Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Proopiomelanocortin (POMC) Deficiency

What is POMC Deficiency?

• Proopiomelanocortin deficiency, also known as POMC (pronounced POM-see) deficiency, is part of a larger group of disorders known as rare genetic disorders of obesity.​
• A life-threatening, ultra-rare orphan disease resulting from a variant of the POMC gene, leading to loss of function in the MC4 pathway.​
• The MC4R pathway tells us when to eat and when we are full. Variants or changes in the POMC gene can stop a part of this pathway from working and prevent this important message from being sent.​
• Estimated to affect 100-500 people worldwide. ​

How Do You Get It?

• 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.​
• The diagnosis of POMC deficiency is suspected in a proband with the following clinical and laboratory findings:​
  • Severe, hyperphagic obesity of onset in infancy​
  • Congenital adrenal insufficiency, resulting from corticotropin (ACTH) deficiency
• The diagnosis of POMC deficiency is confirmed by the presence of biallelic POMC pathogenic variant
  • If a diagnosis of POMC deficiency is suspected by your doctor based on clinical signs and symptoms, a special genetic blood test can be ordered to help confirm the diagnosis by genetic testing.​
• POMC deficiency can also be caused by a variant in the PCSK1 gene, which is also located on the MC4R pathway. ​
  • People with this variant may experience symptoms like insatiable hunger, malabsorptive diarrhea, and endocrine abnormalities.​

What Are The Symptoms?

• Without early treatment, the adrenal insufficiency associated with POMC deficiency can be fatal.
• 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.​
• In infants:
  • Babies with POMC deficiency are typically of average birth weight and have a standard feeding schedule. ​
  • But within the first few weeks of their lives, they can develop an insatiable appetite and cry constantly to be fed. ​
  • Because of these symptoms, babies with POMC deficiency may start to gain weight rapidly, with their body mass index (BMI) likely falling at or above the 95th percentile for their age.​
  • Most people with POMC deficiency also continue to experience insatiable hunger and severe obesity into adult life.​
• Some people, but not all, may also have:​
• Mildly low thyroid levels (hypothyroidism)​
• Adolescent-onset growth hormone (GH) deficiency​
• Delayed puberty in adolescence caused by hormonal imbalances (hypogonadotropic hypogonadism)​
• Red hair and light skin pigmentation​
• Liver disease​

How Is It Treated?

• Treatment of POMC deficiency can be challenging.​
• Patients require life-long glucocorticoid treatment using replacement doses. Mineralocorticoid replacement is not required. ​
• Hypothyroidism should be monitored and treated if present. ​
• Early onset obesity can be very difficult to treat beyond standard dietary and lifestyle measures, but the hyperphagic component is especially challenging. Krude et al  attempted intranasal ACTH treatment in two index cases with the ACTH peptide fragment identical to a-MSH. ​
• However, ACTH treatment at low doses during the first six weeks followed by a high dose (5 mg/day) did not produce a significant response in weight loss.​
• Possible treatment options may include:
  • Phentermine, a psychostimulant that boosts sympathetic activation
  • Topiramate, an anticonvulsant
  • Lorcaserin, a serotonin receptor agonist
  • Benzphetamine, amphetamine that prevents monamine uptake
  • Orlistat, a lipase inhibitor that stops fat absorption
  • Liraglutide, a GLP-1 receptor agonist
  • Naitrexone + bupropion

Where Can I Learn More???

• Check out our cornerstone on this disease here.
• Learn more from Lead for Rare Obesity.