Premature Adrenarche in Children with Prader-Willi Syndrome Treated with Recombinant Human Growth Hormone Seems to Not Influence the Course of Central Puberty and the Efficacy and Safety of the Therapy

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Abstract

Puberty in children with Prader-Willi syndrome (PWS) is usually delayed and/or incomplete but in some patients premature/early adrenarche is observed. We assessed the premature adrenarche (PA) in PWS patients during the recombinant human growth hormone (rhGH) therapy and influence of PA on the course of central puberty (CP), rhGH efficacy and safety, and patients’ metabolic state. Forty-nine PWS patients were treated with rhGH, 11 presented with PA (group 1) and 14 had normal course of adrenarche (group 2). PA was observed in 22.5% of the PWS children treated with rhGH. The mean time between the rhGH start and the adrenarche, the rhGH dose, the growth velocity and the insulin-like growth factor 1 SD (IGF1 SD) during the treatment, as well as the time of CP, final height SD and BMI SD were similar in both groups. There were also no significant differences in the metabolic assessment—the oral glucose tolerance test (OGTT) and lipid profile results. PA may be a part of the clinical picture of PWS, apart from hypogonadotrophic hypogonadism and it seems to have no influence on CP in PWS patients. The rhGH efficacy and safety were comparable in the patients with PA and the normal course of adrenarche.

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Prader-Willi syndrome.

Max D. Driscoll, Sara Cassidy, L. Miller … (2011)

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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Central precocious puberty caused by mutations in the imprinted gene MKRN3.

Ana Abreu, Andrew Dauber, Delanie B. Macedo … (2013)

The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

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Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

Cheri Deal, Michèle Tony, Charlotte Höybye … (2013)

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.

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Journal ID (nlm-ta): Life (Basel)

Journal ID (iso-abbrev): Life (Basel)

Journal ID (publisher-id): life

Title: Life

Publisher: MDPI

ISSN (Electronic): 2075-1729

Publication date (Electronic): 10 October 2020

Publication date Collection: October 2020

Volume: 10

Issue: 10

Electronic Location Identifier: 237

Affiliations

[1 ]Department of Endocrinology and Diabetology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; m.wysocka@ 123456ipczd.pl (M.W.-M.); oddzial.endokrynologia@ 123456ipczd.pl (K.M.-D.); a.rudzka-kocjan@ 123456ipczd.pl (A.R.-K.); m.szalecki@ 123456ipczd.pl (M.S.)

[2 ]Collegium Medicum, Jan Kochanowski University (JKU), 25-369 Kielce, Poland

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[* ]Correspondence: a.lecka-ambroziak@ 123456ipczd.pl

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Publisher ID: life-10-00237

DOI: 10.3390/life10100237

PMC ID: 7600779

PubMed ID: 33050529

SO-VID: ee2fe453-8a09-4ba7-bcb4-286c55a35b12

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Premature Adrenarche in Children with Prader-Willi Syndrome Treated with Recombinant Human Growth Hormone Seems to Not Influence the Course of Central Puberty and the Efficacy and Safety of the Therapy

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Most cited references 31

Prader-Willi syndrome.

Central precocious puberty caused by mutations in the imprinted gene MKRN3.

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

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