Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant

Eline S. van der Valk, Lotte Kleinendorst, Patric J.D. Delhanty, Bibian van der Voorn, Jenny A. Visser, M. M. van Haelst, Laura C.G. de Graaff, Martin Huisman, Anne White, Shosuke Ito, Kazumasa Wakamatsu, Yolanda B. de Rijke, Erica L.T. van den Akker, Anand M. Iyer, Elisabeth F.C. van Rossum*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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OBJECTIVE: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin-stimulating hormone (α-MSH) and desacetyl-α-melanocortin-stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. METHODS: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. RESULTS: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. CONCLUSION: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.

Original languageEnglish
Pages (from-to)e3699-e3704
JournalThe Journal of clinical endocrinology and metabolism
Issue number9
Publication statusPublished - 1 Sept 2022

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© 2022 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.


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