Inherited Adrenal Hypoplasia: Not Just for Kids!

Lin Lin; John C. Achermann


Clin Endocrinol. 2004;60(5) 

In This Article

Isolated ACTH Deficiency: Abnormalities in Pro-Opiomelanocortin Synthesis and Processing

Mutations in several factors involved in ACTH synthesis and processing can cause secondary adrenal hypoplasia due to ACTH insufficiency (Fig. 3).

Expression and processing of ACTH. ACTH deficiency can result from abnormalities in Tpit, pro-opiomelanocortin (POMC), or the cleavage enzyme, pro-hormone convertase 1 (PC1).

The mature ACTH peptide is cleaved from pro-opiomelanocortin (POMC), together with other signalling molecules such as the melanocyte-stimulating hormones (α-MSH, β-MSH) and β-endorphin (Fig. 3). As these factors play a central role in appetite regulation and pigmentation, deletions or mutations in the POMC locus have been identified in patients with the syndrome of ACTH-deficient hypocortisolaemia, red hair and obesity (Krude et al., 1998, 2003; OMIM 176830).

POMC transcription is regulated by the corticotrope-specific transcription factor, Tpit (TBX19; Lamolet et al., 2001). Tpit binds to the T-box (TCACACCA) of the POMC promoter and forms a regulatory complex with Pitx1 (Fig. 3). Tpit plays a crucial role in ACTH synthesis by regulating POMC expression as well as in the differentiation of late POMC expressing corticotropes. Mutations in Tpit have now been described in several families with isolated ACTH deficiency (Lamolet et al., 2001; Pulichino et al., 2003a, 2003b; OMIM 604614). Furthermore, recent data suggest that Tpit is a negative regulator of gonadotrope differentiation through trans-repression of steroidogenic factor-1 (SF-1), highlighting the role that some of these transcription factors can play in switching cell fate in endocrine development (Pulichino et al., 2003b).

The proprotein convertase family of enzymes plays an important role in pro-hormone processing in several endocrine systems, and pro-hormone convertase 1 (PC1; proprotein convertase, subtilisin/kexin-type, 1; PCSK1) is crucial for the cleavage of mature ACTH from POMC (Fig. 3). Mutations in this enzyme have been reported in two patients with hypocortisolaemia (Jackson et al., 1997; Lindley et al., 2003; OMIM 162150). Additional features of this syndrome include abnormal glucose metabolism, obesity, hypogonadotropic hypogonadism and persistent malabsorptive diarrhoea, reflecting the diverse role PC1 plays in peptide processing in the gut. Whether milder forms of this condition exist in adulthood remains to be elucidated.


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