Glycogen storage disease presenting as Cushing syndrome

Abstract

Impaired growth is common in patients with glycogen storage disease (GSD), who also may have “cherubic” facies similar to the “moon” facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic‐pituitary‐adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2 , leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was “appropriate” and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin‐releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo‐CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed “stress‐induced Cushing (SIC) syndrome” to distinguish it from the other causes of CS and pseudo‐CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

Mutational analysis and clinical investigations of medically diagnosed GSD 1a patients from Pakistan

“…Cushingoid appearance, delayed motor development and osteopenia is attributed to untreated GSD Ia [ 23 , 24 ]. These complications are attributed to hypothalamic-pituitary-adrenal (HPA) axis stimulation due to chronic hypoglycemic stress causing elevated glucocorticoid secretion [ 25 ]. In our study cohort, inflammatory bowel disease (IBD) was present in 15 patients (37.5%) (see S1 Table ), that is higher as studies have reported an occasional presence of IBD in GSD Ia cases [ 26 , 27 ].…”