ESPE Abstracts

Background: Isolated hypocortisolism due to ACTH deficiency is a rare condition that can be caused by mutations in the gene encoding pro-opiomelanocortin (POMC). POMC is the precursor to bioactive peptides (ACTH, β-endorphin, and α-β-γ-MSH). Mutations that inactive POMC typically result in secondary adrenal insufficiency, severe obesity and red hair; fewer than 50 affected individuals have been reported in the literature.

Case presentation: A 10-month-old female was referred to our clinic for macrosomia and delayed psyco-motor development. She was the only child to consanguineous Pakistani parents (first cousins), whose family history was not relevant. She was born full-term through spontaneous vaginal delivery (weight 3170 g, length 52 cm, and head circumference 35.8 cm) and neonatal hypoglicemia was reported; since 3 months of age she showed hyperphagia with marked weight and length gain. At the first clinical evaluation, her weight was 15 kg, length was 82.5 cm (both >>97th percentile), and head circumference 50 cm (97th percentile). Neurological examination showed axial hypotonia and delayed motor milestones. Facial dismorphysms (telecanthus, strabismus, wide nasal bridge), pale skin, and dark-brown hair were noted. Laboratory work-up (routine, α-fetoprotein, CEA, β-HCG, metabolic studies, and karyotype) was normal. Thyroid hormones, prolactin, GH, IGF1, and insulin levels were normal, while ACTH and cortisol were very low (<5 pg/ml and <10 μg/l respectively). Brain MRI showed pituitary hypoplasia and partial hypotrophia of corpus callosum. Congenital ACTH deficiency was diagnosed and substitutive therapy with hydrocortisone was started. Due to severe obesity and adrenal insufficiency, although the patient did not have red hair, POMC deficiency was suspected. Gene sequencing of POMC revealed an homozygous c256C>T change causing a stop codon (R86stop), inherited from the heterozygous parents.

Conclusion: POMC gene mutation should be considered in patient with early-onset severe obesity and secondary adrenal insufficiency, even without red hair. Adrenal insufficiency should be treated as usual, while the management of obesity in POMC deficiency remains challenging.