Congenital isolated ACTH deficiency

Congenital isolated ACTH deficiency (IAD) is a rare endocrine disorder characterized by a selective deficiency of adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland, while other pituitary hormones remain normally produced. ACTH is essential for stimulating the adrenal glands to produce cortisol, a hormone critical for stress response, blood sugar regulation, immune function, and blood pressure maintenance. Without adequate ACTH, the adrenal glands fail to produce sufficient cortisol, leading to secondary adrenal insufficiency. Clinical features typically present in the neonatal period or early infancy and can include severe hypoglycemia (low blood sugar), prolonged neonatal jaundice (particularly cholestatic jaundice), seizures due to hypoglycemia, failure to thrive, and recurrent infections. In some cases, adrenal crisis can occur, which is a life-threatening emergency characterized by profound hypotension, dehydration, and shock, particularly during physiological stress such as illness or surgery. Unlike primary adrenal insufficiency, skin hyperpigmentation is absent because ACTH levels are low rather than elevated. Congenital isolated ACTH deficiency can be caused by mutations in the TBX19 gene (also known as TPIT), which encodes a transcription factor essential for the differentiation of pituitary corticotroph cells. Mutations in this gene account for a significant proportion of neonatal-onset cases and follow an autosomal recessive inheritance pattern. Some cases may also be associated with mutations in the POMC gene (proopiomelanocortin), which can present with ACTH deficiency alongside obesity and red hair pigmentation. Treatment consists of lifelong glucocorticoid replacement therapy, typically with hydrocortisone, with dose adjustments during periods of physiological stress. Early diagnosis and prompt treatment are critical to prevent life-threatening hypoglycemia and adrenal crises, and with appropriate management, patients can lead relatively normal lives.

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