Endocrine Abstracts

An 11-year-old boy was diagnosed with adrenal insufficiency during the latter period of the COVID19 pandemic, following three presentations over several years with presumed sepsis requiring IV antibiotics and IV fluid. A cortisol level checked on his third presentation was <2 mmol/l and ACTH >1250 ng/l indicative of ACTH resistance. Adrenal autoantibodies and very long-chain fatty acids were negative. Genetic testing detected a homozygous pathogenic sequence variant in the melanocortin-2-receptor (MC2R) gene. At 11.5 years, pubertal staging suggested slightly early puberty (G3P3, testicular volumes 10mls bilaterally; testicular volumes +2SD above mean based on puberty normogram). Height was on the 75^th centile (mid-parental height 25^th centile) and bone age was advanced by 2 years. Height for bone age was between 9^th and 25^th centile. His pubertal status was re-assessed at 12.5 years (G5P5, testicular volumes 25mls/20mls). Repeat bone age revealed no change in bone maturity and height velocity was 4.9 cm/year (height velocity for bone age 10^th centile). Due to the combination of advanced bone age and early puberty, pubertal suppression was initially discussed. MC2R mutations are responsible for approximately one-quarter of familial glucocorticoid deficiency (FGD) cases, collectively known as FGD type 1. FGD is an autosomal recessive disorder characterised by ACTH resistance, resulting in isolated glucocorticoid deficiency with normal mineralocorticoid secretion. FGD typically presents in childhood with clinical features of glucocorticoid deficiency. Delayed diagnosis may occur due to the lack of characteristic electrolyte abnormalities which occur in other forms of adrenal insufficiency associated with mineralocorticoid deficiency, as is the case in our patient. Tall stature at presentation is recognised in a proportion of individuals with MC2R mutations, along with an advanced or dissociated bone age. It is hypothesised that high concentrations of ACTH may stimulate melanocortin receptors within the bone and cartilaginous growth plate resulting in increased linear growth. Glucocorticoid replacement appears to slow down this excessive growth. Whilst precocious puberty has been described in FGD associated with Nicotinamide Nucleotide Transhydrogenase mutations, to the best of our knowledge, precocious/early puberty have not been described in MC2R mutations. Further studies on pubertal development and management of early puberty in MC2R are needed.