ESPE Abstracts

Background: Melanocortin-2 receptor (MC2R) is a member of the G protein-coupled receptor family. MC2R is selectively activated by adrenocorticotropic hormone (ACTH); the binding of MC2R and ACTH activates the heterotrimeric G protein complex, and in turn stimulates steroidogenesis. Pathogenic variants in the MC2R gene result in glucocorticoid deficiency-1 (GCCD1), an autosomal recessive disorder in which unresponsiveness to ACTH leads to deficient secretion of cortisol and adrenal C19 androgen precursors. Biochemically serum cortisol levels are low with elevated ACTH. Patients with GCCD1 usually present with failure to thrive, hypoglycemia, recurrent infections, hyperpigmentation, and neurological sequel.

Objective(s): To describe a case of two-year old boy with symptoms of adrenal insufficiency and confirmed novel pathological mutation in the MC2R gene.

Case report: The patient is a two-years old boy, full term, product of uneventful pregnancy and normal vaginal delivery. He had repeated episodes of neonatal sepsis starting at the age of 2 days. He had recurrent symptoms of failure to thrive, hypoactivity, hypoglycemia, and recurrent infections.

Methods: Whole Exome Sequence (WES) Analysis was performed using genomic DNA from the patient and his parents, the exonic regions and flanking splice junctions of the genome were captured and sequenced by NextGen sequencing on an illumine system. Reads were aligned to human genome build GRCh37/UCS hg19, and analyzed for sequence variants using Xome Analyzer. Sequence and copy number variants were described according to the Human Genome Society(HGVS) and International System for Human Cytogenetic Nomenclature (ISCN) guidelines, respectively.

Results: His biochemical investigations showed elevated levels of ACTH >1500 (reference 5–60 pg/ml), low levels of cortisol <22 (69–632 nmol/l), low aldosterone 151 pmol/l (reference 194-2579), and hypoglycemia (1.1 mmol/l). WES has identified a p.Leu109Gln (CTG>CAG): c.326 T>A in exon 2 in the MC2R gene.

Conclusion: We report a novel mutation in the MC2R gene leading to severe cortisol deficiency. The L109Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. Further functional analysis will aid in unravelling the molecular mechanism of how the novel mutation leads to adrenal insufficiency.