Familial glucocorticoid deficiency

Familial glucocorticoid deficiency (FGD), also known as hereditary unresponsiveness to adrenocorticotropic hormone (ACTH) or isolated glucocorticoid deficiency, is a rare autosomal recessive disorder characterized by the adrenal glands' inability to produce cortisol in response to ACTH stimulation. Unlike other forms of adrenal insufficiency, mineralocorticoid (aldosterone) production typically remains intact, meaning salt balance and blood pressure regulation are usually preserved. The condition primarily affects the endocrine system, specifically the hypothalamic-pituitary-adrenal axis. The hallmark features of FGD include severe hypoglycemia (low blood sugar), which can cause seizures and brain damage if untreated, as well as pronounced skin hyperpigmentation due to chronically elevated ACTH levels. Symptoms typically present in infancy or early childhood and may include failure to thrive, recurrent infections, collapse, and prolonged jaundice in the neonatal period. Without treatment, the condition can be life-threatening. Some subtypes are associated with tall stature. Several genetic subtypes have been identified. FGD type 1 is caused by mutations in the MC2R gene (melanocortin 2 receptor, the ACTH receptor), while FGD type 2 results from mutations in MRAP (melanocortin 2 receptor accessory protein), which is essential for MC2R trafficking and function. Mutations in NNT (nicotinamide nucleotide transhydrogenase), TXNRD2, and other genes have also been implicated. A related condition, triple A syndrome (Allgrove syndrome), shares features of glucocorticoid deficiency with achalasia and alacrima. Treatment consists of lifelong glucocorticoid replacement therapy, typically with oral hydrocortisone, with dose adjustments during illness or physiological stress. Early diagnosis and treatment are critical to prevent hypoglycemic brain injury and potentially fatal adrenal crises.

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