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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- Workshop Methodology
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 rhGH treatment
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 treatment
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 severe obstructive 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 Evaluation
Testing/Interventions
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 Future Directions
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 Acknowledgments
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 2. Butler MG. Prader-Willi Syndrome: Obesity due to Genomic Im-
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