Adrenal Insufficiency in an Adolescent Boy With Type 1 Diabetes Mellitus - the Importance of Considering X-Linked Adrenoleukodystrophy

Abstract

Background: Primary adrenal insufficiency (PAI) is the rare, life-threatening failure of the adrenal glands to produce sufficient glucocorticoids and mineralocorticoids, presenting with fatigue, weakness, weight loss, hyperpigmentation, hypoglycemia, and hypotension. In adults, PAI is primarily autoimmune, occurring independently or in conjunction with thyroiditis and/or Type I diabetes mellitus (T1DM) as a component of Autoimmune Polyglandular Syndrome-2 (APS-2, Schmidt syndrome). APS-2 is rare (prevalence 1 in 20,000) and more common in females with a peak incidence in the third and fourth decades of life. In children, PAI is most often due to congenital adrenal hyperplasia (CAH), followed by autoimmune disease, but as many as 50% of cases of non-CAH pediatric PAI are not autoimmune. PAI is often the first documented clinical finding in boys with X-linked adrenoleukodystrophy (X-ALD), a rare disorder (prevalence 1 in 15,000) in which deficiency of a peroxisomal membrane protein leads to very long chain fatty acid (VLCFA) accumulation and progressive destruction of the adrenal cortex. A subset of boys with X-ALD develop cerebral ALD (cALD), characterized by progressive central demyelination, neurocognitive decline, and death. 70–80% of boys with X-ALD present with PAI prior to demonstrating neurologic symptoms. Diagnostic workup for X-ALD in pediatric patients presenting with PAI is crucial as timely intervention with hematopoietic stem cell transplant (HSCT) can stop progression of cerebral disease. Clinical Case: An eleven-year-old male was diagnosed with PAI after presenting with poor school performance, growth delay and skin hyperpigmentation. Medical history was significant for well controlled T1DM diagnosed at eight years old. Given his history of T1DM, his PAI was presumed to be autoimmune and further diagnostic testing was not performed. Eleven months later, a brain MRI performed for complaints of visual disturbance and chronic headaches revealed extensive demyelination with gadolinium enhancement consistent with cALD. Elevated VLCFAs and a mutation in the ABCD1 gene confirmed the diagnosis of X-ALD. Unfortunately, the extent of cerebral involvement was so severe that HSCT would not be of significant clinical benefit. In these situations, progressive neurological decline that leads to disability and ultimately death would be expected. Clinical Lessons: This case illustrates that VLCFA testing should be performed in all boys with PAI to rule out X-ALD. In boys, PAI should not be assumed to be autoimmune, even with co-existing autoimmune diseases since APS-2 (Schmidt syndrome) is rare and more likely to occur in adult women. PAI presents early and precedes neurologic symptoms in a majority of boys with cALD. Early identification of X-ALD through VLCFA testing prior to development of severe cALD is critical to allow early intervention with lifesaving HSCT.