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      Prader-Willi syndrome: endocrine manifestations and management


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          Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic dysfunction that can lead to various endocrine changes such as: obesity, growth hormone deficiency, hypogonadism, hypothyroidism, adrenal insufficiency and low bone mineral density. In addition, individuals with PWS have increased risk of developing type 2 diabetes mellitus. This review summarizes and updates the current knowledge about the prevention, diagnosis and treatment of endocrine manifestations associated with Prader Willi syndrome, especially diagnosis of growth hormone deficiency, management and monitoring of adverse effects; diagnosis of central adrenal insufficiency and management in stressful situations; screening for central hypothyroidism; research and treatment of hypogonadism; prevention and treatment of disorders of glucose metabolism. Careful attention to the endocrine aspects of PWS contributes significantly to the health of these individuals. Arch Endocrinol Metab. 2020;64(3):223-34

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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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            Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.

            Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin-a contraction of obese, from the Latin "obedere," meaning to devour, and "statin," denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein-coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.
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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.

                Author and article information

                Arch Endocrinol Metab
                Arch Endocrinol Metab
                Archives of Endocrinology and Metabolism
                Sociedade Brasileira de Endocrinologia e Metabologia
                05 June 2020
                May-Jun 2020
                : 64
                : 3
                : 223-234
                [1 ] orgdiv2Hospital Universitário Prof. Edgard Santos orgdiv1Faculdade de Medicina orgnameUniversidade Federal da Bahia Salvador BA Brasil original Unidade de Endocrinologia Pediátrica, Hospital Universitário Prof. Edgard Santos, Faculdade de Medicina, Universidade Federal da Bahia (UFBA), Salvador, BA, Brasil
                [2 ] orgdiv2Hospital das Clínicas orgdiv1Faculdade de Medicina orgnameUniversidade de São Paulo São Paulo SP Brasil original Ambulatório de Prader-Willi, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP, Brasil
                Author notes
                Correspondence to: Crésio Alves Unidade de Endocrinologia Pediátrica, Hospital Universitário Prof. Edgard Santos, Faculdade de Medicina, Universidade Federal da Bahia Rua Plínio Moscoso, 222/601 40157-190 – Salvador, BA, Brasil cresio.alves@ 123456uol.com.br

                Disclosure: no potential conflict of interest relevant to this article was reported.

                Author information

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 4 April 2019
                : 28 February 2020
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 91, Pages: 12

                prader-willi syndrome,growth hormone,hypogonadism,hypothyroidism, adrenal insufficiency,glucose abnormalities


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