Congenital isolated adrenocorticotropic hormone deficiency is characterized by severe hypoglycemia in the neonatal period, associated with seizures in about half of cases; prolonged cholestatic jaundice; and very low plasma ACTH levels with no significant response to CRH (122560). ... Congenital isolated adrenocorticotropic hormone deficiency is characterized by severe hypoglycemia in the neonatal period, associated with seizures in about half of cases; prolonged cholestatic jaundice; and very low plasma ACTH levels with no significant response to CRH (122560). Plasma cortisol levels are also extremely low (Vallette-Kasic et al., 2005). TBX19 is required for initiation of transcription of the POMC gene (176830), which produces the precursor peptide from which ACTH is derived (Lamolet et al., 2001).
Hung and Migeon (1968) described a 34-month-old black boy with apparent isolated ACTH deficiency. The adrenal medulla was unresponsive to insulin-induced hypoglycemia. Treatment of the adrenocortical insufficiency restored responsiveness. The enzyme phenylethanolamine-N-methyl transferase (PNMT; 171190) is localized to ... Hung and Migeon (1968) described a 34-month-old black boy with apparent isolated ACTH deficiency. The adrenal medulla was unresponsive to insulin-induced hypoglycemia. Treatment of the adrenocortical insufficiency restored responsiveness. The enzyme phenylethanolamine-N-methyl transferase (PNMT; 171190) is localized to the adrenal medulla and catalyzes the N-methylation of norepinephrine to epinephrine. The activity of this enzyme is controlled by glucocorticoids. Lucking and Willig (1975) and Malpuech et al. (1988) each described 2 affected sibs. The patients of Malpuech et al. (1988) were brother and sister. The first-born, the male, died; pathologic findings included bilateral adrenal hypoplasia. Plasma estriol levels were assayed during the mother's next pregnancy. Prenatal diagnosis allowed immediate and effective management of this second affected child. In the second infant, echograms showed small adrenals and from age 3 weeks she tolerated fasting poorly. The diagnosis was confirmed by reduced plasma cortisol levels, particularly during attacks of hypoglycemia. Ichiba and Goto (1983) reported 2 affected sisters. Nussey et al. (1993) investigated a female infant who presented with hypoglycemia in the neonatal period. When studied at 6 weeks of age, she was found to have no measurable ACTH even after injection of corticotropin releasing hormone (CRH; 122560). On the other hand, ACTH precursors were measurable and were stimulated by CRH and suppressed by glucocorticoid administration. By sequencing PCR products from the patient's genomic DNA, the entire coding region of the POMC gene was established to be normal. Nussey et al. (1993) interpreted these results as compatible with a cleavage enzyme defect. As reviewed by Funder and Smith (1993), POMC is cleaved in the anterior pituitary, by an enzyme termed PC1, to yield ACTH and beta-lipotropin. In the brain and pituitary intermediate lobe, the enzyme PC2 cleaves ACTH into products that yield alpha-MSH and CLIP (see 176830) and cleaves beta-LPH into gamma-LPH and beta-endorphin. The human pituitary gland appears to lack an intermediate lobe, except in utero and perhaps in pregnancy; on the other hand, PC2 is present in the human genome and is expressed in neuroendocrine tissues. Funder and Smith (1993) suggested that the patient of Nussey et al. (1993) was either expressing PC2 ectopically in her anterior pituitary or that her PC1 normally expressed in the anterior pituitary had mutated to show a PC2-like pattern of substrate specificity. They also suggested a third intriguing possibility, that of a chimeric gene, with its 5-prime end derived from the PC1 gene and its translated region derived in large part (or entirely) from PC2, giving the tissue localization (and presumably control) characteristic of PC1 and the enzymatic activity of PC2. The precedent they cited was glucocorticoid remediable aldosteronism, which reflects the expression of a chimeric gene (see 103900).
In patients with isolated deficiency of pituitary ACTH, including a patient reported by Malpuech et al. (1988), Lamolet et al. (2001) identified mutations in the TBX19 gene (e.g., 604614.0001).