Cause of sudden, unexpected death of Prader–Willi syndrome patients with or without growth hormone treatment

Abstract

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. 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.

Prader-Willi syndrome

“…56 In another study, the rate of death in affected individuals on and off GH did not differ. 57 A study of the natural history of PWS in one region of the United Kingdom found the overall death rate of individuals with PWS to be as high as 3% per year without GH therapy. 58 Thus, the relationship of GH administration to unexpected death remains unclear.…”

Necdin Plays a Role in the Serotonergic Modulation of the Mouse Respiratory Network: Implication for Prader-Willi Syndrome

“…PWS is also associated with breathing deficits, rhythm instability, severe sleep apneas, and blunted respiratory responses to hypoxia and hypercapnia that may develop before obesity (Nixon and Brouillette, 2002). PWS breathing deficits are risk factors for an early, unexpected sudden death (Schrander-Stumpel et al, 2004;Nagai et al, 2005); however, the physiological cause is still unclear.…”

Growth hormone supplement treatment reduces the surgical risk for Prader–Willi Syndrome patients

“…First, there was a report of sudden death owing to the use of GH treatment [12]. Although the relationship between the sudden death and GH treatment was completely unclear, Nagai et al [13] subsequently reported that the causes of sudden unexpected death did not differ between PWS patients with or without GH treatment. GH treatment has now become contraindicated for patients who are seriously obese or have a high breathing obstacle.…”