Nonclassic Congenital Lipoid Adrenal Hyperplasia: A New Disorder of the Steroidogenic Acute Regulatory Protein with Very Late Presentation and Normal Male Genitalia

Abstract

These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).

Early steps in steroidogenesis: intracellular cholesterol trafficking

“…An attenuated form of the disease called "non-classic lipoid CAH" is caused by mutations that retain about 10-25% of normal StAR activity ( 269,270 ). These patients typically experience adrenal insuffi ciency several years after infancy; the 46,XY individuals may masculinize normally, and mineralocorticoid secretion may be affected minimally.…”

Genetics of Congenital Adrenal Hyperplasia

“…98 Several mutations in the StAR gene have been described and are mostly located in exons 5, 6, or 7: p.Q258X in Asians, and p.R182L in Palestinian Arabs. 97 A milder, "nonclassic" form of lipoid CAH was first described in 2006, 99 and is caused by mutations that retain about 20-30% of normal StAR activity. The majority of these patients carry the StAR mutation p.R188C, which has been found in patients from Canada, Jordan, India, Pakistan and Thailand; however, other StAR mutations causing non-classic lipoid CAH have also been described.…”

Peripheral Benzodiazepine Receptor/Translocator Protein Global Knock-out Mice Are Viable with No Effects on Steroid Hormone Biosynthesis

“…Anchoring STAR in a mitochondrion-affixed TOM20-STAR fusion protein in MA-10 cells resulted in the constitutive production of steroid hormone (30). In humans, STAR mutations cause lipoid congenital adrenal hyperplasia that ranges from an almost complete inability to synthesize steroids (31) to less severe forms that retain partial STAR protein activity (32). Also in support, Star gene-deleted mice showed an almost complete inability to synthesize steroid hormones underscoring its critical role in steroidogenesis (33).…”