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

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.

Keywords: POMC deficiency; adrenal insufficiency; obesity; proopiomelanocortin; setmelanotide; systematic review; type 1 diabetes.

Figure 1

PRISMA flow diagram for systematic case review of POMC deficiency (8).

Figure 2

Modified WHO growth charts* display both case patients. (A) Case patient 1—length for age and weight for age; (B): Case patient 1—BMI for age, (C): Case patient 2—length for age and weight for age, (D): Case patient 2—BMI for age; BLUE ARROW marks the onset of setmelanotide treatment of case patient 1. *Original WHO growth charts were modified due to restrictions of scale and age.

Figure 3

Case patient 1 in childhood, before setmelanotide treatment (A) and after (B).

Figure 4

Graphic representation of (A) the frequency of first presenting signs or symptoms and (B) the frequency of clinical features.

Figure 5

Schematic representation of POMC-derived peptides and genetic variants associated with autosomal recessive POMC deficiency. ACTH, corticotropin; β-LPT, lipotropin β; γ-LPT, lipotropin γ; α-MSH, melanotropin α; β-MSH, melanotropin β; γ, MSH, melanotropin γ; NPP, N-terminal peptide of proopiomelanocortin; SP, signal peptide.