Prader-Willi Syndrome and Growth Hormone Therapy: Take a Deep Breath and Weigh the Data
2012; Elsevier BV; Volume: 162; Issue: 2 Linguagem: Inglês
10.1016/j.jpeds.2012.09.024
ISSN1097-6833
Autores Tópico(s)Epigenetics and DNA Methylation
ResumoSee related article, p 263Prader-Willi syndrome (PWS), a complex neurogenetic disorder originally described in 1956,1Prader A. Labhart A. Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach myatonieartigem Zustand im Neugeborenalter.Schweizerische Medizinische Wochenschrift. 1956; 86: 1260-1261Google Scholar was relatively unknown outside genetics and developmental clinics until the late 1990s when growth hormone replacement therapy (GHRT) emerged as an effective intervention. The cardinal feature is the early onset, unrelenting, treatment-refractory hyperphagia leading to morbid obesity and attendant comorbidities. In addition, however, PWS is characterized by infantile hypotonia and failure to thrive, followed by short stature, hypogonadism, abnormal body composition, sleep and respiratory abnormalities (including impaired ventilatory control, central and obstructive apnea, and excessive daytime sleepiness), and behavioral difficulties. Until recently, a markedly decreased life span was expected, primarily resulting from complications of obesity. With better management and the introduction of GHRT, most affected individuals can now expect a relatively normal life span with better quality of life. See related article, p 263 In this issue of The Journal, Al-Saleh et al highlight 3 issues that continue to plague those charged with providing responsible care to this population: (1) the incidence and cause of sudden unexpected death (SED) in those affected; (2) whether GHRT raises the risk for obstructive sleep apnea (OSA) in patients with PWS and, if so, does this lead to an increased risk of SED; and (3) the appropriate medical management for minimizing any treatment-related risks.2Al-Saleh Al-Naimi A. Hamilton J. Zweerink A. Iaboni A. Narang I. Longitudinal evaluation of sleep disordered breathing in children with Prader-Willi syndrome during 2 years of growth hormone therapy.J Pediatr. 2013; 162: 263-268Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Some historical background is necessary to frame these issues. During the past 15 years, GHRT has become the standard of care for most children with PWS. Randomized, controlled studies in the late 1990s documented accelerated growth velocity, increased muscle mass and strength, decreased fat mass, increased physical activity, behavior improvements,3Carrel A. Allen D. Myers S. Whitman B. Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: a controlled study.J Pediatr. 1999; : 215-221Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 4Lindgren A.C. Hagenas L. Muller J. Blichfeldt S. Rosenborg M. Brismar T. Ritzen E.M. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably.Acta Paediatr. 1998; 87: 28-31Crossref PubMed Google Scholar, 5Ritzen E.M. Lindgren A.C. Hagenas L. Marcus C. Muller J. Blichfeldt S. Swedish Growth Hormone Advisory GroupGrowth hormone treatment of patients with Prader-Willi syndrome.J Pediatr Endocrinol Metab. 1999; 12: 345-349PubMed Google Scholar and improved respiratory function.6Lindgren A.C. Hellstrom L.G. Ritzen E.M. Milerad J. Growth hormone treatment increases CO2 response, ventilation, and central inspiratory drive in children with Prader-Willi syndrome.Eur J Pediatr. 1999; 158: 936-940Crossref PubMed Scopus (96) Google Scholar, 7Myers S.E. Carrel A.L. Whitman B.Y. Allen D.B. Physical effects of growth hormone treatment in children with Prader-Willi syndrome.Acta Paediatr. 1999; 88: 112-114Crossref Google Scholar Pharmacia and Upjohn obtained Food and Drug Administration approval for GHRT for PWS in 2000. Soon thereafter, reports of SED in children in the early phases of GHRT emerged.8Eiholzer U. Nordmann Y. L'Allemand D. Fatal outcome of sleep apnea in PWS during the initial phase of growth hormone treatment. A case report.Horm Res. 2002; 58: 24-26Crossref PubMed Google Scholar, 9Nordmann Y. Eiholzer U. L'Allemand D. et al.Sudden death of an infant with Prader-Willi syndrome—not a unique case?.Biol Neonate. 2002; 82: 139-141Crossref PubMed Scopus (47) Google Scholar Three theories were introduced to explain these deaths: (1) Growth hormone (GH)-mediated tonsillar or soft tissue hypertrophy leading to fatal OSA; (2) a rise in basal metabolic rate with a resultant rise in oxygen demand; and (3) a normalization of body hydration with augmentation of volume load. Subsequent research has focused primarily on the first mechanism. As a result, although the sparse data available at that time indicated that the mortality rate of GH-treated patients with PWS was lower than that of untreated patients with PWS,10Riedl S. Blumel P. Zwiauer K. Frisch H. Death in two female Prader-Willi patients during the early phase of growth hormone treatment.Acta Paediatr. 2005; 94: 974-977Crossref PubMed Scopus (25) Google Scholar the temporal relationship between 7 fatal events worldwide and the initiation of GHRT led Pharmacia and Upjohn to issue a safety warning on May 30, 2003.11Lippe, B. Safety letter. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm168411.htm. Accessed May 2003.Google Scholar It stated that GHRT is contraindicated in patients with PWS who are severely obese or have severe respiratory impairment. Although OSA manifesting during GHRT had previously been documented in other populations, the available research evidence in PWS at that time indicated that GHRT improved overall respiratory function. Nonetheless, based on the presumption that GH-mediated OSA was a strong risk factor for SED, in 2003 the Clinical Advisory Board of the Prader-Willi Syndrome Association-USA developed a set of guidelines for initiating GHRT that included a baseline polysomnogram (PSG) study, followed by repeat studies 6 weeks later and subsequently as clinically indicated.12Clinical Advisory Board Consensus Statement Recommendations for evaluation of breathing abnormalities associated with sleep in Prader-Willi syndrome. PWSA-USA, Orlando, FL2003Google Scholar With much additional data now available, it may be time to relook at these concerns. Although SED was far from unknown in this population,13Stevenson D.A. Anaya T.M. Clayton-Smith J. Hall B.D. Van Allen M.I. Zori R.T. Zackai E.H. Frank G. Clericuzio C. Unexpected death and critical illness in Prader-Willisyndrome: report of 10 individuals.Am J Med Genet, Part A. 2004; 124A: 158-164Crossref PubMed Scopus (84) Google Scholar many argued that even though the mortality rate appeared to be less with GHRT treatment than without, the data were insufficient to disprove an increased risk among those initiating GH treatment. There ensued a number of studies regarding the rates and causes of death in PWS in general. Whittington et al examined the population prevalence, estimated birth incidence, and mortality rate for PWS in one UK health region.14Whittington J.E. Holland A. Webb T. Butler J. Clarke D. Boer H. Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willisyndrome in one UK health region.J Med Genet. 2001; 38: 792-798Crossref PubMed Google Scholar Mortality rates were limited to those between the ages of 6 and 56 years not treated with GH, yielding estimates of 3% per year compared with 0.14% in the general population. Nagai et al estimated an overall death rate of 2.6% per year (13/494) for a GHRT-naive PWS population between the ages of 2 months and 48 years in a Japanese population study.15Nagai T. Obata K. Tonoki H. Temma S. Murakami Katada Y. Yoshino A. et al.Cause of sudden, unexpected death of Prader-Willi syndrome patients with or without growth hormone treatment.Am J Med Genet Part A. 2005; 136A: 45-48Crossref Scopus (80) Google Scholar However, a bimodal distribution of deaths was noted, with those under 3 years and those over 30 years representing 12 of the 13 deaths. The details of these deaths will be noted later. Schrander-Stumpel et al examined the causes of death in 27 GH-naive individuals from The Netherlands, Belgium, Sweden, Finland, Switzerland, and the US, ages ranging from birth to 68 years.16Schrander-Stumpel C.T. Curfs L.M.G. Sastrowijoto P. Cassidy S.B. Schrander J.J.P. Fryns J.P. Prader-WilliSyndrome: Causes of Death in an International Series of 27 Cases.Am J Med Genet Part A. 2004; 124A: 333-338Crossref PubMed Scopus (143) Google Scholar Among the 13 children aged 5 years and under, 2 deaths were deemed unrelated to PWS. Of the remaining 11, 9 died of respiratory causes. Six of these 9 died of acute respiratory infections, and the others died of “hypoventilation, (possibly) in combination with aspiration.” The remaining 2 younger children died unexpectedly of acute gastrointestinal disease. A very obese 9-year-old boy died of pneumonia with cardiac decompensation. Of the 14 older children and adults, 10 died of a variety of obesity-related comorbidities. Three of the remaining 4 died of gastric symptoms compatible with acute gastric dilatation and 1 died of familial cardiomyopathy.16Schrander-Stumpel C.T. Curfs L.M.G. Sastrowijoto P. Cassidy S.B. Schrander J.J.P. Fryns J.P. Prader-WilliSyndrome: Causes of Death in an International Series of 27 Cases.Am J Med Genet Part A. 2004; 124A: 333-338Crossref PubMed Scopus (143) Google Scholar The estimated prevalence of OSA in the general pediatric population is 1%-3%.17Lumeng JC, Chervin RD. Epidemiology of Pediatric Obstructive Sleep Apnea. Proceedings of the American Thoracic Society 2008, Toronto, Ontario, Canada;5:242-52.Google Scholar The peak age for airway restriction from adenotonsillar hypertrophy is reported to be 3-6 years.18Jeans W.D. Fernando D.C.J. Maw A.R. Leighton B.C. A longitudinal study of the growth of the nasopharynx and its contents in normal children.Brit J Radiol. 1981; 54: 117-121Crossref PubMed Scopus (195) Google Scholar A retrospective study in our general pediatric endocrine practice in 1997 reported development of symptomatic sleep apnea in 4 of 145 (2.8%) GH-treated children after 3-40 months of therapy.19Gerard J.M. Garibaldi L. Myers S.E. Aceto T. Kotagal S. Gibbons V.P. et al.Sleep apnea in patients receiving growth hormone.Clin Pediatr. 1997; 36: 321-326Crossref PubMed Scopus (27) Google Scholar All 4 children had symptomatic improvement after adenotonsillectomy. The conclusion drawn was “modifications of the airway, if they occur, are difficult to quantitate accurately, may develop more or less rapidly, and may become variably expressed in different individuals.” Looking specifically at those with PWS, Miller et al followed 25 patients, ages 6 months to 39 years, with PSG at baseline and 6 weeks post-GH initiation.20Miller J. Silverstein J. Shuster J. Driscoll D.J. Wagner M. Short-tem effects of growth hormone on sleep abnormalities in Prader-Willi syndrome.J Clin Endocrinol Metab. 2006; 91: 413-417Crossref PubMed Scopus (94) Google Scholar All 25 patients had sleep disordered breathing during the baseline study, including both obstructive and central apneic events. After 6 weeks of treatment, 19 patients had improved apnea/hypoxia indexes (AHI) with no change in the overall frequency of obstructive events. The other 6 patients had worsening of obstructive events related to upper respiratory infections. Festen et al followed 53 young children (ages 2.1-7.2 years) with PSG at baseline and 6 months post-GH initiation.21Festen D.A.M. de Weerd A.W. van den Bossche R.A.S. Joosten K. Hoeve H. Hokken-Koelega A.C.S. Sleep-related breathing disorder in prepubertal children with Prader-Willi syndrome and the effects of growth hormone treatment.J Clin Endocrinol Metab. 2006; 91: 4911-4915Crossref PubMed Scopus (103) Google Scholar Their results indicated that children with PWS have a high AHI (mean 5.1/h, range 2.8-8.7/h), mainly due to central apneas. AHI did not correlate with age or body mass; however, central apneas decreased with age. During 6 months of GH treatment, the AHI did not change significantly from baseline (4.8/h, range 2.7-6.2/h). One patient died unexpectedly during a mild upper respiratory infection despite a nearly normal PSG. A French review of 64 cases of death in both treated and untreated individuals indicated that 61% died of respiratory insufficiency or infections.22Tauber M. Diene G. Molinas C. Hebert M. Review of 64 Cases of Death in Children with Prader-Willi Syndrome (PWS).Am J Med Genet Part A. 2008; 146A: 881-887Crossref PubMed Scopus (150) Google Scholar There was no difference in cause of death, sex (2:1 male:female), prevalence of obesity, or prevalence of sleep apnea between treated and untreated individuals. Nagai et al analyzed the causes of death in the 13 GH-naïve individuals previously referenced,15Nagai T. Obata K. Tonoki H. Temma S. Murakami Katada Y. Yoshino A. et al.Cause of sudden, unexpected death of Prader-Willi syndrome patients with or without growth hormone treatment.Am J Med Genet Part A. 2005; 136A: 45-48Crossref Scopus (80) Google Scholar comparing them with the 7 deaths prompting the safety warning. The authors concluded that in infants, death was often associated with milk aspiration or hypothalamic dysregulation of respiration. During early and late childhood, irrespective of GHRT, SED was primarily due to viral illness or respiratory problems. Finally, SED of GH-naïve adolescents and adults with PWS was associated with obesity-related complications. Similar findings were reported in an Italian survey.23Grugni G. Crino A. Bosio L. Corrias A. Cuttini M. De Toni T. et al.The Italian national survey for Prader-Willi syndrome: an epidemiologic study.Am J Med Genet Part A. 2008; 146A: 861-872Crossref PubMed Scopus (70) Google Scholar Thus, the data, taken together, indicate that SED occurs in this population at all ages. However, among children with PWS ages 4-5 years and under, whether treated or untreated with GHRT, SED results predominantly from acute respiratory infections, with very obese males most at risk. (Of note, 75% of deaths in treated children have occurred in the first 9 months of therapy.) Among older individuals, death most often results from obesity-related complications or acute gastric illness. Although sleep disordered breathing is essentially ubiquitous in the population with PWS, there is little evidence that initiating GHRT increases that risk in most patients. Nonetheless, in some patients there does appear to be an increased risk of obstructive events possibly related to rapidly increasing or elevated insulin-like growth factor-1 (IGF-1) levels. For example, even though Miller's study indicated that most patients had improvement on short-term GHRT, 2 patients had a worsening of obstructive events on GH correlated with elevated IGF-1 levels.20Miller J. Silverstein J. Shuster J. Driscoll D.J. Wagner M. Short-tem effects of growth hormone on sleep abnormalities in Prader-Willi syndrome.J Clin Endocrinol Metab. 2006; 91: 413-417Crossref PubMed Scopus (94) Google Scholar When the dose of GH was decreased, there was a decrease in the frequency and severity of obstructive events. A 2011 case report described PSG-documented mild OSA in a 3-year-old girl with PWS 6 months after starting GH therapy, resolution with its discontinuation, and severe OSA after restarting therapy at 5 years.24Nixon G.M. Rodda C.P. Davey M.J. Longitudinal association between growth hormone therapy and obstructive sleep apnea in a child with Prader-Willi syndrome.J Clin Endocrinol Metab. 2010; 96: 29-33Crossref PubMed Scopus (26) Google Scholar As her tonsils remained small, the authors postulated an increase in upper airway soft tissue as the underlying mechanism. What, then, is to be done? Al-Saleh et al contribute much needed longitudinal data regarding these issues. With all due respect to the authors, however, we propose a set of guidelines that significantly differ from those recommended. Based on our experience, the data in the paper, and a literature review, we propose the following approach: (1) very young, non-obese children with PWS are mainly at risk for central apnea attributed to a primary disturbance in the central respiratory control mechanism25Bruni O. Verrillo E. Novellia L. Ferric R. Prader-Willi syndrome: sorting out the relationships between obesity, hypersomnia, and sleep apnea.Curr Opin Pulm Med. 2010; 16: 568-573Crossref PubMed Scopus (40) Google Scholar; the decision to perform PSG in this group should be independent of the decision to start GH; and (2) children with PWS who are 2 years and older should undergo a clinical evaluation by an ear, nose, and throat physician either prior to initiation of GH therapy or, for those started on GH in infancy, as a part of routine ongoing care. The treatment team should then decide whether adenotonsillectomy (for significant adenotonsillar enlargement with signs of OSA) or PSG (for signs of OSA without significant adenotonsillar enlargement) is warranted. Of note, the 2011 clinical practice guidelines from the Academy of Otolaryngology-Head and Neck Surgery Foundation recommend PSG prior to tonsillectomy in high risk patients, including those with obesity and hypotonia.26Roland P.S. Rosenfeld R.M. Brooks L.J. Friedman N.R. Jones J. Kim T.W. et al.Clinical practice guideline: polysomnography for sleep-disordered breathing prior to tonsillectomy in children.Otolaryngol-Head Neck Surg. 2011; 45: S1-15Crossref Scopus (308) Google Scholar A multicenter retrospective review of adenotonsillectomy outcomes in the treatment of OSA in the general population concluded that children who are older, obese, or non-obese with asthma or severe OSA should then undergo postoperative PSG to assess for residual OSA.27Bhattacharjee R. Kheirandish-Gozal L.K. Spruyt K. Mitchell R. Promchiarak J. Simakajornboon N. et al.Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children.Am J Respir Crit Care Med. 2010; 182: 676-683Crossref PubMed Scopus (481) Google Scholar PSG should be repeated 3-6 months after initiation of GH therapy in patients with PWS previously diagnosed and treated for OSA. The decision of whether to perform PSG and, if so, when to perform PSG after initiation of GH therapy in low risk patients with PWS remains controversial. A less invasive but informative screening test utilizes a multi-night recording of pulse oximetry. If negative, there can be confidence that OSA is not present; if positive, a PSG can be obtained. Finally, regular screening with questions numbers 1-6 of the pediatric sleep questionnaire by Chervin,28Chervin R.D. Hedger K. Dillon J.E. Pituch K.J. Pediatric sleep questionnaire (PSQ); validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavior problems.Sleep Med. 2000; 1: 21-32Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar validated in the population with PWS,29Stafler P. Wallis C. Prader-Willi syndrome: who can have growth hormone?.Arch Dis Child. 2008; 93: 341-345Crossref PubMed Scopus (28) Google Scholar examination of the oropharynx for tonsillar hypertrophy, and monitoring of IGF-1 levels is recommended for the duration of therapy. Longitudinal Evaluation of Sleep-Disordered Breathing in Children with Prader-Willi Syndrome during 2 Years of Growth Hormone TherapyThe Journal of PediatricsVol. 162Issue 2PreviewTo review longitudinal polysomnography data to assess sleep-related disordered breathing (SRDB) before and up to 2 years after initiation of growth hormone (GH) therapy in children with Prader-Willi syndrome (PWS). Full-Text PDF
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