Lipoid congenital adrenal hyperplasia history and symptoms
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
History and Symptoms
Problems caused to persons with lipoid CAH can be divided into:
- mineralocorticoid deficiency,
- glucocorticoid deficiency,
- sex steroid deficiency, and
- 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.