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. 2017 Jun;19(6):635-642.
doi: 10.1038/gim.2016.178. Epub 2016 Nov 17.

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey

Merlin G Butler  1   2 , Ann M Manzardo  1 , Janalee Heinemann  3 , Carolyn Loker  3 , James Loker  4
Affiliations

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey

Merlin G Butler et al. Genet Med. 2017 Jun.

Abstract

Background: Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS.

Methods: The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards.

Results: A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype.

Conclusions: These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicts to declare.

Figures

Figure 1
Figure 1
Relationship between the reported age and year of death in Prader-Willi syndrome. Scatter plot of the age at death by the year of death for males (red squares) and females (circles) with Prader-Willi syndrome (PWS) with respect to historical benchmarks in genomic discovery and treatment advances in PWS. Trend lines show the correlation coefficient for females (solid line) and males (dotted line).
Figure 2
Figure 2
Causes of death among 312 individuals with Prader-Willi syndrome divided into 13 major categories.
Figure 3
Figure 3
Survival analysis illustrates the effects of gender and cause of death on age of death in Prader-Willi syndrome. Kaplan-Meir plot of survival probability is shown as a function of age at death for A) males vs females with 95% Hall-Wellner Bands and for B) cardiopulmonary vs hyperphagia-related causes by gender. The number of uncensored participants by group are listed at the bottom of each figure.
Figure 4
Figure 4
Survival analysis of deaths due to cardiopulmonary causes as a function of Prader-Willi syndrome (PWS) genetic subtype. Kaplan-Meir plot of survival probability is shown for deaths attributable to cardiopulmonary vs hyperphagia-related causes for individuals with 15q11-q13 deletion (Del) vs maternal uniparental disomy 15 (UPD). The number of uncensored participants by PWS genetic subtype are listed at the bottom of the figure.
See this image and copyright information in PMC

References

    1. Butler MG. Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet. 1990;35(3):319–332. - PMC - PubMed
    1. Butler MG, Lee PDK, Whitman BY, editors. Management of Prader-Willi Syndrome. 3rd. New York: Springer; 2006.
    1. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012;14(1):10–26. - PubMed
    1. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest. 2015;38(12):1249–1263. - PMC - PubMed
    1. Butler MG. Single gene and syndromic causes of obesity: Illustrative examples. Prog Mol Biol Transl Sci. 2016;140:1–45. - PMC - PubMed

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