The Study Of Endocrine And Metabolic Manifestations And Sleep-disordered Breathing In Children With Prader-Willi Syndrome

Background and objective:Prader-Willi syndrome(PWS)was first described by Prader et al.in 1956 and now recognized as a genomic imprinting disorder.There are four main genetic subtypes in PWS:paternal 15q11.2-q13 deletion,maternal uniparental disomy(mUPD),imprinting center(IC)defect and chromosomal translocations.In infancy,it is characterized by hypotonia with poor feeding.As the individual ages,other features such as food seeking with excessive weight gain,developmental delay and cognitive disability become evident.Clinical manifestations such as temperature instability and high pain threshold can be explained by hypothalamic dysfunction,which also gives rise to variable hormone insufficiencies.Children with PWS are also at risk of developing sleep-disordered breathing for several reasons,including obesity,facial dysmorphism,sticky secretions and hypotonia.Initially prompted by the daytime feature of hypersomnolence,many children with PWS were identified with polysomnographic features of sleep-disordered breathing.The purpose of this study was to investigate the changes of endocrine and metabolic manifestations and to evaluate the occurrence of sleep-related breathing disorders in children with Prader-Willi syndrome.Subjects and methods:18 PWS children diagnosed between September 2012 and January 2017 were selected as PWS group from Department of Pediatric Endocrinology,Shandong Provincial Hospital affiliated to Shandong University.36 age-and-sex-matched healthy children were selected as the control group.Clinical manifestations were recorded and used to define major and minor features in PWS group.Children with PWS had magnetic resonance imaging(MRI)to evaluate the hypothalamus and pituitary gland.The differences of pituitary-gland hormone levels and related metabolic indexes were analyzed on two methods,including the t-test for parametric variables and the Mann-Whitney U test for non-parametric variables.After the consultant of professor in sleep medicine center,Some of PWS children underwent overnight polysomnography(PSG).Results:In PWS group,the height standard deviation score(HtSDS)was-0.41±1.19,which was negatively associated with age.The weight were higher than the 90th percentile of normal children of the same gender and age.The body mass index(BMI)was 32.30±7.19 kg/m2,which were higher than 97th percentile of normal children of the same gender and age.Among those children,the average PWS diagnostic score was 8.39.MRI analysis showed that the pituitary height was 0.35± 0.11 cm,and 4 children with PWS had pituitary gland hypoplasia.Compared with the control group,PWS children had lower serum levels of growth hormone(GH),insulin-like growth factorl(IGF-1)and free thyroxine(FT4)(P<0.05).The FT4 in 1 child was<11.5pmol/L.Results of growth hormone stimulation test showed growth hormone deficiency.After the stimulation of GnRHa,the peaks of luteinizing hormone(LH)in 16 children were<2.8 mIU/mL.Human chorionic gonadotropin(hCG)stimulation was performed in 12 PWS boys,and testosterone(TO)of 2 boy was less than 3 times of basal levels after stimulation.PWS children had higher total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),triglyceride(TG),apolipoprotein B(APOB),glycosylated hemoglobin(HbAlc),homeostasis model assessment of insulin resistance(HOMA-IR),insulin(INS),C-peptide(C-P)and lower high-density lipoprotein cholesterol(HDL-C)than the control group(P<0.05).3 children had type 2 diabetes mellitus.5 children in PWS group were identified with polysomnographic features of sleep-disordered breathing,including obstructive sleep apnea(OSA),central sleep apnea(CSA)and nocturnal hypoxemia.The apnea hypopnea index(AHI)were 13.0,37.2,62.0,85.6 and 99.4 respectively,while the lowest oxygen saturation(LSa02)were73%,51%,30%,56%and 48%.5 children were diagnosed with obstructive sleep apnea-hypopnea syndrome(OSAHS).Conclusion:1、With growing up,children with PWS tend to be short stature.2、Children with PWS showed disorders of hypothalamic-pituitary function,including pituitary gland hypoplasia,growth hormone deficiency,central hypothyroidism and hypogonadotropic hypogonadism.3、Lipid metabolism disorder,insulin resistance and glucose metabolism disorder were found in children with PWS.PWS children showed a high prevalence of type 2 diabetes mellitus.4、The sleep-disordered breathing in children with PWS showed OSA,CSA and nocturnal hypoxemia.Some of children were diagnosed with severe OSAHS.The overnight PSG can describe sleep events and sleep architecture,which was useful to screen sleep-disordered breathing and to determine appropriate therapies in PWS.