The GHRH+arginine stimulated pituitary GH secretion in children and adults with Prader–Willi syndrome shows age- and BMI-dependent and genotype-related differences

Marostica, Eleonora; Grugni, Graziano; Nicolao, Giuseppe De; Marazzi, Nicoletta; Crinò, Antonino; Cappa, Marco; Sartório, Alessandro

doi:10.1016/j.ghir.2013.09.004

Cited by 14 publications

(10 citation statements)

References 19 publications

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“…Volume 127 Number 1 January 2017 (49). This finding is consistent with the inference that the short stature and decreased GH levels of individuals with PWS results from a hypothalamic deficiency of PC1.…”

Section: Resultssupporting

confidence: 84%

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Burnett¹,

LeDuc²,

Sulsona³

et al. 2016

Journal of Clinical Investigation

134

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Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

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Section: Resultssupporting

confidence: 84%

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Burnett¹,

LeDuc²,

Sulsona³

et al. 2016

Journal of Clinical Investigation

134

View full text Add to dashboard Cite

show abstract

“…This should be taken into account in the small number of affected individuals with PWS and growth failure who exhibit normal growth hormone responses after standard stimulation tests (109). Additionally, low growth hormone secretion has been found in 24-hour frequent blood sampling studies, which is consistent with neurosecretory GHD based on current knowledge (108).…”

Section: Growth Hormone -Insulin-like Growth Hormone -1 Axis and Growthmentioning

confidence: 84%

“…Therefore, the efficacy of standard GH stimulation tests as an indicator of GH status in younger individuals with PWS is still a topic of debate. Additionally, it has been demonstrated that, using the potentiated GHRH+arginine stimulation test, GH response is greater in children than in adults (108).…”

Section: Growth Hormone -Insulin-like Growth Hormone -1 Axis and Growthmentioning

confidence: 99%

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation

Madeo,

Zagaroli,

Vandelli

et al. 2024

Front. Endocrinol.

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Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

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“… 69 In this context, the deconvolution-based assessment of pituitary GH secretion shows the most delayed GH response in UPD15 subjects, both in children and adults. 45 , 72 On the other hand, stimulated GH levels and integrated GH secretion are similar in PWS individuals carrying type I and type II deletion. 69 …”

Section: Gh and Genotypementioning

confidence: 98%

Growth hormone therapy for Prader–Willi syndrome: challenges and solutions

Grugni¹,

Sartório²,

Crinò³

2016

TCRM

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Prader–Willi syndrome (PWS) is characterized by a dysregulation of growth hormone (GH)/insulin-like growth factor I axis, as the consequence of a complex hypothalamic involvement. PWS’ clinical picture seems to resemble the classic non-PWS GH deficiency (GHD), including short stature, excessive body fat, decreased muscle mass, and impaired quality of life. GH therapy is able to ameliorate the phenotypic appearance of the syndrome, as well as to improve body composition, physical strength, and cognitive level. In this regard, however, some pathophysiologic and clinical questions still remain, representing a challenge to give the most appropriate care to PWS patients. Data about the prevalence of GHD in PWS children are not unequivocal, ranging from 40% to 100%. In this context, to establish whether the presence (or not) of GHD may have a different effect on clinical course during GH therapy may be helpful. In addition, the comparison of GH effects in PWS children diagnosed as small for gestational age with those obtained in subjects born appropriate for gestational age is of potential interest for future trials. Emerging information seems to demonstrate the maintenance of beneficial effects of GH therapy in PWS subjects after adolescent years. Thus, GH retesting after achievement of final height should be taken into consideration for all PWS patients. However, it is noteworthy that GH administration exerts positive effects both in PWS adults with and without GHD. Another critical issue is to clarify whether the genotype–phenotype correlations may be relevant to specific outcome measures related to GH therapy. Moreover, progress of our understanding of the role of GH replacement and concomitant therapies on bone characteristics of PWS is required. Finally, a long-term surveillance of benefits and risks of GH therapy is strongly recommended for PWS population, since most of the current studies are uncontrolled and of short duration.

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The GHRH+arginine stimulated pituitary GH secretion in children and adults with Prader–Willi syndrome shows age- and BMI-dependent and genotype-related differences

Cited by 14 publications

References 19 publications

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation

Growth hormone therapy for Prader–Willi syndrome: challenges and solutions

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The GHRH+arginine stimulated pituitary GH secretion in children and adults with Prader–Willi syndrome shows age- and BMI-dependent and genotype-related differences

Cited by 14 publications

References 19 publications

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation

Growth hormone therapy for Prader&ndash;Willi syndrome: challenges and solutions

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Product

Resources

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Growth hormone therapy for Prader–Willi syndrome: challenges and solutions