Proopiomelanocortin deficiency

Other Names: Obesity, early-onset, adrenal insufficiency, and red hair; POMC deficiency; Obesity due to pro-opiomelanocortin deficiency

Proopiomelanocortin (POMC) deficiency is characterized by severe obesity that begins at an early age. In addition to obesity, people with this condition have low levels of a hormone known as adrenocorticotropic hormone (ACTH) and tend to have red hair and pale skin.

Epidemiology

POMC deficiency is a rare condition; approximately 50 cases have been reported in the medical literature.

Cause

POMC deficiency is caused by mutations in the POMC gene, which provides instructions for making the proopiomelanocortin protein. This protein is cut (cleaved) into smaller pieces called peptides that have different functions in the body. One of these peptides, ACTH, stimulates the release of another hormone called cortisol from the adrenal glands. Cortisol is involved in the maintenance of blood sugar levels. Another peptide, alpha-melanocyte stimulating hormone (α-MSH), plays a role in the production of the pigment that gives skin and hair their color. The α-MSH peptide and another peptide called beta-melanocyte stimulating hormone (β-MSH) act in the brain to help maintain the balance between energy from food taken into the body and energy spent by the body. The correct balance is important to control eating and weight.

POMC gene mutations that cause POMC deficiency result in production of an abnormally short version of the POMC protein or no protein at all. As a result, there is a shortage of the peptides made from POMC, including ACTH, α-MSH, and β-MSH. Without ACTH, there is a reduction in cortisol production, leading to adrenal insufficiency. Decreased α-MSH in the skin reduces pigment production, resulting in the red hair and pale skin often seen in people with POMC deficiency. Loss of α-MSH and β-MSH in the brain dysregulates the body's energy balance, leading to overeating and severe obesity.

POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with more common, complex forms of obesity. Researchers are studying other factors that are likely involved in these forms.

Inheritance

Autosomal recessive inheritance, a 25% chance

POMC deficiency is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with this condition each carry one copy of the mutated gene. They typically do not have POMC deficiency, but they may have an increased risk of obesity.

Signs and symptoms

Affected infants are usually a normal weight at birth, but they are constantly hungry, which leads to excessive feeding (hyperphagia). The babies continuously gain weight and are severely obese by age 1. Affected individuals experience excessive hunger and remain obese for life. It is unclear if these individuals are prone to weight-related conditions like cardiovascular disease or type 2 diabetes.

Low levels of ACTH lead to a condition called adrenal insufficiency, which occurs when the pair of small glands on top of the kidneys (the adrenal glands) do not produce enough hormones. Adrenal insufficiency often results in periods of severely low blood sugar (hypoglycemia) in people with POMC deficiency, which can cause seizures, elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia), and a reduced ability to produce and release a digestive fluid called bile (cholestasis). Without early treatment, adrenal insufficiency can be fatal.

Pale skin that easily burns when exposed to the sun and red hair are common in POMC deficiency, although not everyone with the condition has these characteristics.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 100% of people have these symptoms

• Increased adipose tissue(Increased fat tissue)

80%-99% of people have these symptoms

• Polyphagia(Voracious appetite)

30%-79% of people have these symptoms

• Central adrenal insufficiency
• Childhood-onset truncal obesity
• Cholestasis(Slowed or blocked flow of bile from liver)
• Hypopigmentation of the skin(Patchy lightened skin)
• Red hair(Red hair color)

5%-29% of people have these symptoms

• Acanthosis nigricans(Darkened and thickened skin)
• Delayed puberty(Delayed pubertal development)
• Delayed skeletal maturation(Delayed bone maturation)
• Failure to thrive(Faltering weight)
• Gonadotropin deficiency
• Growth hormone deficiency
• Hyperinsulinemia
• Hypoglycemic seizures
• Pituitary hypothyroidism(Low thyroid gland function due to abnormal pituitary gland)

Treatment

Adrenal insufficiency requires prompt treatment with hydrocortisone to avoid life-threatening complications. patients with genetically confirmed POMC deficiency using setmelanotide, a melanocortin-4 receptor (MC4R; 155541) agonist. The patients had sustainable reduction in hyperphagia and hunger, as well as substantial weight loss and overall improvement in the quality of life.

Prognosis

Without early treatment, the adrenal insufficiency associated with POMC deficiency can be fatal. The overall prognosis for this condition, however is undefined. It remains unclear if individuals with POMC deficiency are prone to weight-related complications like cardiovascular disease, cancer, or type 2 diabetes.  This article incorporates public domain material from websites or documents of the National Center for Biotechnology Information (Reference Sequence collection).

NIH genetic and rare disease info

• NIH info on Proopiomelanocortin deficiency

Proopiomelanocortin deficiency is a rare disease.

Proopiomelanocortin deficiency Resources
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