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Lipoid congenital adrenal hyperplasia

Lipoid congenital adrenal hyperplasia refers to an uncommon form of CAH resulting from defects in the earliest stages of adrenal cortisol synthesis: the transport of cholesterol into the mitochondria of the cells of the adrenal cortex and the conversion to pregnenolone. Lipoid CAH causes mineralocorticoid deficiency in all affected infants and children. XY infants (genetic males) are severely undervirilized and are usually assigned and raised as girls. The adrenals are large and filled with lipid globules derived from cholesterol. more...

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What is CAH?

Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from defects in steps of the synthesis of cortisol from cholesterol by the adrenal glands. All of the forms of CAH involve excessive or defective production of sex steroids and can pervert or impair development of primary or secondary sex characteristics in affected infants, children, and adults. Many also involve excessive or defective production of mineralocorticoids, which can cause hypertension or salt wasting.

The most common type of CAH is due to deficiency of 21-hydroxylase and is covered in detail in the main article on congenital adrenal hyperplasia. Lipoid CAH is one of the less common types of CAH due to deficiencies of other proteins and enzymes involved in cortisol synthesis. Other uncommon types are described in individual articles (links below).

Lipoid congenital adrenal hyperplasia

Lipoid congenital adrenal hyperplasia results from defects in the steps from cholesterol to pregnenolone. The adrenals are large and filled with lipid globules derived from cholesterol. Life-threatening mineralocorticoid and glucocorticoid deficiency becomes apparent in infancy or early childhood. Sex steroid production is greatly impaired. XY infants (genetic males) are severely undervirilized so that the external genitalia at birth are female (normal or slightly virilized). XX infants have normal female anatomy and if their mineralocorticoid and glucocorticoid deficiencies are treated will often undergo spontaneous puberty. Lipid storage damages the adrenals and eventually the gonads as well, so that all persons with this condition have so far been infertile.

Pathophysiology and genetics of lipoid CAH

Our understanding of the molecular basis for this disease has been advanced in the last decade by better understanding of adrenal steroidogenesis as well as genetic studies of affected patients. It used to be assumed that lipoid adrenal hyperplasia resulted from a defect of the enzymes that converted cholesterol to pregnenolone. The conversion reactions are mediated by a single enzyme, formerly referred to as 20,22-desmolase, but now identified as P450scc (side chain cleavage enzyme). However, as of 2003, only a single case of lipoid adrenal hyperplasia due to a mutation and defect of P450scc has been identified.

All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the gene for the enzyme which transports cholesterol into the mitochondria. This enzyme, steroidogenic acute regulatory protein, or StAR, is coded by a gene on 8p11.2. Inheritance is autosomal recessive. OMIM number is 20170 for the deficiency.


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Medical Mystery is Solved with Discovery of Master Control Switch for Steroid Hormone Production
From Business Wire, 3/24/95

SAN FRANCISCO--(BUSINESS WIRE)--March 24, 1995--A UC San Francisco endocrinologist's ten-year search for the cause of a devastating genetic disorder has succeeded with the discovery of a protein every human needs to make a raft of vitally important hormones known as steroids.

The researcher found that a defective version of a protein named "StAR" plays the critical part in a severe hereditary endocrine disease called congenital lipoid adrenal hyperplasia (lipoid CAH), in which no steroid hormones are made.

Steroids normally produced by the gonads and by the adrenal glands that sit atop the kidneys are important in controlling sexual development and function, stress responses and blood pressure.

Until now, lipoid CAH has been a medical mystery. It often eludes diagnosis until death. But when the disease is diagnosed, it can be treated successfully through vigilant, lifelong administration of steroid drugs.

The disorder now can be easily diagnosed through genetic testing of the fetus or newborn, thanks to the work of Walter L. Miller, MD, a professor of pediatrics at UCSF who specializes in endocrine research, and a group of colleagues from across the country. Miller stresses the importance of scientific collaboration in solving the mystery of lipoid CAH.

The team includes Douglas M. Stocco, PhD, and Barbara J. Clark, PhD, of Texas Tech University, who identified the protein; Jerome F. Strauss III, MD, PhD, and Teruo Sugawara, MD, PhD, of the University of Pennsylvania, who located and cloned the human gene that encodes the protein; and Dong Lin, MD, PhD, assistant professor of pediatrics at UCSF, who along with Miller, identified defective forms of the gene that encodes StAR in three patients with lipoid CAH. As a result of the work, prospective parents who might be carriers of a defective copy of StAR also can be identified.

The experiments with StAR (steroidogenic acute regulatory protein), a master switch that permits steroid production by the gonads and the adrenal glands, are reported in this week's issue of Science (March 24). Lin is the first author.

"In three unrelated patients with the disorder, StAR was mutated and nonfunctional," Miller says. "This is genetic evidence that the protein is indispensable for normal steroid hormone production by the adrenal glands and the gonads."

Lipoid CAH is uncommon, but it occurs often enough in Japan that public health officials there are debating the merits of routine blood screening of newborns to detect the disease, according to Miller. In children who inherit from each parent a gene that incorrectly codes for StAR, the adrenal glands and the ovaries or testes fail to make any steroid hormones. Strangely, all infants born with lipoid CAH are girls, regardless of the combination of sex chromosomes inherited. This is a consequence of the fact that all who are affected by the disorder fail to make any testosterone at any time during development.

Girls with lipoid CAH are born with a vagina and clitoris. They may have ovaries and a uterus, or else internalized testes, depending on their sex chromosomes. They undergo normal breast development with estrogen treatment. Those with ovaries and a uterus do not ovulate, but can menstruate when given hormonal treatments similar in composition to birth control pills.

However, the lack of sex steroids is not life-threatening to the survival of affected newborns. More important is the absence of two other classes of steroids. One class consists of hormones called glucocorticoids. These control how the sugar glucose is used to fuel cellular metabolism. Glucocorticoids also control responses to stress.

The major glucocorticoid is the hormone cortisol, which normally is made rapidly in response to a hormonal signal, called ACTH, secreted into the bloodstream by the brain's pituitary gland. This rapid cortisol production is important in the body's emergency "fight-or-flight" response.

Mineralocorticoids make up another class of steroid hormones that are absent in lipoid CAH patients. These control how various salts move within the body. This loss of control over salt regulation results in salt loss, dehydration, low blood pressure and an associated failure to deliver adequate amount of oxygen to vital organs. Ultimately this loss of control can lead to shock, heart stoppage and death. The cascade is made worse by the inability of the glucocorticoid system to respond to the stress caused by the absence of mineralocorticoids.

Over the past decade the adrenal enzymes that convert cholesterol into the three major classes of steroids have been identified and studied by Miller and others, but StAR is not an enzyme in any of these pathways.

Instead, it appears that StAR is needed to get cholesterol into specialized structures called mitochondria, located within cells. Once in the mitochondria of adrenal and gonadal cells, cholesterol can be converted by enzymes into a "pre-hormone," pregnenolone, that in turn is converted by additional cellular enzymes into a whole range of steroid hormones.

Miller had previously determined that steroid production is normal in the placentas of newborns with lipoid CAH.

For many years Stocco had been trying to track down a protein that regulates steroid production. It was known that unidentified proteins in steroid-hormone-producing cells were produced rapidly in response to ACTH stimulation, and that the appearance of these proteins was associated with steroid production. Stucco and Clark eventually were able to purify one such protein from mouse cells, which they named StAR. They then located and cloned its gene.

Strauss and Sugawara used molecular markers derived from Stocco's mouse gene to locate and clone the human StAR gene. They found that StAR is normally not made in placental cells, but that it is made in adrenal and gonadal cells. This result suggested that a defective StAR gene might prevent the adrenal glands and gonads from making working StAR protein, and that this might be the cause of lipoid CAH. Miller and Lin then found StAR gene defects in three lipoid CAH patients.

The Science article describes a Korean and a Japanese patient with identical mutations in their defective StAR genes, suggesting a similar origin for lipoid CAH in those populations, according to Miller. A third patient, a Caucasian, had a different gene mutation.


Jeffrey Norris, 415/476-2557

COPYRIGHT 1995 Business Wire
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