Background Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans leading 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 PWSA (USA) mortality 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 (2mo–67yrs), 70% occurring 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 compared to females and cardiopulmonary factors. 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 towards 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.

The pathogenesis of vascular disease is unclear, but genetic factors play an important role. In this study we performed linkage analyses in two families with supravalvular aortic stenosis, an inherited vascular disorder that causes narrowing of major arteries and may lead to cardiac overload and failure. DNA markers on the long arm of chromosome 7 (D7S371, D7S395, D7S448, and ELN) were linked to supravalvular aortic stenosis in both families with a combined logarithm of likelihood for linkage (lod score) of 5.9 at the ELN locus. These findings indicate that a gene for supravalvular aortic stenosis is located in the same chromosomal subunit as elastin, which becomes a candidate for the disease gene.

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of a mutation of elastin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, suggesting that elastin abnormalities may cause some of the abnormalities found in Williams syndrome.

Background Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia and morbid obesity with increased cardiopulmonary and hyperphagia-related mortality. Survival trends in PWS were evaluated to assess the impact of modern interventions on mortality risk. Methods The PWSA (USA) 40-year mortality syndrome-specific database of 486 death reports was utilized to examine survival trends in PWS and cohort effects for recent deaths (years 2000–2015, N=331) relative to deaths prior to 2000 (N=94). Cox Proportional Hazards regression modeling was applied to generate log rank statistics and Kaplan-Meier curves examining sex, cause of death and cohort. Results Risk for all-cause mortality in PWS was 1.5 (95%CI=1.2–1.9) times higher for the Early than the Recent era cohort reflected in female cardiac failure (HR=1.8; 95%CI=1.3–2.6), pulmonary embolism (HR=6.1; 95%CI=1.7–22), and GI-related (HR=3.2; 95%CI=1.1–7.4) causes. Accidental deaths in males increased in the Recent era cohort (HR=5.7; 95%CI=1.2–27.1) possibly due to enhanced weight management and mobility. Risk of death from respiratory failure was unchanged. Conclusions We report measurable increases in survival effecting cardiovascular and GI-related causes in PWS most likely attributable to earlier diagnosis and proactive interventions to prevent morbid obesity. More research is needed to address underlying vulnerability to respiratory failure, an unchanged mortality risk in PWS.

Prader–Willi Syndrome Association (USA) monitors the ongoing health and welfare of individuals with Prader–Willi syndrome (PWS) through active communication with members by membership surveys and data registries. Thromboembolism and blood clots have emerged in clinical studies as significant risk factors for injury and death in PWS. A 66-item questionnaire was developed by a panel of PWS medical and scientific experts, with input from Prader–Willi Syndrome Association (USA) leadership, so as to probe their membership on the frequency, risk, and protective factors for venous thromboembolism, pulmonary embolism, and related findings. The characteristics of those with and without a reported history of blood clots and related health factors were tabulated and analyzed. Responses were obtained for 1067 individuals with PWS (554 females and 513 males), and 38 (23 females and 15 males) had a history of blood clots. The individuals with clots did not differ by gender, but were significantly older 32.8 ± 15 years vs 20.4 ± 13 years, and were more likely to have a reported history of obesity (76%), edema (59%), hypertension (24%), vasculitis (33%), and family history of blood clots (33%) than those without clots. Growth hormone treatment was more common in individuals without clots. The risk factors for thromboembolism in PWS overlap those commonly observed for the general population.