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Steroid Acute Regulatory Protein (stAR) Deficiency— congenital Lipoid Adrenal Hyperplasia

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p939

2026-08-18

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StAR actively transports cholesterol into the mitochondrion, where cholesterol is converted to pregnenolone by P450 side- chain cleavage enzyme (CYP11A1). Loss of StAR- dependent cholesterol transport causes CLAH, OMIM #201710), leading to an impairment of all three steroidogenic pathways. Classic CLAH is associated with salt- wasting and adrenal failure manifesting within the first month of life, female external genitalia irrespective of karyotype, and hypergonadotropic hypogonadism in both sexes. Non- classic Lipoid CAH may manifest later in life with primary adrenal insufficiency and mild 46,XY DSD or normal male genital development. In some patients, hypocortisolism is the only clinical manifestation and non- classic CLAH might be mis diagnosed as familial glucocorticoid deficiency (Table 1).

Table1. Differential diagnosis of congenital adrenal hyperplasia— clinical, biochemical, and genetic characteristics

The StAR gene (GeneID: 6770, NC_ 000008.10) is localized on chromosome 8p11.23 and consists of 7 exons (Figure 1) encoding for a protein of 285 amino acids. The N- terminus of the protein contains a mitochondrial signal and the C- terminus is in volved in the interaction with cholesterol. Over 40 StAR mutations have been reported (HGMD, August 2018), nine of which are associated with non- classic CLAH. The majority of StAR- inactivating mutations are located in exons 5 to 7 encoding for the C- terminal protein. Recurrent mutations are detected in some populations. The p.Gln258X is found in over 80% of the CLAH- causing alleles in Korean and Japanese patients. The p.Arg182Leu and the c.201_ 202delCT mutations are the most common mutations in Palestinian patients and the p.Arg182His is most frequently found in patients of Saudi Arabian origin. In classic CLAH the genotype- phenotype correlation is good, whereas non- classic CLAH presents with phenotypic variability.

Fig1. Genomic organization of genes causing different forms of congenital adrenal hyperplasia. (1) Genes encoding steroidogenic Cytochrome P450 type II enzymes: (a) The 21- hydroxylase (CYP21A2) gene consists of 10 exons and it is typically amplified in two overlapping fragments. (b) The 17- hydroxylase (CYP17A1) gene consists of 8 exons and different strategies have been employed either amplifying the gene in five or in two fragments. (2) Genes encoding steroidogenic Cytochrome P450 type I enzymes: (c) The 11- hydroxylase (CYP11B1) gene consists of 9 exons and is usually amplified in three overlapping fragments, although non- overlapping strategies have been described. (d) The P450 side chain cleavage (CYP11A1) gene consists of 9 exons and it is usually amplified in small non- overlapping fragments, although different PCR strategies have been described. (e) The aldosterone synthase (CYP11B2) gene consists of 9 exons normally amplified in either two overlapping fragments or three non- overlapping fragments. (3) Genes encoding hydroxysteroid dehydrogenases: (f) The hydroxysteroid dehydrogenase type 2 (HSD3B2) gene has 4 exons; exon 1 and the 5- prime part of exon 2 are not translated. (4) Gene encoding the electron donor of steroidogenic cytochrome P450 type II: (g) The P450 oxidoreductase (POR) gene has 15 translated exons and an untranslated exon (1U). PCR amplification is performed in several small fragments. (5) Gene encoding for a cholesterol transporter: (h) The steroid acute regulatory protein (StAR) gene consists of 7 exons commonly amplified in five fragments.