It's not about the height: Prader–Willi Syndrome. Effects of Growth Hormone Treatment

Abstract

by Urs Eiholzer. Karger, 2001. CHF 88.00/DEM 114.00/US$76.50 (xii + 118 pages) ISBN 3805572565The past decade has seen significant advances in the understanding of Prader–Willi Syndrome (PWS) and in treatments to alleviate its distressing complications. Recent work has focused on the role of underlying growth hormone deficiency (GHD) in the pathophysiology of PWS, and the effects of growth hormone (GH) therapy. This book, written by a steadfast and productive investigator in this area, provides an excellent overview of the current knowledge of hormonal and metabolic consequences of PWS, with special emphasis on GH physiology and treatment.Opening chapters provide a concise, thoroughly referenced account of the clinical, genetic, hormonal and metabolic features of PWS. It is appropriate that non-growth issues, such as carbohydrate metabolism and energy balance, are highlighted, because the main reason for treating PWS with GH is to improve energy use rather than to correct short stature.Eiholzer attempts to draw a line under the long-running debate over whether children with PWS are truly GH deficient or merely appear so because of the suppressive effects of obesity on GH secretion. His compelling argument for the existence of true GHD in PWS cites differences from non-PWS normal obese children in growth patterns, bone-age advancement and IGF-I levels; however, it could have been strengthened by a discussion of the exaggerated deceleration of growth caused by caloric restriction and the GHD-like body composition displayed by PWS children. Nevertheless, several interesting observations regarding the possible influence of coexisting GHD on gonad and thyroid function, and reports of primary gonad failure in PWS patients add to our conventional knowledge of this disorder.The bulk of the text details Eiholzer's GH treatment trial of 35 children with PWS for up to five years, where comparisons were made with historical control data. Although treatment with GH results in impressive improvements in growth rate, body proportion, body composition, blood lipid composition, physical capability and motor development, it is not made clear in how many children and for how long each parameter was studied. For instance, long-term growth (i.e. three years) is described for only 20 of the 35 children. Dual energy X-ray absorptiometry (DEXA) studies were carried out in only 16 children, endurance and anaerobic tests in only four, and psychomotor development assessment in ten. As a result, conclusions drawn about the benefits of GH therapy in these areas, although correct, are actually substantiated most strongly not by the author's data, but by other studies that are cited only briefly.Two parts of the book are particularly enlightening. The first is a discussion of carbohydrate metabolism. Contrary to previous reports (drawn primarily from studies of older children or adults with PWS), Eiholzer describes subnormal fasting insulin levels in his subjects, with no difference noted between obese and non-obese children. These findings of heightened insulin sensitivity compared with results in similarly obese non-PWS children refute the view that obesity of PWS does not differ from usual exogenous obesity, and also strengthen the argument for relative GH deficiency in these children. A second valuable contribution of this book is the photographic documentation of selected patients, which not only provides the reader with insight into the variable presentation of PWS, but also effectively conveys the long-term effects of GH therapy that cannot be captured in data tables.Notably absent from the text is a discussion of the complex ethical issues that have both affected and arisen from GH therapy for PWS. Progress towards this potential use of GH was undoubtedly hampered by the prejudgment that children with mental disabilities would not experience a benefit similar to that for other short children, and were therefore not as ‘entitled’ to therapy. However, GH therapy of children with PWS has raised awareness of the fairness of targeting this expensive therapy to those children that can benefit the most from it, even if mental disabilities coexist. Finally, GH therapy for PWS children has provided the major impetus for a broader view of non-growth benefits of GH during childhood. Indeed, improvements in physical function, body composition and lipid profiles appear to overshadow increased height as a benefit of treatment, and raise important new questions about even more possible diverse indications for GH therapy during childhood.In his forward to the book, Martin Savage states ‘this volume differs from the others in this series in that it is a detailed account of a single disorder, written by a single contributor.’ In a nutshell, this sentence describes both the strengths and weaknesses of this book. The scientific breadth, logistical challenge and results of these studies are truly impressive. However, sample sizes are frequently small, and the studies are not prospectively controlled. Although other relevant studies with better design (e.g. prospective controlled versus observation/historical controls), techniques (e.g. DEXA scanning versus skinfold thickness) or greater patient numbers are appropriately referenced, they are usually discussed briefly or included in tables, and cited primarily to support the author's data and experience. A more thorough discussion of these other studies would have added depth to areas where the author's experience is not extensive, and would have provided readers with a broader appreciation for contributions of other investigators to the ‘state-of-the-art’ knowledge about PWS and GH therapy.Nonetheless, the author's clinical insights, derived from many years of study of this challenging group of patients, really comes across. These important observations, combined with the comprehensive treatment of a focused clinical problem and a superb reference list make this book worthwhile reading for pediatric geneticists and endocrinologists, and others interested in PWS.