Two Cases With an Early Presented Proopiomelanocortin Deficiency-A Long-Term Follow-Up and Systematic Literature Review.

Nadan Gregoric,Urh Groselj,Jasna Suput Omladic,Magdalena Avbelj Stefanija,Mojca Zerjav Tansek,Natasa Bratina,Jernej Kovac,Marusa Debeljak,Primoz Kotnik,Tadej Battelino

doi:10.3389/fendo.2021.689387

Abstract

Proopiomelanocortin (POMC) deficiency is an extremely rare inherited autosomal recessive disorder characterized by severe obesity, adrenal insufficiency, skin hypopigmentation, and red hair. It is caused by pathogenic variants in the POMC gene that codes the proopiomelanocortin polypeptide which is cleaved to several peptides; the most notable ones are adrenocorticotropic hormone (ACTH), alpha- and beta-melanocyte-stimulating hormones (α-MSH and β-MSH); the latter two are crucial in melanogenesis and the energy balance by regulating feeding behavior and energy homeostasis through melanocortin receptor 4 (MC4R). The lack of its regulation leads to polyphagia and early onset severe obesity. A novel MC4R agonist, setmelanotide, has shown promising results regarding weight loss in patients with POMC deficiency. A systematic review on previously published clinical and genetic characteristics of patients with POMC deficiency and additional data obtained from two unrelated patients in our care was performed. A 25-year-old male patient, partly previously reported, was remarkable for childhood developed type 1 diabetes (T1D), transient growth hormone deficiency, and delayed puberty. The second case is a girl with an unusual presentation with central hypothyroidism and normal pigmentation of skin and hair. Of all evaluated cases, only 50% of patients had characteristic red hair, fair skin, and eye phenotype. Central hypothyroidism was reported in 36% of patients; furthermore, scarce adolescent data indicate possible growth axis dysbalance and central hypogonadism. T1D was unexpectedly prevalent in POMC deficiency, reported in 14% of patients, which could be an underestimation. POMC deficiency reveals to be a syndrome with several endocrinological abnormalities, some of which may become apparent with time. Apart from timely diagnosis, careful clinical follow-up of patients through childhood and adolescence for possible additional disease manifestations is warranted.

Highlights

Proopiomelanocortin (POMC) is a precursor polypeptide hormone secreted primarily in the hypothalamus
Besides adrenal insufficiency and early onset obesity, another prominent physical feature was extremely pale skin and red hair that was in contrast to his immediate family members
The patient followed a restriction diet program which success was only short-lived; the patient continued to gain weight (Figure 2A) until 7 years of age when he lost 4 kg due to symptomatic hyperglycemia and was hospitalized due to diabetic ketoacidosis. His C-peptide and insulin levels were low, and he was diagnosed with type 1 diabetes

Summary

Introduction

Proopiomelanocortin (POMC) is a precursor polypeptide hormone secreted primarily in the hypothalamus. The posttranslational process and cleavage give rise to several polypeptides, the melanocortins. Among these are adrenocorticotropic hormone (ACTH), alpha-, beta- and gamma-melanocyte-stimulating hormones (a-MSH, b-MSH, and g-MSH), b-lipotrophin, and endorphins [1]. These polypeptides bind to melanocortin receptors of different subtypes. The melanocortin 1 receptor (MC1R) regulates skin pigmentation; stimulation of MC2R induces adrenal steroidogenesis; MC3R and MC4R regulate energy balance through appetite regulation, whereas MC5R is expressed in sebaceous glands and is involved in sebogenesis [1]. To add to the complexity, the POMC neurons in the central nervous system are highly heterogeneous in their regulation and action; the POMC-derived peptides can have opposing effects on appetite regulation, a-MSH suppressing and b-endorphin, on the other hand, promoting appetite [2]

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Discussion

Conclusion