Acth Deficiency, Isolated

A number sign (#) is used with this entry because isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) can be caused by homozygous or compound heterozygous mutation in the TBX19 gene (604614) on chromosome 1q24.

Description

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).

Clinical Features

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).

Expanding on a previous report by Vallette-Kasic et al. (2005), Couture et al. (2012) reported 37 patients from 29 families with isolated ACTH deficiency. The patients presented with severe neonatal hypoglycemia, often associated with seizures, and prolonged cholestatic jaundice. Neonatal death occurred in 25% of the families. All patients had very low plasma ACTH and cortisol with normal pituitary imaging. Only 2 patients had partial and transient growth hormone deficiency.

Molecular Genetics

In 2 patients with isolated deficiency of pituitary ACTH, including the sister of a patient reported by Malpuech et al. (1988), Lamolet et al. (2001) identified mutations in the TBX19 gene (604614.0001-604614.0002).

Expanding on a previous report by Vallette-Kasic et al. (2005), Couture et al. (2012) studied 91 patients with IAD and identified 21 mutations in the TBX19 gene (see, e.g., 604614.0005) in 37 patients from 29 families with neonatal-onset complete IAD. Although mutations were found throughout the gene, most occurred in the T box, resulting in DNA binding defects. Mutation types comprised missense, nonsense, splice site, frameshift, and small intragenic deletions, consistent with a loss of protein function. In vitro functional expression studies of 4 of the missense mutations showed significantly decreased or absent transcriptional activity. The patients with TBX19 mutations accounted for 65% of those with neonatal-onset complete IAD. No TBX19 mutations were identified in any of the 22 patients with juvenile-onset IAD.

Heterogeneity

In a brother and sister with congenital isolated adrenocorticotropic hormone deficiency, Kyllo et al. (1996) reported that 22 markers defining the chromosomal haplotype flanking CRH (122560) were compatible with linkage of the disorder to the immediate area of that gene on chromosome 8. The family included 2 unaffected sibs and unaffected, unrelated parents. There was no detectable mutation of the proopiomelanocortin gene (POMC; 176830), and tests for linkage using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the respective genes excluded POMC and neuroendocrine convertases 1 (162150) and 2 (162151).

Corticotropin (ACTH) is one of several peptides derived from the POMC gene. For this reason mutations in POMC were considered a possible cause of ACTH deficiency. While proopiomelanocortin deficiency (609734) resulting from mutations in POMC includes ACTH deficiency, proopiomelanocortin deficiency is characterized by a distinctive phenotype. Further, it is possible that there are other causes, such as deficiency of an enzyme involved in the proteolytic cleavage of POMC to produce ACTH.