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      Sleep-disordered breathing and genetic findings in children with Prader-Willi syndrome in China

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          Abstract

          Background

          Sleep-related breathing disorders are common in individuals with Prader-Willi syndrome (PWS), and can include hypersomnolence and obstructive sleep apnea, as well as central sleep breathing abnormalities that are present from infancy. Here we describe the sleep-disordered breathing (SDB) and genetic findings in patients with PWS in China.

          Methods

          In all, 48 patients confirmed by genetic tests were enrolled, 32 were under 2 years of age and 16 were older children. There were 37 (77.1%) patients with paternal 15q11-13 deletions, 11 (22.9%) patients with maternal uniparental disomy (mUPD), and no patients with imprinting defect (ID).

          Results

          Compared with infants, a significantly higher proportion of older children with PWS were overweight or obese (15/16 children vs. 4/32 infants) and children had a higher serum level of free thyroxine (FT4) (0.9±0.2 vs. 0.7±0.7) and thyroxine (T4) (9.0±2.5 vs. 7.5±1.7). Age was correlated significantly with body mass index (BMI), T4, and FT4 (r=0.626, P=0.000; r=0.426, respectively). Overall, 42 of 48 (87.5%) patients had sleep apnea on polysomnography (PSG). Infants, when compared with older children, were more likely to experience central sleep apnea (71.8% vs. 25%). In infants, there were no significant differences in the prevalence of SDB between the deletion group and the mUPD group.

          Conclusions

          Being overweight or obese was more common in older children with PWS. Compared with infants, a higher proportion children were overweight or obese and had higher serum levels of FT4 and T4. The prevalence of SDB was high in those with PWS, and central sleep apnea was found to be prevalent in infants. The pattern of SDB in infants with PWS was not significantly associated with the genotypes.

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          Most cited references35

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          Development of a WHO growth reference for school-aged children and adolescents.

          To construct growth curves for school-aged children and adolescents that accord with the WHO Child Growth Standards for preschool children and the body mass index (BMI) cut-offs for adults. Data from the 1977 National Center for Health Statistics (NCHS)/WHO growth reference (1-24 years) were merged with data from the under-fives growth standards' cross-sectional sample (18-71 months) to smooth the transition between the two samples. State-of-the-art statistical methods used to construct the WHO Child Growth Standards (0-5 years), i.e. the Box-Cox power exponential (BCPE) method with appropriate diagnostic tools for the selection of best models, were applied to this combined sample. The merged data sets resulted in a smooth transition at 5 years for height-for-age, weight-for-age and BMI-for-age. For BMI-for-age across all centiles the magnitude of the difference between the two curves at age 5 years is mostly 0.0 kg/m(2) to 0.1 kg/m(2). At 19 years, the new BMI values at +1 standard deviation (SD) are 25.4 kg/m(2) for boys and 25.0 kg/m(2) for girls. These values are equivalent to the overweight cut-off for adults (> or = 25.0 kg/m(2)). Similarly, the +2 SD value (29.7 kg/m(2) for both sexes) compares closely with the cut-off for obesity (> or = 30.0 kg/m(2)). The new curves are closely aligned with the WHO Child Growth Standards at 5 years, and the recommended adult cut-offs for overweight and obesity at 19 years. They fill the gap in growth curves and provide an appropriate reference for the 5 to 19 years age group.
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            Prader-Willi syndrome.

            Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available.
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              Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings

              Introduction Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65–75 % of cases), maternal uniparental disomy 15 (20–30 % of cases), and imprinting defect (1–3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS. Methods An extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS. Conclusions Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder.
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                Author and article information

                Journal
                Ann Transl Med
                Ann Transl Med
                ATM
                Annals of Translational Medicine
                AME Publishing Company
                2305-5839
                2305-5847
                August 2020
                August 2020
                : 8
                : 16
                : 989
                Affiliations
                [1 ]Department of Respiratory, Children’s Hospital of Fudan University , Shanghai, China;
                [2 ]Department of Endocrinology and Inherited Metabolic Diseases, Children’s Hospital of Fudan University , Shanghai, China
                Author notes

                Contributions: (I) Conception and design: A Lu, W Lu; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: A Lu, X Zhang, L Wang, C Sun; (V) Data analysis and interpretation: A Lu, X Zhang, L Wang, F Luo, W Lu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                Correspondence to: Dr. Wei Lu. Department of Endocrinology and Inherited Metabolic Diseases, Children’s Hospital of Fudan University, No 399, Wanyuan Road, Minhang District, Shanghai, China. Email: wei_lu77@ 123456163.com .
                Article
                atm-08-16-989
                10.21037/atm-20-4475
                7475489
                32953789
                c2d5083e-9423-412e-924c-81595b7b798c
                2020 Annals of Translational Medicine. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                : 15 May 2020
                : 23 July 2020
                Categories
                Original Article

                prader-willi syndrome (pws),sleep-disordered breathing (sdb),polysomnography (psg),sleep apnea,genotype

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