UNVEILING THE MYSTERIES

GENETIC PERSPECTIVE ON PRIMARY ADRENAL INSUFFICIENCY

Abstract

INTRODUCTION
Primary adrenal insufficiency (PAI) in childhood is rare and potentially life-threatening. The most common cause is congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency. Advancements in molecular genetics have revealed more genetic mutations causing PAI, which helps in explaining associated clinical features and prognosis. Clinical data and genetic tests were reviewed for two patients who presented with PAI.

CASE 1
LA presented with hypotonia and global developmental delay at the age of 1 year, with normal brain MRI/MRA and inborn error of metabolism (IEM) workup. She defaulted follow-ups until she presented again with generalized hyperpigmentation to dermatology at 3 years. Workup showed ACTH >278 pmol/L, normal 17-hydroxyprogesterone (17-OHP), and no rise in cortisol (<1.8 nmol/L) on ACTH stimulation test. Adrenal ultrasound was normal. Genetic testing was positive for NGLY-1 gene mutation, which is associated with global developmental delay, movement disorders, seizures, liver disease and alacrimia.

CASE 2
MI presented with being “easily tired” and hyperpigmentation since the age of 6 years. The endocrine team was consulted due to low cortisol. Investigations revealed ACTH >278 pmol/L, normal 17-OHP and flat response following ACTH stimulation test. Adrenal CT was normal. Genetic studies came back positive for ABCD1 mutation, a condition of adrenomyeloneuropathy, associated with progressive lower limb weakness and spasticity in the third or fourth decade of life. With hydrocortisone replacement and fludrocortisone therapy, LA and MI improved noticeably by decreasing skin hyperpigmentation.

CONCLUSION
Non-specific presentations of PAI and the rising numbers of genetic aetiologies discovered warrant genetic testing in affected individuals. This will facilitate prompt diagnosis based on clinical features and prognostication. It provides opportunities for tailored patient management, family counselling and heightened surveillance of possible comorbidities.