Lipoid Congenital Adrenal Hyperplasia

A number sign (#) is used with this entry because of evidence that lipoid congenital adrenal hyperplasia (LCAH) is caused by homozygous or compound heterozygous mutation in the gene encoding steroidogenic acute regulatory protein (STAR; 600617) on chromosome 8p11.

Description

Lipoid congenital adrenal hyperplasia, the most severe disorder of steroid hormone biosynthesis, is caused by a defect in the conversion of cholesterol to pregnenolone, the first step in adrenal and gonadal steroidogenesis. All affected individuals are phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy (summary by Lin et al., 1991 and Bose et al., 1996).

Clinical Features

Affected individuals may have a severe deficiency of adrenal or gonadal steroids. All affected individuals are phenotypic females irrespective of gonadal sex, and frequently die in infancy if mineralocorticoid and glucocorticoid replacement are not instituted. Only 11 of the first 32 patients described survived infancy (Hauffa et al., 1985), although some treated patients have survived to adulthood (Hauffa et al., 1985; Kirkland et al., 1973).

In the series of 15 patients reported by Bose et al. (1996), 3 were XX females but all had phenotypically normal female genitalia at birth. All patients had normal birth weight and gestational ages. Their plasma corticotropin and renin values were high; serum cortisol and testosterone values varied substantially but responded poorly to corticotropin and chorionic gonadotropin. There were substantial variations in the degree of hyponatremia and hyperkalemia and in the age of onset of symptoms, with 1 child surviving for 6 months without hormonal replacement. At least 5 neonates had hyperglycemia, and at least 5 had respiratory disorders. Bose et al. (1996) noted that both of these features could be caused by glucocorticoid deficiency. At least 12 patients had hyperpigmentation at birth, indicating intrauterine glucocorticoid deficiency, which caused excessive corticotropin secretion.

Fujieda et al. (1997) reported clinical, endocrinologic, and molecular analyses of 2 unrelated Japanese kindreds with 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were identified as having lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9-alpha-fludrocortisone. Spontaneous thelarche (breast development) occurred in association with increased serum estradiol levels at the age of 10 and 11 years, respectively. Pubic hair developed at the age of 12 years in one subject, and menarche occurred at the age of 12 years in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. These findings demonstrated that ovarian steroidogenesis can be spared to some extent through puberty when the STAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis that characterize lipoid CAH.

Pathogenesis

Bose et al. (1996) concluded that the congenital lipoid adrenal hyperplasia phenotype is the result of 2 separate events: the primary defect is genetic loss of steroidogenesis that is dependent on STAR protein; there is a subsequent loss of steroidogenesis that is independent of STAR due to cellular damage from accumulated cholesterol esters. Deficient fetal testicular steroidogenesis in patients with a 46,XY karyotype results in phenotypically normal female genitalia. The adrenal cortex becomes engorged with cholesterol and cholesterol esters; consequent deficient adrenal steroidogenesis leads to salt wasting, hyponatremia, hypovolemia, hyperkalemia, acidosis, and death in infancy, although patients can survive to adulthood with appropriate mineralocorticoid- and glucocorticoid-replacement therapy.

Inheritance

The first clue to the genetic basis of this syndrome was the observation of consanguinity in the parents of cases (Prader and Siebenmann, 1957).

Population Genetics

Lipoid congenital adrenal hyperplasia is common among the Japanese, Korean, and Palestinian Arab populations, but is rare elsewhere (Bose et al., 2000).

Molecular Genetics

Because studies had shown that LCAH was caused by an inability to convert cholesterol to pregnenolone, the disorder was initially mislabeled '20,22 desmolase deficiency,' and was thought to involve the cholesterol side-chain cleavage enzyme P450scc (CYP11A1; 118485); see HISTORY. In a newborn Korean infant with XY karyotype and characteristics of lipoid congenital adrenal hyperplasia and in a Japanese patient previously described by Matteson et al. (1986), Lin et al. (1991) found by Southern blotting patterns that the CYP11A1 gene was grossly intact. Furthermore, sequencing of the gene demonstrated no abnormalities in either the gene or in gonadal RNA. Northern blots of gonadal RNA from the Korean patient contained normal-sized mRNAs for P450scc and also for adrenodoxin reductase, adrenodoxin, sterol carrier protein-2, endozepine, and GRP-78 (the precursor of steroidogenesis activator peptide). Thus, the lesion responsible for lipoid CAH did not reside in the P450SCC gene in these patients.

In 3 unrelated patients with LCAH, 2 of whom were previously studied by Lin et al. (1991), Lin et al. (1995) demonstrated homozygous mutations in the STAR gene (600617.0002; 600617.0014).

Tee et al. (1995) described an unusual intronic mutation in the STAR gene (600617.0001) that resulted in an mRNA splicing error and caused lipoid CAH. All patients with this disorder studied up to the time of report had mutations in STAR, suggesting to the authors that they are the sole cause of this disorder.

Bose et al. (1996) sequenced the gene for STAR in 15 patients with this disorder from 10 countries. Among 14 patients, 15 different mutations in the STAR gene were found: gln258 to ter (Q258X; 600617.0002) was found in 80% of affected alleles from Japanese and Korean patients, whereas arg182 to leu (R182L; 600617.0003) was found in 78% of affected alleles from Palestinian patients. The investigators found that 13 of the 15 identified mutations were in exons 5, 6, or 7.

Fujieda et al. (1997) found homozygosity for the Q258X mutation (600617.0002) in exon 7 in one patient; a second patient was a genetic compound for the Q258X mutation and a frameshift mutation in the other allele that rendered the STAR protein nonfunctional. Their clinical findings demonstrated that ovarian steroidogenesis can be spared to some extent through puberty when the STAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis that characterize lipoid CAH.

Baker et al. (2006) studied the gene encoding STAR in 3 children from 2 families who presented with primary adrenal insufficiency at 2 to 4 years of age; the males had normal genital development. DNA sequencing identified homozygous STAR mutations val187 to met (600617.0011) and arg188 to cys (600617.0012) in these 2 families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wildtype activity. The authors referred to these patients as cases of nonclassic lipoid congenital adrenal hyperplasia, and stated that they represented a new cause of nonautoimmune Addison disease (primary adrenal failure).

History

In steroidogenic tissues such as adrenal cortex, testis, ovary, and placenta, the initial and rate-limiting step in the pathway leading from cholesterol to steroid hormones is the cleavage of the side chain of cholesterol to yield pregnenolone. This reaction, known as cholesterol side-chain cleavage, is catalyzed by a specific form of cytochrome P-450 called P450scc or P45011A (118485), which is localized to the inner mitochondrial membrane. The conversion of cholesterol to pregnenolone entails 3 steps, all mediated by P450scc (EC 1.14.15.67). The 3 steps are: 20-hydroxylation, 22-hydroxylation, and cleavage of the C20-C22 bond to produce pregnenolone and isocaproic acid. Degenhart et al. (1972) had the opportunity to study postmortem adrenal gland from a patient with congenital lipoid adrenal hyperplasia. They proposed deficiency of 20-alpha-cholesterol hydroxylase. The earliest step in the conversion of cholesterol to hormonal steroids is hydroxylation at carbon 20, with subsequent cleavage of the 20-22 side chain (a desmolase reaction) to form pregnenolone. This process is essential to the formation of all adrenal and gonadal steroids.