2 d of structured talks and breakout sessions,
for the use of rhGH in this context with adherence to The
participants formulated and categorized levels of recom-
Principle of Respect for Persons (32) as the guiding ethical
Copyright 20132013 by The Endocrine Society
Received November 11, 2012. Accepted March 26, 2013.
A: Evidence or general agreement that a given proce-
Baseline evaluation of the GH-IGF Axis before
dure of treatment is beneficial, useful and effective
B: Weight of evidence is in favor of usefulness or
Previous expert opinions (17) have suggested that GH
testing is not necessary in children with PWS, although
C: Usefulness or efficacy is less well established by ev-
some countries require it in order for treatment reimburse-
ment. It was agreed that over 50% of infants and children
D: Evidence or general agreement that the procedure or
with PWS are, or will become GH deficient by standard
treatment is not useful or effective and in some cases may
testing protocols (4, 10, 26, 38, 50, 69 –73). No consensus
was reached concerning the frequency of testing in cases
To each recommendation, a CEBM level of evidence
where GH sufficiency is initially documented. Determin-
score was assigned to reflect the origins of the data which
ing the presence of GHD after attainment of adult height
may be beneficial, however, since reports from dynamictesting in adults suggest that GHD is not universal, and
Overview of Evidence Quality
many countries require testing prior to treatment of adults
Multiple pediatric RCTs with rhGH have reported sta-
with GHD (28). It is not known if GH secretory status
tistically significant effects in patients with PWS on
predicts metabolic response to rhGH treatment. Further-
growth, body composition, resting energy expenditure,
more, within a research context, and in order to increase
motor development (infants and children), muscle
our understanding of genotype-phenotype relationships,
strength, exercise tolerance, bone health and lipid profiles.
GH testing may be desirable. Since serum IGF-I is a useful
(20 –26, 33– 41, 50) Overall, these trials have been per-
biomarker for monitoring compliance with treatment as
formed in small populations and durations were short
well as sensitivity to GH, all participants agreed that base-
compared to the length of rhGH treatment in the real life
line IGF-I levels should be determined.
setting; quality grade ranged from low (10 publications) tohigh (1 publication). There is only one placebo-controlled
Additional considerations prior to starting rhGH
study (35) and one controlled dose-response study (34) in
the pediatric population, although the adult trials include
All participants agreed that evaluation of patients prior
placebo-controlled groups (7, 29, 59, 60). Most patients
to beginning treatment should ideally include a complete
had genetically-confirmed diagnoses. Methodological is-
assessment coordinated by a multidisciplinary team with
sues were noted in several studies including incomplete
expertise in PWS, and summarized in Table 2. This stems
reporting of patient numbers, lack of discussion of ran-
from the importance of diagnosing and treating comor-
domization methods, rare inclusion of intent-to-treat
bidities that may impact on GH safety as well as on GH
analyses, limited statistical details (P-values only), and
minimal information about important confounders (e.g.,
Product labeling information for all of the rhGH prep-
socio-economic status, degree of adherence to diet, exer-
arations commercially available (regardless of approved
cise plan). Only 2 studies reported individual patient re-
diagnosis) lists several contraindications to rhGH use, in-
cluding acute critical illness, severe obesity or severe re-
It is difficult to criticize the validity of these studies
spiratory impairment, active malignancy, active prolifer-
based on flawed methodologies, since the effects are con-
ative or severe nonproliferative diabetic retinopathy, and
sistent at least in the short term (1 y data), as demonstrated
hypersensitivity to the product. Workshop participants
by recent meta-analyses in children and adults (19, 28).
acknowledged these exclusion criteria and felt that active
There are data regarding clear benefits to rhGH treatment
psychosis should also be included. Psychiatric illness is
in infants, childhood, adolescence, transition to adult-
now increasingly recognized in patients with PWS (74).
hood, and in young adulthood, but there are less long-term
Careful attention should be given to the clinical criteria
data available after the fourth decade.
used to define severe pediatric obesity, since there are no clear definitions as in adults (BMI Ͼ 40 kg/m2). Workshop Summary of Recommendations participants felt it prudent to consider obesity in the pe-
The workshop participants established 15 recommen-
diatric population with PWS as “severe” if a child with a
dations dealing with rhGH use in PWS, as shown in Table
BMI over the 9fifth percentile manifests complications of obesity such as sleep apnea, nonalcoholic fatty liver dis-
Considerations specific to each recommendations are
ease, or abnormalities of carbohydrate metabolism. Since
discussed in a companion review (68) and are briefly sum-
treatment with rhGH decreases insulin sensitivity, uncon-
trolled diabetes mellitus, regardless of the presence or ab-
Summary of Clinical Care Guidelines for rhGH Therapy in PWS
I. After genetic confirmation of the diagnosis of PWS, rhGH treatment should be considered and, if initiated, continued for as long as demonstrated benefits outweigh the risks. (Recommendation level A; level of evidence 1)
II. GH stimulation testing should not be required as part of the therapeutic decision-making process in infants and children with
PWS. (Level of recommendation A; level of evidence 3)
III. Adults with PWS should have an evaluation of the GH/IGF axis prior to rhGH treatment. (Recommendation level A; level of
IV. Prior to initiation of rhGH therapy, patients with PWS should have a genetically confirmed diagnosis and expert multi-
disciplinary evaluation. (Recommendation level A; level of evidence 5)
V. Exclusion criteria for starting rhGH in patients with PWS include severe obesity, uncontrolled diabetes, untreated severeobstructive sleep apnea, active cancer and active psychosis. (Recommendation level A; level of evidence 4)
VI. Scoliosis should not be considered a contraindication to rhGH treatment in patients with PWS. (Recommendation level A; level
VII. Infants and children with PWS should start with a daily dose of 0.5 mg/m2/day subcutaneously with subsequent adjustments
toward 1.0 mg/m2/day every 3– 6 months according to clinical response* and guided by maintenance of physiologic levels ofIGF-I**. (Recommendation level A; level of evidence *1, **5)
VIII. Adults with PWS should receive a starting dose of 0.1– 0.2 mg/day based on age, presence of edema, prior rhGH exposure
and sensitivity, and concomitant oral estrogen use. Subsequent dosage titration should be based on clinical response, age, andsex appropriate IGF-I levels in the 0 to ϩ2 SD range. (Recommendation level A; level of evidence 2)
IX. Selection of patients with PWS for rhGH therapy and dosing strategy should not depend on the genetic class of PWS (DEL15;
UPD15; ID). (Recommendation level A; level of evidence 2)
X. IGF-I levels in patients with PWS on rhGH treatment should be maintained within the upper part of normal range (ϩ1 to ϩ 2
SDS) for healthy, age-matched normal individuals. (Recommendation level B, level of evidence 3 (adults), 5 (children))
XI. Clinical outcome priorities should vary depending on the age, and on the presence of physical, mental, and social disability.
(Recommendation level A; level of evidence 1)
XII. Monitoring of GH treatment in patients with PWS should address specific benefits and risks of treatment in this population
and the potential impact of other hormonal deficiencies. (Recommendation level A; level of evidence 3)
XIII. Patients with PWS receiving GH must be followed carefully for potential adverse effects during GH treatment.
(Recommendation level A; level of evidence 1)
XIV. Treatment with GH must be in the context of appropriate dietary, environmental, and lifestyle interventions necessary for care
of all patients with PWS. (Recommendation level A; level of evidence 4)
XV. Cognitive impairment should not be a barrier to treatment with GH for patients with PWS. (Recommendation level A; level of
Recommendation levels: A, Evidence or general agreement that a given procedure of treatment is beneficial, useful and effective; B, Weight of evidence is in favor of usefulness or efficacy; C, Usefulness or efficacy is less well established by evidence or opinion; D, Evidence or general agreement that the procedure or treatment is not useful or effective and in some cases may be harmful. Levels of evidence: 1, Systematic review of randomized trials; 2, Randomized trial or observational study with dramatic effect; 3, Non-randomized controlled trial/follow-up study; 4, Case-series, case-control or historically controlled studies; 5, Mechanism-based reasoning
sence of diabetic complications such as retinopathy, de-
subsequent episodes of respiratory infection unless indi-
mands attention prior to initiation of rhGH therapy in
cated because of onset of breathing difficulties.
Scoliosis in PWS is not a contraindication to rhGH
Children with PWS have a high incidence of both cen-
treatment; its occurrence is common (up to 30%– 80%
tral apnea and obstructive apnea (75–77). Marked obesity
depending on age), but neither its incidence nor its rate of
or intercurrent respiratory tract infection (often underdi-
progression are influenced by rhGH therapy (21).
agnosed because of the absence of fever), can exacerbate
The potential role of the GH-IGF axis in cancer inci-
obstructive apnea and may even lead to sudden death (78 –
dence and/or progression has received a great deal of re-
82). Since rhGH therapy can theoretically lead to lym-
cent attention (83) despite the safety record, to date, of
phoid tissue growth in children due to increased IGF-I
rhGH treatment. The recent SAGhE publications do not
effects (100) patients and parents must be fully informed
specifically address rhGH use in patients with PWS, and a
about the potential association between rhGH therapy
true appreciation of dose-related risks of rhGH will re-
and unexpected death during the pretreatment consenting
quire better and longer surveillance protocols, since all
process, and polysomnography should be performed be-
observational studies are subject to bias (84, 85)., (86, 87)
fore starting therapy. rhGH therapy is contraindicated in
The potential development of central adrenal failure,
children with breathing difficulties until ENT surgery and
which may not be clinically relevant except during inter-
treatment of respiratory-compromising obesity has been
current illness and/or surgical intervention, was also dis-
achieved. Therapy should not be initiated during an acute
cussed. Investigations have not uniformly documented a
respiratory infection, but it need not be interrupted during
high incidence of central adrenal failure in PWS (88 –90).
Multi-disciplinary Evaluation of Pediatric and Adult Patients with PWS Before Starting rhGH Treatmenta
length/height, BMI (and if possible, waistcircumference and skinfold thickness),pubertal status and presence of additionalendocrine deficiencies
● Evaluation of hypothyroidism (TSH,free T4, free T3) and commencementof replacement if appropriate
● Determination of IGF-I level and, ifpossible, GH response to provocativetesting particularly in adult individuals
● Evaluation of metabolic status if age[mteq] 12 y and obesity: HbA1c,fasting insulin and glucose; consideroral glucose tolerance test (OGTT) iffamily history of diabetes, acanthosisnigricans or ethnic risk factors
● Evaluation of cardiovascular riskprofile as per guidelines for obeseindividuals:b fasting total cholesterol,triglycerides, LDL-cholesterol and HDL-cholesterol
● Assess for hepatic steatosis as perguidelines for obese individuals:b ASTand ALT levels, abdominal ultrasoundand biopsy where appropriate
● Body composition evaluation ifavailable (Dual-energy x-ray photonabsorptiometry or bioelectricalimpedance)
● Consider need for evaluation ofadrenal function on an individual basis
● Nutritional evaluation and adviceincluding use of food diary, control offood environment, diet compositionand caloric intake
● Assessment of developmental and cognitive
● Assessment of motor function if possible
● Physiotherapy and OccupationalTherapy referral
● ENT referral if history of sleep-disordered
breathing, snoring, or enlarged tonsils and
● Referral to Pneumologist/Sleep Clinic
● Sleep oxymetry is mandatory prior tostarting rhGH in all patients,preferably completed bypolysomnographic evaluation
including benefits and risks of the treatment
aAdapted and modified from: Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M. Recommendations for the diagnosis andmanagement of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(11):p 4188.(17)
bFor guideline references in obesity, see Lau et al., 2007(128), August et al., 2008(129) and Australian Government Department of Health andAgeing, 2009(130)
No consensus was reached concerning the need for adre-
b. Adults. In adults with PWS rhGH doses tested in pla-
nal axis testing prior to initiation of rhGH, but families
cebo-controlled and open-label trials have varied between
and clinicians should remain vigilant and not hesitate to
0.2 and 1.6 mg per day s.c., depending on the time period
use stress doses of glucocorticoids as clinically indicated.
under rhGH treatment, weight and induced IGF-I levels. This dose range gives an acceptable side effect profile, (29,
Age at treatment initiation
59, 61– 64, 96) as well as beneficial effects on body com-
According to observational data, rhGH treatment is
position, psychological and behavioral problems, Quality
usually initiated at a mean age of 7 y, as reported by
of Life (QoL), and heart function and results in IGF-I levels
Takeda et al. (91) Increasingly, rhGH treatment is initi-
within the range of age matched controls (59, 61, 63, 64,
ated earlier (10, 17, 72). Published data support benefits
96, 97). It was unanimously concluded that in adults with
of rhGH treatment when started between 4 – 6 mo of age,
PWS, the optimal IGF-I level, i.e., the level where the rhGH
(25, 34) but some experts are currently treating from as
treatment will have clear beneficial effects and at the same
early as 3 mo. There was no consensus reached on age of
time the lowest, possible risk of adverse events, will be a
rhGH start although all agreed to the benefits of treating
value similar to 0 to ϩ2 SDS (SD score, z-score) for age-
before the onset of obesity, which often begins by 2 y of
Monitoring and Potential Side Effects There was unanimous agreement that rhGH therapy a. Infants and children. Evidence for efficacy in infants and should be supervised by pediatric or adult endocrinolo-
children is based on trials using a dosage of 1.0 mg/m2/day
gists, ideally those experienced with the care of patients
achieved within approximately one month of starting
with PWS. Periodic monitoring of the safety and efficacy
treatment (50). Given that patients with PWS exhibit vari-
of the treatment is mandatory (Table 3).
able degrees of GHD and that salutary outcomes in RCTs
In the past, rhGH therapy dose adjustments in children
were routinely performed based on growth response
were associated with doses of 1.0 mg/m2/day (higher than
and/or weight (or BSA) increases. Epidemiological data
the dose of rhGH routinely used in congenital GHD) or
suggesting a potential link between IGF-I levels and some
higher, it is unknown whether similar outcomes could be
adverse events (83, 84, 98, 104) have motivated investi-
replicated with rhGH doses that result in consistently nor-
gators to consider maintaining IGF-I levels within the
mal IGF-I levels. IGF-I levels and IGF-I/IGFBP-3 ratios rise
physiologically normal range (0 to ϩ 2 SDS), an approach
to above 2SD in some patients on this dosage, theoretically
shown to be feasible in other conditions, such as rhGH
presenting some risk (83)., (26, 35, 38, 40, 51, 92, 93) The
treatment of children with idiopathic short stature or
efficacy of doses lower than 1.0 mg/m2/day administered
small for gestational age (SGA), where pharmacologic
over a long period of time is unknown, however it has been
doses are used (99, 100). Workshop participants felt that
suggested that the efficacy of lower doses of rhGH on body
for the pediatric age range, IGF-I levels in patients with
composition is decreased (50, 51). Infants and children
PWS on rhGH treatment could therefore safely be main-
with PWS should start with a daily dose of 0.5 mg/m2/day
tained within the upper part of normal range (ϩ1 to ϩ 2
subcutaneously to minimize side effects, with subsequent
SDS) for healthy, age-matched normal individuals. For the
adjustments toward 1.0 mg/m2/day; there was disagree-
adult population, where discontinuation of treatment be-
ment as to how rapidly this should occur (3– 6 mo). If not
cause of side effects is more frequently noted, an IGF-I of
using body surface area (BSA)-based calculations (recom-
mended) it was felt prudent to base dose calculations on a
Table 4 summarizes the side effects that should be rou-
nonobese weight for height in cases where overweight for
tinely monitored. While rhGH therapy has a favorable
height (BMI ϭ 8fifth to 9fifth percentile) or obesity exists,
safety profile, the postulated association between unex-
particularly when starting rhGH therapy. There was a
pected death and rhGH treatment in children with PWS
difference of opinion regarding the timing and frequency
deserves special attention not only in the consenting pro-
of IGF-I measurement before increasing dosage to 1.0 mg/
cess and pretreatment evaluation, but also during treat-
m2/day in the pediatric population with PWS. Notably,
ment (16, 97, 101, 102). During rhGH treatment, changes
patients with PWS appear to be highly sensitive to GH in
in breathing (particularly during sleep) should be
terms of IGF-I generation (94, 94), and standard rhGH
promptly reported and evaluated by repeat oximetry
doses often results in IGF-I levels outside the normal range.
and/or polysomnography within the first 3 to 6 mo of
Since lymphoid hyperplasia is related to the levels of IGF-I,
starting therapy. Longer-term rhGH therapy has been as-
(95) this might increase the risk of sleep apnea (81).
sociated with improvement in respiratory function in chil-
Multi-disciplinary Evaluation of Pediatric Patientsa with PWS During rhGH Treatmentb
● Regular clinical assessment of height, weight, BMI, pubertal status, scoliosis, IGF-I, and side effects every 3–6
● Clinical assessment of body composition every 6–12 months by one or more of the following: waist circumference, skinfold
thickness, DEXA (or other available technique for determining body fat and lean body mass).
● Yearly bone age determination, particularly during pubertal age range
● IGF-I determination every 6–12 months
● ENT assessment and sleeping oxymetry, or ideally, repeat polysomnography within the first 3–6 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
● Fasting glucose, insulin and HbA1c; if obese and/or older than 12 y and/or acanthosis nigricans and/or family history of diabetes/
● x-ray Ϯ orthopedic assessment if concern or doubt about scoliosis progression
● Monitoring for hypothyroidism yearly or if symptoms
● Lipid profiles and liver function tests and/or liver ultrasound according to family history, age and weight status as per clinical
guidelines for non-PWS patients, with referral to gastroenterologist if non-alcoholic fatty liver disease is suspected
● In cases of acute illness and suggestive symptomatology, obtain critical blood samples for measurement of cortisol and ACTH
levels if possible, and assess adrenal glucocorticoid response to provocative testing where indicated
Continued contact with nutritionist, physiotherapist/occupational therapist, speech therapist and psychologist (frequency to
● If marked deterioration in behavior with or without overt psychiatric symptoms, psychiatry assessment
aApplicable to adult patients with PWS with the exception of the radiologic evaluations (bone age monitoring, scoliosis monitoring). bAdapted and modified from: Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M. Recommendations for the diagnosis andmanagement of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(11):p 4188.(17)
Ⅲ Changes in physical features and body proportions (faces, hands, feet) or bone growth
Ⅲ Sleep apnea/disordered breathing: snoring, respiratory pauses, excessive daytime sleepiness
Ⅲ Pseudotumor cerebri/ benign intracranial hypertension: headache, visual changes, nausea, dizziness
Ⅲ Slipped capital femoral epiphysis: hip and/or knee pain, gait disturbance
Ⅲ Insulin resistance: elevated fasting insulin
Ⅲ Decreased T4 level (requires measurement of T3 to differentiate from true central hypothyroidism)
Ⅲ Scoliosis (recent data suggest no causal relationship or exacerbation of progression)Long-term Surveillance on, or following, cessation of rhGH
Ⅲ Glucose intolerance/Type 2 Diabetes Mellitus particularly in obese patients or patients with positive family history
Ⅲ Epilepsy (no known relationship but should be reported)
Ⅲ De novo neoplasia (no known relationship but should be reported)
aShown are the reported side effects of GH treatment primarily in the pediatric population with, or without PWS. No published data are availableconcerning GH treatment in adults with PWS on joint pain, sleep apnea, epilepsy, intracranial hypertension, neoplasia and stroke/intracranialbleeding. Furthermore, none of the studies in PWS adults (longest follow-up 5 yr) have reported breast tenderness/enlargement, unexpecteddeath.
dren and adults, primarily due to improvements in respi-
bolic syndrome in patients with PWS may vary depending
ratory muscle function as indicated by increases in peak
upon degree of obesity, adipose tissue distribution, genetic
expiratory flow (35, 50, 96). Data concerning rhGH ef-
background risk and use of antipsychotics (105–109).
fects on central respiratory drive are few and are difficultto interpret because of multiple confounders (103, 104). Tolerability
No data are available concerning rhGH treatment and
Tolerability of rhGH by pediatric and adult patients
with PWS is high, according to the workshop participants
There was a consensus to include an evaluation of di-
involved in RCTs. (7, 24, 25, 29, 35, 36, 38, 41, 59 – 64,
abetes risk (determination of HbA1c, fasting glucose and
96) However, relatively few adults with PWS have been
insulin) in patients with PWS who are obese and/or who
studied and insufficient data are available to judge
are older than 12 y or who have a positive family history
whether adverse effects of rhGH, death due to other
of diabetes. Further studies are needed to refine these rec-
causes, or personal choice accounted for treatment cessa-
ommendations since insulin sensitivity and risk of meta-
tion. For children with PWS treated with rhGH and fol-
lowed in phase 4 postmarketing surveys, the reported rate
height velocity SDS [mteq] ϩ1. Workshop participants
of side effects leading to treatment cessation in trials over-
acknowledged the difficulty of having alternative, easily
all is low (110). The enthusiasm of parents of PWS chil-
measurable, robust, validated, affordable clinical end-
dren for rhGH therapy suggests that early cessation is
points other than the initial growth response. When pos-
lower than in other rhGH-treated patients with conditions
sible, attempts should be made to document favorable
like idiopathic short stature, Turner syndrome, and chil-
changes in psychomotor progress and development, body composition, strength and exercise tolerance and QoL for both patient and caregivers, and findings should be re- Clinical Outcome Variables and rhGH viewed with all involved in the decision to continue treat- Non-Responsiveness ment. Parameters that define the sustained success of ther-
In untreated children with PWS, auxological and body
apy include adult height SDS, adult height SDS minus
composition parameters tend to deteriorate over time, so
height SDS at start of rhGH, adult height minus predicted
if these continue to improve or to stabilize, treatment is
height at start of treatment, and adult height minus target
usually continued until adult height or near-adult height is
height (based on sex-corrected mean parental height).
reached. However, if adult height attainment is used for
Emerging data on genotype-phenotype correlations rele-
the decision to stop rhGH therapy in adolescents with
vant to specific outcome measures targeted with rhGH
PWS, it is important to note that these patients often ex-
therapy need to be repeated in additional cohorts before
perience premature adrenarche and obesity, causing early
firm conclusions can be drawn (12, 101, 107).
closure of growth plates (111, 112).
For adults with PWS and GHD, treatment duration
Use of Adjunct Therapies
depends on primary clinical outcome (body composition,
Nutritional management remains the mainstay of treat-
lipid metabolism, physical and psycho-social functioning)
ment of patients with PWS even during rhGH therapy.
and occurrence of side effects (impairments of glucose me-
Regular contact with a dietitian knowledgeable about
tabolism, edema, heart disease) (62).
PWS is essential, initially to calculate desirable caloric in-
Controlled studies of continuous treatment through
creases during the failure to thrive period often observed
childhood, adolescence and the transitional period into
in infants with PWS. Once the failure to thrive period is
adulthood are not available in PWS, yet there is a strong
over, caloric requirements vary according to the nutri-
likelihood of continued benefit by inference from non-
tional phase of the patient and are typically approximately
PWS organic GHD and observational studies in PWS.
80% those of children and adults without PWS (114). This
It was agreed that psychomotor development should be
entails surveillance of vitamin and trace element intake to
the priority during infancy with body composition and
insure that recommended daily allowances are achieved.
growth becoming important during childhood and ado-
When hyperphagia begins, or if weight percentiles are in-
lescence. The data on cognitive benefits of rhGH treat-
creasing (usually age 2– 4 y), close supervision must be
ment in the pediatric setting are limited, but should pos-
maintained to minimize food stealing. Locking the
itive effects be extended, this would likely become a top
kitchen, refrigerator, and/or cupboards is often necessary.
treatment priority (25, 26, 35, 113). The workshop par-
As members of the treating team, dieticians must regularly
ticipants concluded that metabolic outcome variables
reinforce adherence to diet, environmental control and
should become the important priority in adults with PWS,
programmed physical activity (115–117).
although muscular hypotonia, mental retardation and
In some children, particularly those who have inade-
psycho-social dysfunction should continue to receive at-
quate dietary, environmental and/or lifestyle interven-
tention throughout the lifespan. The ultimate goal is an
tions, unacceptable weight gain may occur during ther-
improvement in the patient’s well-being.
apy. All attempts should be made to sensitize the family as
The definition of nonresponsiveness to rhGH is arbi-
to the increased risks for obesity-related health concerns,
trary, since there is a continuum in GH response. Many
and to explain that rhGH therapy should not be viewed as
other anthropomorphic and biochemical parameters pla-
teau after some years of treatment, but deteriorate subse-
Recent studies in adolescent and adult patients with
quently if rhGH is stopped. Response criteria to rhGH will
PWS (90% untreated with rhGH) using cyclic, intensive
vary according to age, pubertal status, degree of growth
exercise and nutritional restriction successfully lead to
retardation and duration of therapy. Workshop partici-
BMI reductions during the period of participation in the
pants felt that a successful first year pediatric response to
study (up to 6 y) (118). Long-term, rigorous exercise and
rhGH treatment includes a delta height SDS Ͼ 0.3, a first
strict nutritional control have not been tested against
year height velocity increment of [mteq] 3 cm/year, or a
Multiple pharmacological approaches in PWS aimed at
successful long term (initial weight loss followed by weight
increasing energy expenditure and weight loss have not
regain) and have been associated with frequent complica-
been successful in limited short-term trials, and are sum-
tions (intestinal malabsorption, infectious complications,
marized in Table 5. The workshop participants agreed
gastric perforation and death), and should therefore be
that surgical strategies to achieve weight loss have not been
Pharmacological Mechanism of Limitations/Adverse Strategies References
- Poor long-termcompliance- Gastrointestinalside effects
and increasesenergy expenditure- Naltrexone: Opiod
2009(134)-Plodkowskiet al.,2009(135)- ZipfandBerntson,1987(136)
Table 5. Continued Pharmacological Mechanism of Limitations/Adverse Strategies References
Paresthesia,Somnolence,Ataxia, Dizziness,Nephrolithiasis,Word-findingdifficulty, Mildconfusion,Sedation
peripheral nervoussystems and otherkey cells involved inbody energymetabolism
- Lack ofcompliance inadults with PWSdue to high risk ofpsychiatric sideeffects (mooddisorders, suicide)
Additional studies are required to ascertain the safety,
efficacy, and tolerability of alternative pharmacological
Table 5. Continued Pharmacological Mechanism of Limitations/Adverse Strategies References
- Possible benefitson psychomotordevelopment, butmasked by thenaturaldevelopment
fats are notabsorbed by thebody (stomachreduction and/orbypass)
malabsorption (i.e. nutritionaldeficiencies)- Postoperative
approaches to weight loss in PWS either alone or in com-
Issues of Consent/Assent
bination with rhGH. Thus there is insufficient evidence to
There are differences in national legal regulations dic-
support use of currently available obesity management
tating when a child reaches the age of consent (e,g, 18 in
medications or bariatric surgery in conjunction with
many countries). Informed assent of a child is required in
rhGH treatment for weight reduction in patients with
circumstances where he or she is beginning to make more
PWS, and indeed, some may be contraindicated.
complex decisions; this requires that the child is capable of
some degree of understanding and appreciation of the clin-
may be relatively modest. However, a true understanding
of the healthcare burden of treating individuals with PWS
Even in cases of cognitive disability in an older child or
requires long term health outcome research studies.
adolescent with PWS, it is optimal that legal guardiansremain surrogate decision-makers, but that physicians
strive to obtain the patient’s assent for rhGH therapy, even
At the end of the meeting, workshop participants were
if the patient has limited decision-making capacity. An
asked to individually rank, in order of importance, areas
adult patient with intellectual disability due to PWS may
needing further research that had been discussed during
be capable of consenting to rhGH treatment if he/she is
breakout sessions. It is not surprising that continued sur-
able to understand and appreciate his or her clinical cir-
veillance of long-term effects of rhGH treatment was con-
cumstances. In circumstances in which an adult patient
sidered the top priority, particularly with regards to glu-
does not have the capacity to consent, a surrogate deci-
cose metabolism and diabetes risk, as well as sleep and
sion-maker is appropriate, guided by country- and state-
sleep-disordered breathing. The impact of rhGH treat-
specific guardianship laws (125). This assent/consent pro-
ment on quality of life (QOL), not only of patients but also
cess fosters a doctor – patient relationship based on
of their families, was also ranked as an important aspect
partnership, mutual trust, understanding and respect (32,
of treatment response that needs additional documenta-
tion. Most of the attendees who were not physicians saw
It is not known to what degree the cognitive impairment
an important place for future clinical trials combining
of the individual with PWS plays a role in physicians’ lack
rhGH with other therapeutic approaches, particularly
of recommendation for rhGH use, whether because of per-
those targeting hyperphagia and behavior. The top 10 ar-
ceived difficulty in obtaining truly informed consent or
eas that received the highest priority scores can be seen in
because of physicians’ views on healthcare priorities. All
participants felt that cognitive impairment should not bea barrier or a contraindication to discussion of rhGHtreatment with the patient and caregivers. Conclusion Issues of Fair Access to rhGH.
It is hoped that this PWS Workshop Summary will give
According to several PWS support associations, access
patients, caregivers and physicians a framework with
to the option of rhGH therapy is currently unevenly pro-
which to optimize care. More importantly, it is hoped that
vided even in countries with drug approval for this indi-
it will help harmonize the healthcare access of the pediatric
cation. Members of the workshop felt that several factors
and adult populations with PWS, not just with regards to
currently contribute to differences in the availability of the
rhGH treatment but also with regards to the need for life-
option for rhGH therapy for patients with PWS: 1) A lack
long follow-up of these patients by multidisciplinary
of parental awareness of treatment options and general
teams with experience in PWS. Finally, we stress the im-
impediments to healthcare, 2) Inadequate numbers of phy-
portance of the ethical framework in which healthcare
sician willing and qualified to prescribe rhGH and to reg-
specialists working with patients with PWS should prac-
ularly assess treatment response and potential adverse
tice, and which should emphasize principles of informed
events, 3) Inability to pay for rhGH either through per-
consent/assent, respect for persons and distributive
sonal wealth or by participation in a healthcare system
that supports rhGH treatment and monitoring costs forPWS.
In considering efficiency and best distribution of
healthcare resources among desirable interventions forpatients with PWS, a long list of important interventions
The workshop participants would like to thank the Foundationfor Prader-Willi Research and the EVIDEM Collaboration, in
must be considered, such as occupational and physical
particular, Dr. Mireille Goetghebeur (President of the nonprofit
therapy (PT), speech and language therapy, social skills
EVIDEM Collaboration), for her help in preparing the method-
therapy, weight management therapy and behavioral ther-
ological approach to this CPG and, along with Patricia Camp-
apy, ophthalmologic and orthopedic interventions, and
bell, for the design and support of the PWS GH Evidence Registry
neurologic, psychiatric and endocrine care (replacement
and Workshop Website. We would also like to thank Dominika
therapies for sex hormones, GH, L-thyroxin, cortisol). Al-
Kozubska, CHU-Ste-Justine Research Center, for her expert ad-
though rhGH therapy is costly, (91) compared to the cost
ministrative assistance of the workshop. We gratefully acknowl-
of the provision of all of these services, the cost of rhGH
edge the provision of rhGH safety data from the following com-
Areas Regarding rhGH Use for PWS Requiring Prioritized Attention in Future Studiesa
TOP 10 areas for further research
i. Effects of rhGH therapy in adults with PWS on quality of lifeii. Long-term post-treatment effect of rhGH on mortality and morbidity using registriesiii. The optimal timing and dosage of rhGH treatment initiation in early lifeiv. The effect of rhGH interruption at completion of growthv. Effects of rhGH on behavior and cognitive function across the age rangevi. Impact of rhGH treatment on activities of daily living and well-being as defined by WHOvii. Influence of IGF-I titration on clinical effectsviii. Effect of rhGH on glucose metabolism/diabetes risk, mainly long term effectix. Effects of rhGH therapy on sleep and sleep-disordered breathing in PWS adultsx. RCT trials investigating combination approaches to treatment
Additional areas for future research
xi. Effects of GH/IGF-I on nasopharyngeal tissue and mainly if adenotonsillectomy changes the course or may avoid potentialside effects of rhGH on sleep disorders and OSAxii. Dose response relationships investigating efficacy of physiologic (rather than pharmacologic) dosingxiii. Effects of rhGH treatment in children and adults on visceral adiposity and ectopic fat e.g. muscle, liver and pancreasxiv. Effects of rhGH on timing of development or severity of hyperphagiaxv. Effect of rhGH on bone maturation and premature pubarchexvi. Effects on structural brain developmentxvii. Scoliosis and slipped capital femoral epiphysis in childrenxviii. Is there hypersensitivity to rhGH in PWS?xix. Thyroid function before and after rhGHxx. Effects on cardiac functionxxi. Effects of rhGH on lipid metabolismxxii. Effects of rhGH on water retentionxxiii. Intracranial hypertension (difficult to assess in young children)
aAll participants were asked to discuss areas for future investigation within breakout groups. All participants were then asked to order, by priority,using a secret ballot.
panies: Genetech-Hoffman LaRoche, Lilly, Novo-Nordisk,
P.: Metabolic and Molecular Imaging Group, MRC Clinical Sci-
ences Centre, Imperial College London, and Imperial Centre forEndocrinology, Hammersmith Hospital, UK, Greggi, Tiziana:
Address all correspondence and requests for reprints to: Cor-
Spine and Surgical Division, Istituto Ortopedico Rizzoli, Italy,
responding author, to whom reprint requests should be directed:
Grugni, Graziano: Pediatric Endocrinologist, Istituto Auxo-
Cheri Deal, Ph.D., M.D., F.R.C.P.C., Endocrine Service, CHU-
logico Italiano, Research Institute, Italy, Hokken-Koelega Anita
Sainte-Justine/Université de Montréal, 3175 Côte Ste-Catherine,
C.: Erasmus University Medical Center/ Sophia Children’s Hos-
pital Rotterdam, Johannsson, Gudmundur: Department of En-
docrinology, Institute of Medicine, Sahlgrenska Academy, Uni-
a Participants of the workshop: Ambler, Geoffrey R.: Institute
versity of Gothenburg, Johnson, Keegan: Foundation for Prader-
of Endocrinology and Diabetes, The Sydney Children’s Hospi-
Willi Research, USA, Kemper, Alex: Department of Pediatrics,
tals Network (Westmead) and The University of Sydney, Aus-
Duke University, USA, Kopchick, John J. : Edison Biotechnology
tralia, Battista, Renaldo: Department of Health Administration,
Institute, OH University, USA, Malozowski, Saul: National In-
University of Montreal, Canada, Beauloye, Veronique: Clin-
stitutes of Health, USA, Miller, Jennifer: Pediatric Endocrinol-
iques Universitaires Saint-Luc, Université Catholique de Lou-
ogist, University of Florida, USA, Mogul, Hariette R.: Division
vain, France, Berall, Glen: Division of Gastroenterology, Hepa-
of Endocrinology, NY Medical College, USA, Muscatelli, Fran-
tology and Nutrition, Department of Pediatrics, The Hospital for
coise : Mediterranean Institute of Neurobiology (INMED), IN-
Sick Children, Canada, Biller, Beverly MK: Department of Med-
SERM U901, France, Nergardh, Ricard: Division of Pediatric
icine, MA General Hospital, USA, Butler, Merlin G: Depart-
Endocrinology, Astrid Lindgren Childrens Hospital, Karoliska
ments of Psychiatry, Behavioral Sciences and Pediatrics, KS Uni-
Institute, Sweden, Nicholls, Robert D.: Division of Medical Ge-
versity Medical Center, USA, Cassidy, Suzanne B.: Division of
netics, Department of Pediatrics, Children’s Hospital of Pitts-
Medical Genetics, Department of Pediatrics, University of Cal-
burgh, USA, Radovick, Sally: Pediatric Endocrinology, John
ifornia, USA, Chihara, Kazuo: Hyogo Prefectural Kakogawa
Hopkins Children’s Center, USA, Rosenthal, M. Sara: Associate
Medical Center, Japan, Cohen, Pinchas: Department of Pediatric
Professor, Program for Bioethics, Depts. of Internal Medicine
Endocrinology, Mattel Children’s Hospital at UCLA, USA,
and Pediatrics, University of Kentucky, USA, Sipilä, Ilkka : Pe-
Craig, Maria: Institute of Endocrinology and Diabetes, Sydney
diatrics, Hospital for Children and Adolescents, University of
Children’s Hospital Network (Westmead); University of New
Helsinki, Finland, Tarride, Jean-Eric: Associate professor (part
South Wales, University of Sydney, Australia, Farholt, Stense:
Time), Department of Clinical Epidemiology and Biostatistics,
Centre for Rare Diseases, Aarhus University Hospital Skejby,
McMaster University, Canada, Tony, Michèle: Département
Denmark, Goetghebeur, Mireille: LA-SER, Montreal Canada;
d’administration de la santé, Université de Montréal, Canada,
Department of Health Administration, University of Montreal,
Vogels, Annick: Kinder-en jeugdpsychiater, Centrum Menseli-
Canada; EVIDEM Collaboration, Canada, Goldstone, Anthony
jke Erfelijkheid, Belgium, Waters, Michael J.: Institute for Mo-
lecular Bioscience and School of Biomedical Sciences, University
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Are homosexuals born that way? For a comprehensive account of the contribution of genes, hormones, brain microstructure, intersex conditions and environment to homosexu-ality see My Genes Made Me Do It! - a scientific look at Sexual Orientation, Neil and Briar Whitehead, Huntington House, 1999. Researchers have tried for decades to identify a biomedical basis to homosexuality, but haven’
Asian J. Exp. Sci., Vol. 22, No. 1, 2008; 143-146 Concurrent Effects of Eyestalk Ablation and Fluoxetine on the Nutrient Depostion During Ovarian Development in a Fresh Water Prawn, Machrobrachium lamarrei lamarrei R. Eswaralakshmi, J. Jayanthi and M.G. Ragunathan Department of Advanced Zoology and Biotechnology, Guru Nanak College, Abstract : The organic compounds like protein, carboh