Lipoid congenital adrenal hyperplasia

Lipoid congenital adrenal hyperplasia is 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.

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. Lipoid CAH is one of the less common types of CAH due to deficiencies of other proteins and enzymes involved in cortisol synthesis.

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
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 CAH 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 CAH 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 a protein which transports cholesterol into the mitochondria. This steroidogenic acute regulatory protein (StAR) is coded by a gene on 8p11.2. Inheritance is autosomal recessive. The OMIM number is 20170 for the deficiency.

Deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of adrenocorticotropic hormone (ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency.

ACTH stimulates growth of the adrenal cells, and increases LDL receptors to amplify transport of cholesterol into the adrenal cells, where it accumulates because little is transferred into the mitochondria. The adrenals become markedly enlarged by the combination of ACTH-induced hyperplasia and accumulated lipid. Lipid accumulation is thought to damage the cells further (“second hit hypothesis”).

Because the StAR protein is also involved in cholesterol transport into testicular and ovarian cells for sex steroid synthesis, testicular production of testosterone and ovarian production of estrogen are also impaired. Lipid accumulation damages the Leydig cells of the testes more completely than the granulosa cells of the ovaries.

Lipoid CAH is quite rare in European and North American populations. Most cases have occurred in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal recessive inheritance, there has been an unexplained preponderance of genetic females in reported cases.

The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected enzyme (StAR) is a transport protein rather than a steroidogenic enzyme. Second, because the defect is so proximal, all steroid synthesis is compromised and there are no effects of excessive mineralocorticoids or androgens to be suppressed. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement, gonadal function and fertility cannot be preserved.

Clinical manifestations of lipoid CAH
Problems caused to persons with lipoid CAH can be divided into:
 * 1) mineralocorticoid deficiency,
 * 2) glucocorticoid deficiency,
 * 3) sex steroid deficiency, and
 * 4) damage to gonads caused by lipid accumulation.

Mineralocorticoid deficiency
Most infants born with lipoid CAH have had genitalia female enough that no disease was suspected at birth. Because the adrenal zona glomerulosa is undifferentiated and inactive before delivery, it is undamaged at birth and can make aldosterone for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe 21-hydroxylase-deficient CAH.

Most came to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe hyponatremia, hyperkalemia, and metabolic acidosis (a "salt-wasting crisis"). Renin but not aldosterone is elevated. Many infants born with this condition died before a diagnosis was recognized and treatment begun. In a few cases, signs and symptoms of mineralocorticoid and glucocorticoid deficiency have only developed after months or even years.

Glucocorticoid deficiency
Inefficiency of cortisol synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked hyperpigmentation even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause hypoglycemia, and contributes to the high mortality rate in infancy.

Sex steroid deficiency and gonadal damage
Impaired synthesis of both androgens and estrogens in adrenals and gonads produce different problems in XX and XY children. Even prenatal production of DHEA by the fetal adrenal glands is impaired, resulting in abnormally low maternal estriol levels by the middle of pregnancy.

Genetic XX females with lipoid CAH are born with normal external and internal pelvic anatomy. They come to medical attention after weeks, months, or even years when they develop a salt-wasting crisis or other signs of progressive adrenal insufficiency.

With glucocorticoid and mineralocorticoid replacement, these girls will reach the age of puberty. Because the ovaries are relatively inactive in fetal life and childhood, they sustain little damage from lipid accumulation during childhood. When rising gonadotropin levels initiate puberty, despite the inefficiency of sex steroid synthesis, the ovaries will usually make enough estradiol to produce breast development, and in some cases even menarche. Ovarian and adrenal androgen production is minimal and produces little pubic or other body hair.

However insufficient estradiol and progesterone are produced to induce maturation of an egg and ovulation. Although prepubertal ovaries are inactive enough that no lipid accumulates to cause damage, once they have begun to produce estrogen, lipid damage begins to accrue and the ability to produce estrogen, as well as ovulate, is slowly degraded. Women with lipoid CAH have been infertile due to this anovulation.

The genitalia of XY fetuses with lipoid CAH are severely undervirilized due to impairment of steroid hormone synthesis. The fetal testes make AMH, which prevents a uterus and inner vagina from forming, but lipid accumulation damages the testicular Leydig cells so that by birth the testes are usually still in the abdomen or inguinal canals, nonfunctional, unable to produce either testosterone or sperm even in response to hCG. The external genitalia in most of these infants look like normal female infants (though the vagina is a short, blind pouch), or slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such with no reports of later gender identity problems.

Because of the more complete Leydig cell damage the testes are nonfunctional and usually removed when the diagnosis is made. Even if they have not been removed, XY girls with lipoid CAH have no significant sex steroid production at puberty and no spontaneous pubertal changes (androgenic or estrogenic) will occur. Spermatogenesis and fertility cannot occur.

Management of lipoid CAH
Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting congenital adrenal hyperplasia: saline and fludrocortisone.

Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.

XX females with lipoid CAH may need estrogen replacement at or after puberty. To date, ovulation and pregnancy has not been reported even with early diagnosis and careful glucocorticoid replacement to suppress ACTH-induced lipid damage to the ovaries.

Nearly all XY children have been so undervirilized that they have been raised as girls. The testes have been uniformly nonfunctional and are removed to prevent long term neoplastic risk.