ESPE Abstracts

Introduction: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by ACTH-resistant isolated cortisol deficiency. FGD usually presents with hypoglycemia, convulsions, prolonged jaundice, and marked skin hyperpigmentation in the early period of life. Several defects in MC2R, MRAP, MCM4, NNT, and TXNRD2 genes are related to FGD. In all these situations, plasma ACTH is high. By contrast, all reported cases of glucocorticoid deficiency due to mutations in the gene encoding proopiomelanocortin (POMC), the precursor protein from which ACTH is derived, had low or undetectable plasma ACTH. Patients with POMC defects generally present early-onset obesity, hyperphagia, red hair, hypopigmentation and ACTH deficiency. Only 3 cases of POMC gene mutations characterized by a bioinactive ACTH, mimicking FGD, have been so far described in literature.

Case Report: We report the case of a boy who presented at the age of 2 years with a history of recurrent hypoglycemia. Biochemical evaluation revealed high ACTH levels (815 pg/ml, nv 10-130 pg/ml) and undetectable cortisol (<0,16 mcg/dl, nv 4,3-22,4 mcg/dl) leading to a diagnosis of primary adrenal insufficiency (PAI). Skin and mucosae were not hyperpigmented and the patient had red hair. Treatment with glucocorticoids and mineralcorticoids was started with resolution of symptoms. During the follow-up he also developed epilepsy, mild psychomotor delay and obesity with hyperphagia. Several genes known to cause FGD, adrenal hypoplasia or metabolic and syndromic diseases associated with PAI resulted to be normal. An extensive work-up excluded acquired conditions of PAI. In order to reach a definitive diagnosis, whole exome sequencing (WES) was performed. Three variants in POMC gene were identified: the p.R145C variant (inherited from the mother), already described in two children with glucocorticoid deficiency; p.R137C and p.K136N (inherited from the father), which are novel variants never described in the literature.

Conclusions: We report a unique case of hypocortisolism, obesity and hyperphagia caused by secretion of bioinactive ACTH molecule due to novel mutation of POMC gene. This case expands our knowledge on genetic conditions responsible of AI in children and highlights how POMC mutations should be considered in children with otherwise unexplained PAI, in particular when associated with early-onset obesity and hyperphagia. PAI in children and young people often has a genetic basis and establishing the specific etiology can influence management and treatment.