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      Survival Trends from the Prader-Willi Syndrome Association (USA) 40-Year Mortality Survey

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          Abstract

          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.

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          Most cited references23

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          Prader-Willi syndrome: current understanding of cause and diagnosis.

          Prader-Willi syndrome (PWS) is characterized by hypotonia, obesity, hypogonadism, short stature, small hands and feet, mental deficiency, a characteristic face, and an interstitial deletion of the proximal long arm of chromosome 15 in about one-half of the patients. The incidence is estimated to be about 1 in 25,000, and PWS is the most common syndromal cause of human obesity. DNA abnormalities, usually deletions or duplications of chromosome 15, have been identified in individuals with PWS with or without recognizable chromosome 15 deletions. Paternal origin of the chromosome 15 deletion by cytogenetic and DNA studies has been found in nearly all PWS individuals studied. No cytogenetic evidence for chromosome breakage has been identified, although an environmental cause (e.g., paternal hydrocarbon-exposed occupations) of the chromosome 15 abnormality has been proposed. PWS patients with the chromosome 15 deletion are more prone to hypopigmentation compared with PWS individuals with normal chromosomes, but no other clinical differences are consistently identified between those with and without the chromosome deletion. Anthropometric, dermatoglyphic, and other clinical findings indicate homogeneity of PWS patients with the chromosome deletion and heterogeneity of the nondeletion patients. A review of our current understanding of the major clinical, cytogenetic, and DNA findings is presented, and clinical manifestations and cytogenetic abnormalities are summarized from the literature.
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            Prader-Willi Syndrome: Obesity due to Genomic Imprinting

            Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS.
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              Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology.

              Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11-q13 region. PWS is considered the most common syndromal cause of life-threatening obesity and is estimated at 1 in 10,000 to 20,000 individuals. A de novo paternally derived chromosome 15q11-q13 deletion is the cause of PWS in about 70% of cases, and maternal disomy 15 accounts for about 25% of cases. The remaining cases of PWS result either from genomic imprinting defects (microdeletions or epimutations) of the imprinting centre in the 15q11-q13 region or from chromosome 15 translocations. Here, we describe the clinical presentation of PWS, review the current understanding of causative cytogenetic and molecular genetic mechanisms, and discuss future directions for research.
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                Author and article information

                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                23 June 2017
                06 July 2017
                06 January 2018
                : 10.1038/gim.2017.92
                Affiliations
                [1 ]Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA
                [2 ]Bronson Children’s Hospital, Kalamazoo, Michigan USA
                [3 ]Prader-Willi Syndrome Association (USA), Sarasota, Florida, USA
                Author notes
                Corresponding Author: Ann M Manzardo, PhD, Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 4015, Kansas City, Kansas 66160, Phone: 913-588-6473, Fax: 913-588-1305, amanzardo@ 123456kumc.edu
                Article
                NIHMS885105
                10.1038/gim.2017.92
                5756527
                28682308
                07cd040f-02b2-4cad-948c-e6b2a2b9b563

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Genetics
                prader-willi syndrome,survival,mortality,obesity,cardiac and respiratory failure,thromboembolism,gi-related problems

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