Several recent studies have begun to look more carefully at the causes of death in PWS, particularly in cases where death was sudden and/or unexpected. A review of 64 cases of death in children with PWS noted a high occurrence of respiratory infections in cases with fatal outcomes [Tauber 2008 , and references therein]. In addition, there have previously been suggestions in the medical literature that people with PWS may have unrecognized deficiencies in the adrenal system [Stevenson 2003 , and references therein]. Since a properly functioning adrenal system is critical during times of acute illness, some authors have speculated that deficiencies in the adrenal system may contribute to unexpected deaths in PWS. A new study begins to address the function of the adrenal system in individuals with PWS, and suggests that this is an area deserving of more attention.

Roderick and colleagues [High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome] tested for the possibility of central adrenal insufficiency (CAI) in PWS under conditions that mimic stress (here, stress refers to the stress that would be associated with illness). Normally, physiological responses to the stress of illness include increased cortisol production, which is mediated by increased secretion of ACTH (adrenocorticotropic hormone ) from the pituitary gland. Adrenal insufficiency , in which this response is inadequate, can pose a serious problem during acute and/or critical illness, and can increase mortality rates [Asare, 2007 ]

The authors of this study did not detect any baseline deficiency of the adrenal system in healthy children with PWS as measured by cortisol levels in the saliva, but the results were different when the adrenal system was stressed. To assess CAI in healthy individuals with PWS, these investigators used a laboratory test in which a drug (metyrapone ) is administered. This drug dramatically reduces cortisol production, which mimics the stress of illness, and should stimulate ACTH secretion.

The metyrapone test was administered to twenty-five children with PWS. Of these, 15 (60%) had an inadequate ACTH response to the drug. Based on this finding, the authors suggest that the lack of adequate adrenal response during illness may be contributing to the high rates of death in PWS during infection. Further, they recommend that doctors consider hydrocortisone therapy during acute illness in PWS patients, unless CAI has been ruled out. Short term use of low dose corticosteroids carries relatively low risk and has been shown to decrease morbidity and mortality in those with adrenal insufficiency and critical illness [Asare 2007 ]. Finally, this is another indication that the hypothalamic-pituitary-adrenal (HPA) axis is frequently disrupted in PWS.

There are several limitations in this study. First, it was a small group of children tested. Second, the designation of CAI was based on a laboratory test that is a very demanding on the adrenal system; thus, it may it may not truly represent what happens during illness and may overdiagnose CAI. There are other tests for adrenal function, and it will be interesting to see if additional studies using different methods suggest similarly high rates of CAI. Finally, this study never actually measured adrenal function during illness. Despite these limitations, this study does suggest the need for additional investigation into adrenal function in PWS. In the meantime, parents and caregivers should be aware of the possibility of adrenal insufficiency in PWS. Further, especially during times of illness, this possibility should be brought to the attention of their physicians so that coritsol levels can be appropriately monitored and treatment administered as needed.

A copy of the full article is available for free here:
http://jcem.endojournals.org/cgi/rapidpdf/jc.2007-2294v2

{**Many thanks to Dr. Todd Porter and Dr. Jen Miller for helpful discussions about this blog}

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