Endocrine Abstracts

Background: Primary adrenal insufficiency (PAI) can be associated with significant morbidity in children of all ages, the most common cause being Congenital Adrenal Hyperplasia (CAH). Several other rare inherited causes of PAI have been identified over the years which lack diagnostic phenotypic or biochemical signs, leaving genetic testing as the only approach to make a definitive diagnosis. Our cohort involves >440 patients who presented with features of PAI – hypoglycaemia, hyperpigmentation and hypocortisolaemia without diagnostic characteristics of CAH. Targeted and whole exome sequencing has been conducted in 377 patients to date.

Aim: Genotype:phenotype characterisation for our cohort’s five most common genes causing PAI.

Results: We identified the genetic cause in 322/377 patients, the most common being mutations in MC2R (n=68/322), MRAP (n=53/322), NNT (n=44/322), STAR (n=28/322) and CYP11A1 (n=23/322). The relative risk of early age of onset of symptoms with an MRAP mutation as compared to other gene mutations causing PAI within our cohort was 1.5158 (95%CI: 0.9988-2.3003, P<0.05). Comparing the cortisol levels, individuals with MRAP mutations have the lowest (difference = 303.54 nmol/l; 95%CI: 225.15-381.93, P<0.0001) while those with CYP11A1 variants have the highest levels (difference = 223.44 nmol/l; 95%CI: 122.70 – 324.18, P<0.0001) amongst our cohort. For CYP11A1 2/4 (50%) adrenals were described as small whereas for all others only 11/102 (11%) were abnormal. No other significant association with height or levels of other steroids were found between the genotypic and phenotypic characteristics of PAI.

Discussion: A limitation of this study was the small sample size for each gene defect owing to the rarity of the disease. Our results suggest MRAP mutations present the earliest with lowest cortisol, while CYP11A1 have higher cortisol and smaller adrenal size however, with overlapping ranges this cannot be used for diagnosis. For CYP11A1 the higher cortisol levels may be due to over-representation of partial loss-of-function rs6161 variant in our population. These findings also highlight the importance of genetic testing since few clear genotype:phenotype correlations are obvious at diagnosis. Gaining a genetic diagnosis allows for the monitoring of patients for the pathological sequelae which can develop with different forms of PAI.