Comorbidity and mortality in Prader-Willi syndrome

Abstract

Background: Prader-Willi syndrome (PWS) is a multisymptomatic, rare, genetic, disorder, due to lack of the expression of paternal genes in the q11-q13 region of chromosome 15. The main characteristics of PWS are muscular hypotonia, hyperphagia, obesity, behavioral problems, cognitive disabilities, and endocrine deficiencies. Comorbidities, are frequent, including sleep apnea. Mortality rate is high, and life expectancy short. The aim of this thesis was to further describe comorbidity, use of medication and mortality in PWS, and to evaluate long-term cortisol exposure and the effects of GH treatment on respiratory parameters.

Methods: Data of comorbidity, mortality and use of drugs were retrieved from Swedish National registers and categorized into groups and subgroups (study 1). Long-term cortisol exposure was assessed in hair in adults with PWS and age and sex matched controls, and related to responses to questionnaires on health and medication (study 2). The effect of GH treatment on polysomnographic measurements were evaluated in 12 months randomized, placebocontrolled GH trial, followed by a two-year open phase GH treatment period (study 3).

Results: In 411 patients, 37658 comorbidity diagnoses were registered, and in 365 patients, 83629 different drug prescriptions. Many codes were unspecific, but mental and behavioral problems and corresponding prescriptions were the most common; followed by diabetes, and antidiabetic treatments. The most common cause of death (n=144, mean age 24,7 years, (SD 17,4) range 0 months to 67 years, 61% males), were unspecific (34%) cardiovascular (23%), and endocrine (diabetes and obesity complications) (13,9%) (study 1). Hair cortisol in patients with PWS (n=29) was higher (12.8±25.4 pg/mg) than in controls (n=105) (3.8±7.3 pg/mg), and increased with BMI and reported stress (study 2). In the GH treatment trial apnea-hypopnea index (AHI) was 1.4 (0.0-13.9). No differences in sleep or respiratory parameters were seen between GH and placebo treated patients. The sleep efficiency improved throughout the study, independent of BMI. AHI inconsistently increased within normal range (study 3).

Conclusion: The pattern of comorbidity, mortality and prescribed drugs confirmed the multisymptomatic character of the syndrome. The high frequency of unspecific codes for comorbidity and mortality could indicate undetected hypocortisolism, but the long-term cortisol exposure suggested an adequate cortisol response to chronic stress. No clinically significantly negative impact of GH treatment on respiration was seen. The increased morbidity and mortality were mainly related to diseases secondary to obesity, which underscore the need for continued and intensified efforts to prevent obesity in this vulnerable group.