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.

When Obesity Is Hard to Fight: Homozygous Pomc Mutation in a Hispanic Male

“…As seen in this report, this patient was diagnosed with adrenal insufficiency shortly after birth and began showing excessive weight gain by six months of age. Later in life, hypopigmentation of the skin due to lack of MSH, signs of hypothyroidism due to lack of TSH, and hypogonadotropic hypogonadism due to insufficient luteinizing hormone and the folliclestimulating hormone may become evident [5]. The presented patient did not have hypogonadotropic hypogonadism but displayed hypopigmented skin and hypothyroidism, suggesting impaired signaling of MSH and thyrotropin-releasing hormone.…”

Serum kisspeptin and proopiomelanocortin in cystic fibrosis: a single study

“…Although originally characterized as stress signal-induced neurohormones in the context of the classical hypothalamic–pituitary–adrenal stress axis, it has now been established that POMC and its derivative peptides can also be autonomously generated in many peripheral tissues 37 – 39 . POMC deficiency is related to early-onset severe obesity, adrenal insufficiency, skin hypopigmentation and red hair 21 . Furthermore, decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients 40 .…”

“…POMC neurons in the central nervous system are highly heterogeneous in their regulation and action. Therefore, POMC-derived peptides can have opposing effects on appetite regulation, while α-MSH suppressing -MSH and β-endorphin, promoting appetite 20 , 21 . The purpose of our study was to estimate the concentration of KISS and POMC in sera of patients with CF and to determine the correlation between these hormones and clinical parameters of patients.…”

Genetics of Obesity in Humans: A Clinical Review

“…Hence, a deficiency of POMC leads to hyperphagia, lower resting metabolic rate, and resultant severe obesity with red hair and pale skin [ 16 ]. Errors in the cleavage of master proteins such as POMC require pro-hormone convertase, which cleaves this large protein into smaller functional peptides and as noted, interacts with appetite control, pigment, and obesity [ 17 ].…”