Primary Adrenal Insufficiency: New Genetic Causes and Their long-Term Consequences

Federica Buonocore; John C. Achermann


Clin Endocrinol. 2020;91(1):11-20. 

In This Article

Nonclassic Steroidogenic Disorders: STAR and CYP11A1

Steroidogenic acute regulatory protein (STAR) and cytochrome P450 side-chain (P450scc, encoded by CYP11A1) are two key factors involved in the initial stages of steroidogenesis in the adrenal gland and gonads.[55]

STAR is located on the outer mitochondrial membrane and facilitates transfer of cholesterol from the cytoplasm to the mitochondrial inner membrane (Figure 3A). P450scc is the limiting step in steroidogenesis and catalyses the three steps needed for conversion of cholesterol to pregnenolone (Figure 3A).[55]

Figure 3.

Partial defects in STAR and CYP11A1 cause a predominant glucocorticoid insufficiency phenotype. (A) Cartoon showing the actions of STAR and P450scc/CYP11A1 in steroidogenesis in the adrenal gland (and gonad). Selected variants associated with partial phenotypes are indicated. (B) Model of STAR indicating the position of codons V187 and R188 at the core of the protein, which interact with cholesterol. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane. Panel (B) modified with permission from Baker BY, Lin L, Kim CJ, et al Nonclassic congenital lipoid adrenal hyperplasia: A new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab. 2006;91(12):4781–4785. © 2006 The Endocrine Society

Severe disruption of STAR or P450scc/CYP11A1 causes a block in all aspects of adrenal and gonadal steroid synthesis.[56–58] For STAR defects this is known as congenital lipoid adrenal hyperplasia (CLAH).[56] Individuals with these conditions tend to present in the first month of life with salt-losing adrenal insufficiency and cortisol insufficiency. Infants with a 46,XY karyotype have female-typical genitalia due to a lack of testosterone biosynthesis in utero. Ovarian insufficiency can occur variably in 46,XX girls at adolescence.

In addition to these "classic" conditions, it has now become apparent that partial defects in these enzymes cause nonclassic disorders; patients present with a predominant adrenal phenotype, usually affecting glucocorticoid synthesis and often resembling familial glucocorticoid deficiency (FGD).

Nonclassic Congenital Lipoid Adrenal Hyperplasia – STAR

Nonclassic congenital lipoid adrenal hyperplasia (NCLAH) was first reported in 2006 due to biallelic pathogenic missense variants in STAR.[59] Two brothers had predominant glucocorticoid insufficiency and normal genitalia (p.R188C), and a 46,XX girl had low cortisol and extremely high ACTH (p.V187M) (Figure 3A). These variants reduce interactions with the 3-βOH group of cholesterol and cause partial loss of function (Figure 3B). In some individuals, variants in other codons (eg p.R192, p.G221) are found.[37,60,61] Given the overlap with features of familial glucocorticoid deficiency (resistance), NCLAH is sometimes termed FGD3. Long-term reproductive follow-up is required to ensure that puberty development occurs appropriately and adequate testosterone and oestrogen biosynthesis is maintained in adulthood. If semen analysis shows viable sperm, appropriate counselling and sperm banking might be offered in case progressive issues occur in the future.

Nonclassic CYP11A1 Deficiency

Similar to NCLAH, it is now emerging that partial loss of function of CYP11A1 (encoding P450scc) also presents with a predominant adrenal phenotype, affecting glucocorticoids and sometimes mineralocorticoid synthesis.[62,63] Patients can present at different ages throughout childhood, often with hyperpigmentation, hypoglycaemia or prolonged illness with infections.

Genetic analysis has revealed that many European individuals and families of European ancestry with this condition are compound (double) heterozygous for a c.940G > A variant (rs6161) on one allele of CYP11A1 and a severely disruptive change on the other allele (Figure 3A).[64] Although the c.940G>A variant is predicted to cause a benign protein change (p.E314K), detailed molecular studies have shown that it generates a novel splice site so that missplicing occurs.[64,65] This variant is carried by approximately 1:140 people of European descent, but is likely to cause adrenal insufficiency only when inherited with a very rare disruptive change on the other allele. Partial CYP11A1 insufficiency can also occur in other populations, such as due to the p.R451W variant common in central Turkey.[37,63]

As with NCLAH, long-term monitoring of sex hormone production and fertility is warranted at puberty and in adulthood. Fertility has been reported in men, although raised gonadotrophins are sometimes seen, and testicular adrenal rest tumours (TART) can occur if glucocorticoid insufficiency is poorly controlled.[66] Sperm banking might also be considered.