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Autoimmune polyglandular syndrome type 2 (APS-2) is a rare complex autoimmune endocrinological entity and is reported even more rarely in children and adolescents. It consists of primary adrenal insufficiency (Addison's disease), autoimmune thyroiditis (AIT) and/or type 1 diabetes mellitus (T1DM). Treatment of the AIT component of the disease with levothyroxine as hormone replacement therapy has been reported rarely to cause adrenal crisis. This treatment adverse event is possibly explained due to the increase of basal metabolic rate and subsequently the increased demand and clearance of cortisol after levothyroxine therapy and should always be considered by physicians in order to avoid the development of adrenal crisis. We report the case of a 13-year-old adolescent girl with hypothyroidism due to Hashimoto's thyroiditis (HT) who developed signs of adrenal insufficiency after initial levothyroxine therapy. She was initially admitted with symptoms of hyperthyroidism, including weight loss, anxiety, and oligomenorrhea. A more thorough examination revealed pallor, signs of dehydration, tachycardia, and additionally serum electrolyte imbalance and extremely low cortisol levels in combination with very high adrenocorticotropic hormone (ACTH) levels. The patient received emergency treatment for adrenal insufficiency and recovered well. Due to positive adrenal autoantibodies, APS-2 was confirmed. This case report highlights the necessity of careful adrenal function screening in patients with hypothyroidism and HT before initiating thyroid therapy in order to avoid the rare occurrence of adrenal crisis.