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Research Notes: Sudden Unexpected Death (SED) in Prader-Willi SyndromeSee also: Clin Endocrinol (Oxf). 2007 Jun. OBJECTIVE: Prader-Willi syndrome (PWS) is a genetic obesity syndrome characterized by hyperphagia, behavioural disturbance and intellectual disability. PWS appears to be associated with a high incidence of sudden death, suspected to be cardiopulmonary in origin. We therefore sought to provide an assessment of cardiac and vascular structure and function in patients with PWS. PATIENTS: Nine patients with genetically confirmed PWS, mean age 28 years, body mass index (BMI) 42 kg/m2, were compared with nine age- and gender-matched lean controls. MEASUREMENTS: Lipid parameters, high-sensitivity C-reactive protein (hs-CRP) and fasting glucose and insulin were measured. To assess cardiac structure and function, a resting electrocardiogram (ECG), exercise stress test, 24-h continuous ECG monitoring, and echocardiogram were obtained. Patients and control subjects also underwent comprehensive noninvasive vascular assessment, including venous-occlusion forearm plethysmography, brachial artery flow-mediated dilatation (FMD), radial artery tonometry and carotid intima-media thickness (IMT) measurements. RESULTS: All patients with PWS had significantly elevated hs-CRP (> 3.0 mg/l) (mean 11.5 mg/l, median 11.47, interquartile range: 4.48-15.8 mg/l), compared with controls (P < 0.001). Five of nine patients with PWS had subnormal exercise capacity (< 4 mets on exercise stress testing). Twenty-four-hour ECG monitoring revealed prolonged sinus pauses in one patient, up to 4.8 s, requiring pacemaker insertion. Microvascular function as assessed by peak hyperaemic flow response was decreased in PWS (6.1 +/- 1.0 times baseline flow vs. controls 13.5 +/- 1.6 times baseline flow, P = 0.01). Other measures were similar between PWS and controls. CONCLUSIONS: This group of PWS patients had significantly raised levels of the inflammatory marker hs-CRP and evidence of microcirculatory dysfunction, both of which are associated with coronary artery disease and early sudden death. The sinus node dysfunction may in itself be a risk factor for sudden cardiac death. J Clin Endocrinol Metab. 2006 Dec. CONTEXT: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited. OBJECTIVE: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children. DESIGN: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them. PATIENTS: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1-7.2) yr and body mass index of +1.0 sd score (-0.1-1.7). INTERVENTION: Intervention included treatment with GH 1 mg/m2.d. RESULTS: Apnea hypopnea index (AHI) was 5.1 per hour (2.8-8.7) (normal 0-1 per hour). Of these, 2.8 per hour (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = -0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6-7.9) at baseline to 4.0 (2.7-6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography. CONCLUSIONS: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered. Excerpt from the full text article: One patient in our study died unexpectedly. This 3-year old boy had GH-treatment for 13 months. He responded very well in terms of growth and body composition. In this particular patient, PSG was performed before (AHI 1.7/h, 100% central) and after 6 months of GH (AHI 1.4/h, 67% central, 33% hypopnea). Six weeks before his death, BMI was 1.6 SDS and tonsils were assessed as Brodsky I-II. He had mild URTI and was clinically evaluated by his paediatrician the day prior to his death. At that time he had URTI, but was in good condition, running around and not generally ill. During the night, he suddenly deteriorated and was found dead in the morning. Autopsy did not reveal the cause of death. ... We found an increased AHI in 53 young, pre-pubertal children with genetically confirmed diagnosis of PWS. The high AHI was mainly due to central apneas and hypopneas. In the total group of mainly non-obese PWS children, obstructive apneas were rare. In contrast, obstructive apneas were found in 4 of the 8 overweight patients. After 6 months of GH-treatment a non-significant decrease of AHI was found, mainly due to a decrease in central apneas. No significant change in obstructive apneas was found during GH. Illness or adenoid/tonsil hypertrophy, however did result into a marked increase in sleep-related breathing disorders, and particularly obstructive sleep apnea. Our study also shows that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. ... One of our patients died unexpectedly during an episode of URTI. One of the most alarming findings is that this patient had near-normal sleep-related breathing during PSG, both before and during GH-treatment. This points out that a near-normal PSG in a healthy PWS child does not guarantee he/she won't die during mild URTI. It might be related to a rise of apneas (both central and obstructive) during illness as shown in 4 of our patients who had a PSG during an episode of mild URTI. Unexpected deaths have been described in PWS children both without and during GH and have been attributed to several possible causes, such as respiratory dysfunction, cardiomyopathy, temperature instability and adrenal insufficiency or combinations of these. Clin Endocrinol (Oxf). 2006 Aug. OBJECTIVE: To evaluate the response to recombinant GH treatment and adverse events in children with Prader-Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database. PATIENTS: A total of 328 children (274 prepubertal, median age 6.0 years; 54 pubertal, median age 12.7 years) were treated for 1 year and 161 children were treated for 2 years with GH. RESULTS: Height standard deviation score (SDS) increased significantly during treatment; the response was greater in prepubertal (-0.7 vs.-1.8 pretreatment) compared with pubertal children (-1.5 vs.-1.8). Predictors of first-year height velocity in multiple regression analysis were GH dose, body weight (positively correlated), height SDS minus mid-parental height SDS and chronological age (negatively correlated), together accounting for 39% of the variation in response to GH. Body mass index (BMI) SDS did not change significantly during 2 years of treatment. Of all the 675 GH-treated PWS patients in KIGS, there were five cases of sudden death (age range 3-15 years). Three were obese (weight for height > 200%) and causes of death included bronchopneumonia, respiratory insufficiency and sleep apnoea. Scoliosis was the most commonly reported adverse event (n = 24), four children developed hyperglycaemia and six had presumptive diabetes (type 2 in five, and one case of type 1). CONCLUSIONS: Short-term growth improved in response to conventional doses of GH in children with PWS. Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients. GH should be used with caution in those with extreme obesity or disordered breathing and all patients should be closely monitored for adverse events. Pediatr Int. 2005 Oct. Background: Thermoregulation problems, resulting in hypo- or hyperthermia, have been infrequently reported in children with Prader Willi syndrome (PWS), yet their clinical details remained unknown. Methods: The clinical characteristics of three infants with PWS are reported. Results: Etiologies of high fever could not be identified in three children with PWS. One of these children was also admitted to the intensive care unit with extremely high body temperature in a life-threatening condition, similar to septic shock, without a plausible explanation. Conclusion: Hyperthermia may be a part of the clinical spectrum in young infants with PWS and should be carefully monitored, since it may cause life-threatening complications. Am J Med Genet A. 2005 Jul 1. Patients with Prader-Willi syndrome (PWS) are recognized to have a tendency of sudden, unexpected death (SED), but its exact cause is unknown because of paucity of such case reports. Since growth hormone (GH) treatment was applied to PWS patients worldwide, several cases of death have been reported. However, whether the therapy is directly related to their SED remains unknown, too. We collected 13 deceased PWS patients (Group A, aged 9 months to 34 years) who had never received GH therapy, and seven deceased patients (Group B, all boys aged 0.7-15 years) having received the therapy from the registration in PWS-patient-support associations and from the literature, respectively. We then compared the cause of SED between the two groups. Irrespective of GH therapy, SED of infants under age 1 year was associated with milk aspiration or hypothalamic dysregulation of respiration, while SED of patients in early childhood or adolescence occurred at sleeping in association with preceding viral infections. In contrast, SED of four adult (>20 years of age) patients who never received GH therapy was associated with complications, such as leg cellulites and pulmonary embolism, secondary to massive obesity and diabetes mellitus (DM). Two Group-B patients (aged 14 and 20 years) without any obesity-related or diabetes-related complications died of drowning in a bath tub, and their drowning death could be related to poor respiratory control [or cataplexy?]. These findings indicated that the cause of SED is not essentially different between PWS patients with and without GH treatment. Deceased PWS patients may have had underlying respiratory dysregulation and hypothalamic dysfunction, and GH therapy might have led to certain obstructive respiratory disturbances that exacerbated the respiratory conditions. This will call clinicians' attention when using GH in PWS patients, for example, careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems. Acta Paediatr. 2005 Jul. Reports on sudden death in Prader-Willi syndrome (PWS) patients after the start of growth hormone (GH) treatment have been published recently. We observed a 4.7-y-old girl who showed a continuous increase in pulmonary artery pressure and died of cardiorespiratory failure 7 wk after GH therapy had been initiated, and a 9.3-y-old girl with additional trisomy 21 who died during a minor respiratory infection 6 mo after GH had been started. Both patients were overweight (weight for height 127% and 224%, respectively). GH-induced fluid retention may have occurred in the younger girl. In contrast to the reported cases, our PWS patients were female. CONCLUSION: Our cases illustrate the difficulty of differentiation between possible GH side effects and the natural course of disease, in particular with respect to obesity-related comorbidity and mortality. J Endocrinol Invest. 2005 Jun. A few cases of death worldwide during GH treatment in pediatric patients with Prader-Willi syndrome (PWS) have been recently described. The evaluation of further cases is needed to better identify possible causal mechanism(s), as well as to suggest some additional guidelines for prevention. We report the death of 2 additional children with genetically confirmed PWS in the first months of GH therapy. Case 1: This 3.9-yr-old girl was born at 39 weeks gestation. Low GH response to two stimulation tests was observed. GH administration was started at the age of 3.5 yr (0.33 mg/kg per week), when the patient was at 130% of her ideal body weight (ibw). Hypertrophy of adenoids was previously demonstrated. Snoring and sleep apnea were present before GH treatment, and did not increase during therapy. Four months later she died at home suddenly in the morning. Case 2: This patient was a 6.3-yr-old boy. He was born at term after an uneventful pregnancy. At the age of 6 yr, his weight was at 144% of his ibw. He showed reduced GH secretion during provocation tests, and GH therapy was started (0.20 mg/kg per week). The previously reported nocturnal respiratory impairment had worsened after beginning GH administration. Tonsils and adenoids hypertrophy were noted. At the age of 6.3 yr he died at home in the morning following an acute crisis of apnea. These additional cases seem to confirm that some children with PWS may be at risk of sudden death at the beginning of GH therapy. Int J Legal Med. 2005 May. A case of sudden cardiac death in a 3-year-old young male affected by Prader-Willi syndrome, clinically diagnosed and confirmed by means of DNA methylation, is presented. The infant suddenly collapsed at home and was taken apparently unconsciousness by his mother to the emergency clinic where he was pronounced dead. A complete postmortem examination was performed and the histological findings led to the definition of cardiac death with a typical picture of contraction band necrosis. Pulmonary hypoxic alterations are frequently reported as the primary cause of death in PWS cases. In this fatal case according to the macroscopic and microscopic findings, the cause of death was most likely cardiac and possibly related to contraction band necrosis linked with ventricular fibrillation and sudden death. Horm Res. 2005. We describe a child with Prader-Willi syndrome (PWS) aged 3 years and 11 months who suddenly died 7 months after the initiation of GH therapy. The child never showed respiratory problems, but suffered from severe obesity. This case raises the question about the association between sudden death in children with PWS (with or without respiratory problems) and GH therapy, as already suspected in the recent past. We suggest that further epidemiological studies are required in order to determine more accurately the frequency of this causal connection and better understand its pathogenesis. Horm Res. 2005. We describe a child with Prader-Willi syndrome (PWS) aged 3 years and 11 months who suddenly died 7 months after the initiation of GH therapy. The child never showed respiratory problems, but suffered from severe obesity. This case raises the question about the association between sudden death in children with PWS (with or without respiratory problems) and GH therapy, as already suspected in the recent past. We suggest that further epidemiological studies are required in order to determine more accurately the frequency of this causal connection and better understand its pathogenesis. Horm Res. 2005. Irrespective of GH treatment, children with Prader-Willi syndrome (PWS) suffer more frequently and more seriously from respiratory problems than healthy children. The pathogenesis of such respiratory problems in PWS seems to be multifactorial in origin, but mainly related to insufficiency of respiratory muscles and pharyngeal narrowness. Deaths of children with PWS are reported among GH treated as well as untreated children. Our data show that also disturbed body composition plays an important role in fatal outcomes, possibly enhancing the ventilation disorder. For several years, in our recommendations we have pointed out the secondary risks of increasing obesity. In addition, it is recommended for all children with PWS, in particular before institution of GH therapy, to have polysomnography and an otorhinolaryngologic examination performed, and tonsillectomy in the case of enlarged tonsils. Furthermore, upper airway infections should be treated aggressively. Am J Med Genet A. 2004 Jan 15. Individuals with Prader-Willi syndrome (PWS) generally survive into adulthood. Common causes of death are obesity related cor pulmonale and respiratory failure. We report on a case series of eight children and two adults with unexpected death or critical illness. Our data show age-specific characteristics of PWS patients with fatal or life-threatening illnesses. Under the age of 2 years, childhood illnesses in general were associated with high fever and rapid demise or near-demise. Hypothalamic dysfunction likely plays a role in exaggerated fever response, but also perhaps in central regulation of adrenal function. Below average sized adrenal glands were found in three children, which raises the possibility of unrecognized adrenal insufficiency in a subset of individuals with PWS and emphasizes the vital role of autopsy. The tub drowning death of an adult patient could be related to central hypersomnia [or cataplexy?], which has been reported in PWS. We suggest that increased risk for critical illness be considered in the discussion of anticipatory guidance for the care of infants with PWS. Since a number of children died while hospitalized, particularly close observation of PWS children who are ill enough to warrant hospital admission is recommended. J Pediatr. 2004 Jan. A 4-year-old boy with Prader-Willi syndrome died suddenly while asleep on day 67 of growth hormone treatment. During treatment, snoring had worsened. Autopsy showed multifocal bronchopneumonia. This case and two others recently published suggest that growth hormone may be associated with obstructive apnea, respiratory infection, and sudden death in this condition. Biol Neonate. 2002 Aug. Only in the recent past has Prader-Willi syndrome (PWS) also been diagnosed in newborns and infants, and the first descriptions of respiratory disturbances in young, not yet obese patients have been published only recently. We report an infant with PWS and respiratory problems, who suffered sudden death. To our knowledge, this is the first such case. In order to avoid fatalities, it seems mandatory to monitor respiratory function in infants with PWS and to suspect PWS in all hypotonic newborns to determine the frequency of the syndrome more accurately, and, more importantly, to diagnose PWS at an earlier stage in order to take appropriate measures. Genet Couns. 2002. We report on the sudden death of a 3.5-year-old girl with Prader-Willi syndrome (PWS) and 15q11-q13 deletion. She suffered from severe chronic breathing disturbances and recurrent bronchitis. During an episode of acute bronchitis she had a cardiac arrest and died two months later of the sequelae. Brain CT imaging three weeks after the arrest showed bilateral symmetrical haemorrhages in the basal ganglia region. The spatial distribution of the haemorrhages can possibly suggest that the basal ganglia in PWS may be especially susceptible to hypoxemia. Horm Res. 2002. The case of a boy with Prader-Willi syndrome (PWS) who suffered from respiratory problems since birth and suddenly died at the age of 6.5 years, 4 months after initiation of GH therapy, is presented. This case indicates the possibility of fatal courses in infants and children with PWS as a consequence of respiratory problems and raises the question as to a causal connection between the initiation of GH therapy and the sudden death of this child. Aust Paediatr J. 1983 Dec. Fourteen children with the Prader-Willi syndrome have been managed at the Royal Alexandra Hospital for Children between the years 1964-1980 - twelve male, two female. Six male children developed features of the obesity hypoventilation syndrome. The age of onset of this complication ranged from 4.0 to 12.6 years. With one exception those children with the obesity hypoventilation syndrome were more obese than those without it. At the time of onset of the syndrome, five of six patients had weights greater than or equal to 6.5 standard deviations above ideal body weight. Those children without the obesity hypoventilation syndrome had a range of standard deviations 1.0 to 4.2 above the ideal body weight. In four of six cases weight reduction and a cardiac failure regimen resulted in reversal of the obesity hypoventilation syndrome. With two of the six children there had been cardiomegaly and increased pulmonary venous vascularity on x-ray at a chronological age of three months. Two of the six children died. |