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A Comprehensive Team Approach to the Management of Introduction. The treatment of children with Prader-Willi syndrome
Prader-Willi syndrome (PWS) is
(PWS) represents a new challenge in the field of pediatric endocrinology. characterized by infantile hypotonia;
The handicaps and problems of affected children are manifold, more so short stature; small hands and feet; increased than in any other typical disease of pediatric endocrinology, perhaps with the exception of craniopharyngioma. Therefore, management of children decreased muscle mass; scoliosis; reduced with PWS may be most successful with a team approach to comprehen- resting energy expenditure (REE); reduced bone mineral density (BMD), which may leadto osteopenia and osteoporosis; hypogo- We thank Pharmacia Corporation for organizing a workshop on such an nadism; hypothalamic dysfunction; and a par- approach in St. Julians, Malta, on April 24, 2001. This newsletter sum- ticular facial appearance. These clinical fea- marizes the proceedings of that workshop. The reader will notice that the tures are accompanied by hyperphagia, cogni- development of a comprehensive professional team approach to PWS has tive disabilities, and behavioral problems, only just begun. Much work remains to be done, primarily to define what, including skin picking. In 70% of individuals, exactly, a “comprehensive team approach” to PWS means. For example, the syndrome is the phenotypic expression of a it appears necessary for one highly experienced specialist team member complex genetic disorder resulting from a to assume leadership, to allow patients and their families to interact with paternally derived de novo deletion of the prox-imal long arm of chromosome 15 (at bands one single professional. Further, growth hormone treatment has become a very important tool in the management of PWS. Nevertheless, it must 15s from the mother) is seen in about 25% of be emphasized that without a comprehensive team approach, especially to restrict caloric intake and provide psychosocial support for families, imprinting defect in the rest.1 Prader-Willi syn- children receiving growth hormone therapy will not lose weight, and the drome and its sister syndrome, Angelman syn- impact on their quality of life may remain relatively small. drome (an entirely different clinical syndrome),were the first examples in humans of genetic Some centers have a great deal of experience and know-how in managing imprinting, or the differential expression of PWS. This know-how, however, is most often attributable to the experi- genetic information depending on the parent ence of a single person. Through intensive study of the experience and of origin. Prader-Willi syndrome is one of the strategies of such centers and individuals, a professional comprehensive most common conditions seen in genetics clin- team approach can be developed that will allow centers all over the ics worldwide and the most common genetic world to offer optimum care to their patients with PWS. cause of marked obesity yet identified,2 and its various clinical manifestations are major caus- es of morbidity and social limitations. Learning Meeting Participants
Panelists
Moderator
Presenters
Sponsored by the International Prader-Willi Syndrome Organization through an unrestricted educational grant provided by A Comprehensive Team Approach to the Management of only in conjunction with a multidiscipli- family dynamics, in addition to cognition and behavior, may all be adversely affect- studied extensively in the United States, experience and to identify strategies for American Experience
to respond to at least two of the stimuli, individuals with PWS require a variety of cologic stimuli appeared to be related to reported for the first time that GH thera- py led to significant increases in the lin- ear growth rate of patients with PWS.6 All the patients in their study initially had and family interaction, support, and care.
composition, strength and agility, respira- observed in these cases were not an arti- nator, a geneticist, a psychologist, and a ise that the poor linear growth in patients dietitian. This newsletter describes such at baseline.7 Thirty-five children received GH EFFECTS ON PHYSICAL
PARAMETERS IN PWS
ed the results of an uncontrolled trial of increased height velocity (Figure 1),
cipal cause of short stature in the major- abnormalities.14 All 12 children initially had low serum levels of GH, IGF-1, there was no significant increase in REE.
therapy. Dual-energy x-ray absorptiometry value in improving some physical disabil- (DEXA) at baseline revealed increased fat ities experienced by children with PWS.
Within 3 months of the patients’ begin- regulation may contribute not only to the excess of body fat and the deficit of lean of fat mass from the trunk to the thighs.
improved behavior and appetite control.
promotes growth of lean body mass,7,8,11,12 Evaluation
Growth (cm/yr)
• Complete examination• Dietary evaluation and counseling• Physical therapy evaluation Figure 1. Height velocity in patients with PWS treated with growth hormone (GH). Thirty-five
children received GH at a dose of 1 mg/m2/day for 24 months and 19 were untreated. After 12 months, the GH-treated children showed significantly increased height velocity. The growth rate slowed • Initial discussion of growth hormone between 12 and 24 months, although height velocity remained significantly higher than at baseline (*P<0.01 compared with baseline [0 months]). (Reproduced with permission from Carrel AL, Myers SE,Whitman BY, Allen DB. Prader-Willi syndrome: the effect of growth hormone on childhood body compo- sition. Endocrinologist. 2000;10(suppl 1):43S-49S.) • DNA studies • IGFBP-3, IGF-1, thyroid panel, lipid social services, and educational services, and agility.8 Height velocity remained sig- as well as readily available facilities for (P<0.01), although the growth rate physiology. The Table lists the compo-
nents of the initial evaluation and test- should be started early; GH therapy start- considered for them on the basis of clin- DEXA=dual-energy x-ray absorptiometry; IGF-1=insulin-like Swiss Experience
growth factor-1; IGFBP-3= IGF binding protein-3.
py in infants. (In the United States, clin- ical trials of GH therapy in infants with ture remain the basic defects in PWS.
stabilize their weight for height. Such a reduction of food intake is possible only activity, which is probably caused by the through close, strict parental supervision, During the first year of the study, no sig- nificant difference in scoliosis progres- muscle mass, in turn, is the cause of the group (from a mean of 9.2° at baseline to efit of GH therapy for children with PWS, 12.1°) and the control group (from 14.7° quent increase in REE. If energy intake is the GH-treated group also was not signif- not increased, these alterations lead to a ed and treated in a multidisciplinary clin- notype (Figure 2). However, even though
tal overweight children. All were treated cialist, geneticist, psychologist, and die- titian. Ancillary resources should include A Comprehensive Team Approach to the Management of satiety but increases the energy expendi- had become not only taller but also slim- was rather limited. The investigators con- only if energy intake is not increased at the same time. It is therefore imperative that parents continue to keep patients’ and height predictions reach the parental Figure 2. A child with PWS before and 12
months after treatment with growth hormone
(GH). For GH therapy to increase lean body mass,
reduce body fat, and stabilize weight for height, children with PWS must maintain their energy intake at about 75% that of healthy children.
older children (group 3) was considerable leagues used the Griffith test19 to study (Figure 3). The influence of exogenous
the first year of GH treatment.20 At base- line, the children were significantly more retarded on the “locomotor” and “hear- addition, the increase in fasting insulin ing and speech” scales than on the other sient.22 Three years of GH therapy did not er than untreated children with PWS.
served, the investigators speculated that sition during GH therapy result from sev- eral therapeutic interventions. It is criti- cal to maintain control of nutrient intake of the parents—the most important ther- apeutic effect of GH.21 After 1 year of GH certain aspects of lipid metabolism differ still correlated with abdominal obesity), formance leads to an increase in activity, decreased.23 These lipid levels normalize for the first time that insulin secretion in Lean mass
SDS for height
SDS for height 1
olism, as described in adult patients with Swedish Experience
Duration of GH therapy (mo)
deficiency seen in the syndrome was aresult of the characteristic obesity, and Figure 3. Body composition measured by DEXA in 16 children with PWS. Body composition is expressed
as the height-related standard deviation score and compared with reference values for a Dutch population older than 4 years or taller than 100 cm.16 The graphs show medians ( , thick black lines) and individual courses of young underweight (n=4; ■, blue lines), prepubertal overweight (n=8; ■, blue lines), and puber- tal children with PWS (n=4; ●, dotted lines) treated with growth hormone (GH). Significant differences vs baseline at 6, 24, and 42 months (*P<0.05, **P<0.01 [Wilcoxon test]). (Reproduced with permission from Eiholzer U, Bachmann S, l’Allemand D. Is there growth hormone deficiency in Prader-Willi syndrome? Six arguments to support the presence of hypothalamic growth hormone deficiency in Prader-Willi Syndrome.
Horm Res. 2000;53(suppl 3):44-52.) inary results of this study in 199725 and5-year results in 1999.10 CLINICAL MANAGEMENT OF
PWS-ASSOCIATED BEHAVIORS
patients with PWS between the ages of months, height velocity declined dramat- 3 and 7 years were randomized into ically in both groups; height SDS fol- role in regulating appetite, sensitivity to group A (n=15), which received GH lowed a similar pattern. Growth hormone the second year. After 2 years, all chil- prove that the effects of GH therapy were again increased (Figure 4). Body mass
low levels of insulin. During the first year of the study, IGF-1 levels increased rap- children, levels of fasting insulin, glu- unchanged in group B (no treatment).
cooperative.26 By adolescence, behavioral first year of GH therapy in group A, fol- the second year. In group B, height veloc- ity SDS decreased slightly during the first A Comprehensive Team Approach to the Management of sive, manipulative, irritable, mood-labile, age, appears to affect the entire brain.
frustrated. Transitioning from one activity to another becomes increasingly difficult, ioral manifestations reflect a distributed includes an inability to recognize cause- izing this disorder, and the food behavior four cognitive difficulties have been iden- ent approach to traditional behavior man- link punishment or reward with anantecedent behavior. Many patients withPWS who frequently exhibit problem instituted. These changes require creativ- ity, hard work, and, often, many monthsbefore a behavior is altered, and some unalterable. It is particularly difficult Height SDS
Height SDS
Time from start of study (yr)
Time from start of study (yr)
level of conflict over child rearing.
Although this is also true for normal chil- Figure 4. Height velocity standard deviation scores (SDS) in patients with PWS treated with different
regimens of growth hormone (GH) over 30 months. Group A received GH at a dose of 0.1 IU/kg/day
flexibility seen in normal children.
(0.033 mg/kg/day) for 2 years. Group B was untreated for the first year and then received GH at a dose of 0.2 IU/kg/day (0.066 mg/kg/day) during the second year. After 2 years, all children stopped GH therapy for 6 months and then restarted GH therapy at a dose of 0.1 IU/kg/day (0.033 mg/kg/day). Values are means ± SD.
(*P<0.001 compared with baseline; †P<0.03 compared with baseline.) (Reproduced with permission from Lindgren AC, Ritzén EM. Five years of growth hormone treatment in children with Prader-Willi syndrome. The Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl. 1999;433:109-111. at behavioral management, and pharma-cologic interventions are often consid- mately are responsible for the inability of deficits,27 and failure to develop the abil- adults with PWS to succeed in alternative living and work placements. Interestingly, iors in these individuals. A survey of par- scores in the 90s or somewhat higher.
judgment, denial of deficits, inability to Functional aptitude, however, is entirely conflicts, are also seen in patients with Psychotropic medication shouldbe used only From the standpoint of diet, two distinct phases of PWS are apparent: initial fail- nizes that the constant feeling of hunger 2 months to meet energy requirements.
almost every available psychotropic agent Signs of poor feeding in infants with PWS behavioral difficulties and refractoriness rence of targeted symptoms; only three— tion, respiratory infections, irritability tine—were effective.30 More recently, it has been found that all serotonin-specif- deterioration is, in fact, a positive out- marked reduction in irritability, and less perseveration, but with no specific anti- and less perseveration.26,32 In addition, transition to solid food, with 42% of chil- therapy also produced positive effects on drug to achieve a benefit; increasing the 6 months of patients’ starting treatment.
engage in food seeking and food stealing.
dose to “normal” often results in toxicity and a return of the problem behavior.31 In eating drive that results from their dis- patients’ social interaction. Furthermore, have attempted to control their children’s and environmental changes, have failed.
weight, but dietary compliance is poor.
Severe caloric restriction for short peri- of physical activity without parental prod- fective in controlling food-seeking behav- hospital setting may be helpful, but most IMPROVING QUALITY OF LIFE IN
PATIENTS WITH PWS: DIET, EXER-
CISE, AND LIFESTYLE CHANGES
which are often effective in the so-called A Comprehensive Team Approach to the Management of 19. Brandt I. Griffiths Entwicklungsskalen zurBeurteilung der Entwicklung in den ersten beiden 1. Butler MG, Thompson T. Prader-Willi syndrome: clini-cal and genetic findings. Endocrinologist 2000;10(suppl Lebensjahren. Weinheim and Basel: Beltz Verlag; 1983.
20. Eiholzer U, Malich S, l’Allemand D. Does growthhormone therapy improve motor development in infants tured exercise program. Aerobic exercise, 2. Carrel AL, Myers SE, Whitman BY, Allen DB. Prader-Willi syndrome: the effect of growth hormone on child- with Prader-Willi syndrome? [letter]. Eur J Pediatr.
hood body composition. Endocrinologist. 2000;10(suppl 21. Eiholzer U, Gisin R, Weinmann C, et al. Treatment 3. Lee PDK. Effects of growth hormone treatment in with human growth hormone in patients with Prader- children with Prader-Willi syndrome. Growth Horm IGF Labhart-Willi syndrome reduces body fat and increases Res. 2000;10(suppl B):S75-S79.
muscle mass and physical performance. Eur J Pediatr.
4. Eiholzer U, Bachmann S, l’Allemand D. Growth hor- mone deficiency in Prader-Willi syndrome.
22. L’Allemand D, Schlumpf M, Torresani T, Girard J, Endocrinologist. 2000;10(suppl 1):50S-56S. Eiholzer U. Insulin secretion before and under 3 years of trampoline, dancing, and ball playing.
growth hormone (GH) therapy in Prader-Willi syndrome 5. Eiholzer U, Bachmann S, l’Allemand D. Is there (PWS) [abstract]. Exp Clin Endokrinol Diabetes. 2000 growth hormone deficiency in Prader-Willi syndrome? Six arguments to support the presence of hypothalamic mented certainly include control of food- growth hormone deficiency in Prader-Willi syndrome.
23. L’Allemand D, Eiholzer U, Schlumpf M, Steinert H,Riesen W. Cardiovascular risk factors improve during 3 Horm Res. 2000;53(suppl 3):44-52.
years of growth hormone therapy in Prader-Willi syn- 6. Lee PDK, Wilson DM, Rountree L, Hintz RL, drome. Eur J Pediatr. 2000;159:835-842.
Rosenfeld RG. Linear growth response to exogenous growth hormone in Prader-Willi syndrome. Am J Med 24. Vahl N, Jorgensen JO, Hansen TP, et al. The favourable effects of growth hormone (GH) substitution tal controls designed to limit hyperphagia on hypercholesterolaemia in GH-deficient adults are not 7. Carrel AL, Myers SE, Whitman BY, Allen DB. Growth associated with concomitant reductions in adiposity. A hormone improves body composition, fat utilization, 12 month placebo-controlled study. Int J Obes Relat physical strength and agility, and growth in Prader-Willi Metab Disord. 1998;22:529-536.
syndrome: a controlled study. J Pediatr. 1999;134:215- 25. Lindgren AC, Hagenäs L, Müller J, et al. Effects of growth hormone treatment on growth and body composi- 8. Myers SE, Carrel AL, Whitman BY, Allen DB.
tion in Prader-Willi syndrome: a preliminary report. The Sustained benefit after 2 years of growth hormone on Swedish National Growth Hormone Advisory Group. Acta body composition, fat utilization, physical strength and Paediatr Suppl. 1997;423:60-62.
agility, and growth in Prader-Willi syndrome. J Pediatr.
tions may actually discourage social inte- 26. Whitman BY, Myers S, Carrel A, Allen D. A treat-ment/control group study of growth hormone treatment: 9. Eiholzer U, l’Allemand D. Growth hormone normalises impact on behavior—a preliminary look. Endocrinologist.
height, prediction of final height and hand length in chil- dren with Prader-Willi syndrome after 4 years of therapy.
SUMMARY AND CONCLUSION
27. Dykens EM, Hodapp RM, Walsh K, Nash LJ.
Profiles, correlates, and trajectories of intelligence in 10. Lindgren AC, Ritzén EM. Five years of growth hor- Prader-Willi syndrome. J Am Acad Child Adolesc mone treatment in children with Prader-Willi syndrome: Psychiatry. 1992;31:1125-1130.
Swedish National Growth Hormone Advisory Group. Acta 28. Whitman BY, Greenswag L. The use of psychotropic Paediatr Suppl. 1999;433:109-111.
medications in persons with Prader-Willi syndrome. In: 11. Lindgren AC, Hagenäs L, Müller J, et al. Growth hor- Cassidy S, ed. Prader-Willi Syndrome and Other mone treatment of children with Prader-Willi syndrome Chromosome 15q Deletion Disorders. Berlin: Springer Clinical trials confirm that GH treatment affects linear growth and body composition favourably.
Verlag in cooperation with NATO Scientific Affairs Acta Paediatr. 1998;87:28-31.
12. Eiholzer U, l’Allemand D, van der Sluis I, Steinert H, 29. Greenswag LR, Whitman BY. Long term follow-up of Gasser T, Ellis K. Body composition abnormalities in use of Prozac as a behavioral intervention in 57 persons children with Prader-Willi syndrome and long-term with Prader-Willi syndrome. Proceedings: 2nd Prader- effects of growth hormone therapy. Horm Res.
Willi Syndrome International Scientific Workshop and 13. Parra A, Cervantes C, Schultz RB. Immunoreactive 30. Whitman B, Greenswag L. Psychological issues in insulin and growth hormone responses in patients with Prader-Willi syndrome. In: Greenswag L, Alexander R, Prader-Willi syndrome. J Pediatr. 1973;83:587-593.
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33. Shaw V, Lawson M. Principles of paediatric dietetics.
16. Boot AM, Bouquet J, de Ridder MA, Krenning EP, de In: Shaw V, Lawson M, eds. Clinical Paediatric Dietetics, Muinck Kaizer-Schrama SM. Determinants of body com- 2nd ed. Oxford, UK: Blackwell Science; 2001:Chap 1.
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