Clinical history: The female index patient (age 25 years) was born small for gestational age, with a rapid weight gain to the 97th percentile in her first year. At the age of 7 she was diagnosed with adrenal insufficiency after multiple hospitalizations with respiratory tract infections with fever, vomiting and ketotic hypoglycemias. Furthermore she had been treated for pulmonary tuberculosis. She had gingival, areolar and palmar hyperpigmentations and remarkable features, such as tapering and hyperlaxity of the fingers, elongation of the metacarpalic and phalangic bones, increased height and a large head circumference (both p97). Strikingly, her ACTH was very high (396ng/L). Also, since a young age she had hyperphagia and obesity. Throughout childhood her TSH was elevated and developed to overt hypothyroidism at the age of 14. At the age of 18 she developed growth hormone deficiency. Currently, at the age of 25 years her BMI is 40kg/m².
Her younger sister (age 21 years) presented concomitantly with adrenocortical insufficiency with elevated ACTH. She has a mild psychomotor impairment and suffers from obesity since the age of 15. Initial genetic testing revealed no abnormalities in NR0B1, MC2R, GNAS and MRAP. Eventually whole exome sequencing of the index patient revealed a homozygous mutation in the POMC gene (pomc c.457_459del p.(lys153del), located on exon 3 (that is translated to ACTH and α-MSH). Defects in the POMC gene are known to cause early onset obesity with hyperphagia, ACTH deficiency, and hypopigmentation of the skin and red hair. Conversely, these patients display high ACTH in combination with hypocortisolism. We hypothesize that their ACTH is defective. Currently, we aim to identify the underlying mechanism.

Conclusion: We describe a novel homozygous POMC mutation combined with a striking phenotype of early onset obesity, multiple endocrine disorders including hypocortisolism, several mental problems, and dysmorphic features. This finding is also relevant as medication in the melanocortin pathway is currently under development.