Prader-Willi Syndrome and Growth Hormone Therapy: Take a Deep Breath and Weigh the Data

Prader-Willi Syndrome and Growth Hormone Therapy: Take a Deep Breath and Weigh the Data

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rader-Willi syndrome (PWS), a complex neurogenetic Subsequent research has focused primarily on the first mechdisorder originally described in 1956,1 was relatively anism. As a result, although the sparse data available at that unknown outside genetics and developmental clinics time indicated that the mortality rate of GH-treated patients until the late 1990s when growth hormone replacement with PWS was lower than that of untreated patients with therapy (GHRT) emerged as an effective intervention. The PWS,10 the temporal relationship between 7 fatal events worldwide and the initiation of GHRT led cardinal feature is the early onset, unrelentSee related article, p 263 Pharmacia and Upjohn to issue a safety ing, treatment-refractory hyperphagia leadwarning on May 30, 2003.11 It stated that GHRT is contraining to morbid obesity and attendant comorbidities. In dicated in patients with PWS who are severely obese or have addition, however, PWS is characterized by infantile hypotosevere respiratory impairment. Although OSA manifesting nia and failure to thrive, followed by short stature, hypogoduring GHRT had previously been documented in other nadism, abnormal body composition, sleep and respiratory populations, the available research evidence in PWS at that abnormalities (including impaired ventilatory control, centime indicated that GHRT improved overall respiratory tral and obstructive apnea, and excessive daytime sleepiness), function. Nonetheless, based on the presumption that GHand behavioral difficulties. Until recently, a markedly demediated OSA was a strong risk factor for SED, in 2003 the creased life span was expected, primarily resulting from Clinical Advisory Board of the Prader-Willi Syndrome complications of obesity. With better management and the Association-USA developed a set of guidelines for initiating introduction of GHRT, most affected individuals can now exGHRT that included a baseline polysomnogram (PSG) study, pect a relatively normal life span with better quality of life. followed by repeat studies 6 weeks later and subsequently as In this issue of The Journal, Al-Saleh et al highlight 3 isclinically indicated.12 With much additional data now availsues that continue to plague those charged with providing able, it may be time to relook at these concerns. responsible care to this population: (1) the incidence and cause of sudden unexpected death (SED) in those affected; What Is the Incidence and Cause of SED (2) whether GHRT raises the risk for obstructive sleep apnea Among Those with PWS? (OSA) in patients with PWS and, if so, does this lead to an increased risk of SED; and (3) the appropriate medical manAlthough SED was far from unknown in this population,13 agement for minimizing any treatment-related risks.2 Some many argued that even though the mortality rate appeared historical background is necessary to frame these issues. to be less with GHRT treatment than without, the data During the past 15 years, GHRT has become the standard were insufficient to disprove an increased risk among those of care for most children with PWS. Randomized, controlled initiating GH treatment. There ensued a number of studies studies in the late 1990s documented accelerated growth regarding the rates and causes of death in PWS in general. velocity, increased muscle mass and strength, decreased fat Whittington et al examined the population prevalence, estimass, increased physical activity, behavior improvements,3-5 and improved respiratory function.6,7 Pharmacia and mated birth incidence, and mortality rate for PWS in one Upjohn obtained Food and Drug Administration approval UK health region.14 Mortality rates were limited to those between the ages of 6 and 56 years not treated with GH, yielding for GHRT for PWS in 2000. Soon thereafter, reports of estimates of 3% per year compared with 0.14% in the general SED in children in the early phases of GHRT emerged.8,9 Three theories were introduced to explain these deaths: (1) population. Nagai et al estimated an overall death rate of Growth hormone (GH)-mediated tonsillar or soft tissue hy2.6% per year (13/494) for a GHRT-naive PWS population pertrophy leading to fatal OSA; (2) a rise in basal metabolic between the ages of 2 months and 48 years in a Japanese poprate with a resultant rise in oxygen demand; and (3) a normalulation study.15 However, a bimodal distribution of deaths was noted, with those under 3 years and those over 30 years ization of body hydration with augmentation of volume load. 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 AHI Apnea/hypoxia indexes 27 GH-naive individuals from The Netherlands, Belgium, GH Growth hormone GHRT Growth hormone replacement therapy Sweden, Finland, Switzerland, and the US, ages ranging IGF-1 OSA PSG PWS SED

Insulin-like growth factor-1 Obstructive sleep apnea Polysomnogram Prader-Willi syndrome Sudden unexpected death

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Vol. 162, No. 2  February 2013 from birth to 68 years.16 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.16

Does GHRT Raise the Risk for OSA in Patients with PWS? The estimated prevalence of OSA in the general pediatric population is 1%-3%.17 The peak age for airway restriction from adenotonsillar hypertrophy is reported to be 3-6 years.18 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.19 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.20 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.21 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.

What Is the Increased Risk, if Any, of SED Associated with GHRT? A French review of 64 cases of death in both treated and untreated individuals indicated that 61% died of respiratory insufficiency or infections.22 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-na€ıve individuals previously referenced,15 comparing them with the 7 deaths prompting the safety warning. The au-

thors 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-na€ıve adolescents and adults with PWS was associated with obesity-related complications. Similar findings were reported in an Italian survey.23 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.20 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.24 As her tonsils remained small, the authors postulated an increase in upper airway soft tissue as the underlying mechanism.

Discussion 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 mechanism25; 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.26 A multicenter 225

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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.27 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,28 validated in the population with PWS,29 examination of the oropharynx for tonsillar hypertrophy, and monitoring of IGF-1 levels is recommended for the duration of therapy. n Barbara Y. Whitman, PhD Susan E. Myers, MD Department of Pediatrics St. Louis University School of Medicine St. Louis, Missouri Reprint requests: Barbara Y. Whitman, PhD, St. Louis University School of Medicine, 1465 South Grand Ave, St. Louis, MO 63104. E-mail: whitmanb@slu. edu

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