Lipoid congenital adrenal hyperplasia
Lipoid congenital adrenal hyperplasia | |
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Other names | Congenital lipoid adrenal hyperplasia due to StAR deficency[1] |
Lipoid congenital adrenal hyperplasia is inherited in an autosomal recessive manner |
Lipoid congenital adrenal hyperplasia is an
Presentation
Problems that emerge in persons with lipoid CAH can be divided into:[citation needed]
- 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.[citation needed]
Most come 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 ("Addisonian or adrenal crisis"). Renin but not aldosterone is elevated. Many infants born with this condition died before a method for diagnosis was recognized for proper treatment to begin. In some cases, the condition is more mild with signs and symptoms of mineralocorticoid and glucocorticoid deficiency appearing after months or even years (late onset).[citation needed]
Glucocorticoid deficiency
Insufficiency 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.[citation needed]
Sex steroid deficiency and gonadal damage
In development
Prenatal production of
Female patients
Genetic XX females with lipoid CAH are born with normal external and internal pelvic anatomy. They come to medical attention when they develop a salt-wasting adrenal crisis or other signs of progressive adrenal insufficiency.[citation needed]
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. In the case of lipoid CAH due to StAR deficiency, when rising
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. Cysts also form in the ovaries. Women with lipoid CAH have been infertile presumably due to anovulation.[citation needed]
Male patients
The genitalia of XY fetuses with lipoid CAH are severely undervirilized due to impairment of steroid hormone synthesis. The fetal testes make
In addition to the testes remaining inside, formation of the penis, also dependent on testosterone, is compromised. Hence, the external genitalia in most of infants resemble that of normal females (though the vagina is a short, blind pouch), or is slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such.[citation needed]
Late onset forms of the disease
Milder, late onset cases of lipoid CAH have been described that arise from less severe mutations that compromise but do not eliminate the ability of StAR to instigate steroid production.[2] In these cases, mineralocorticoid deficiency emerges up to several years after birth. Sex steroid production may be sufficient to allow for normal sexual development as well and even fertility.[citation needed]
These nonclassic forms of the disorder are sometimes diagnosed as
Genetics
This inherited disease is
Lipoid CAH is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone.
Pathophysiology
The deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of
ACTH stimulates growth of the adrenal cells and increases
Because P450scc and StAR are also essential for sex steroid synthesis in the
The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected gene in most cases is that for a transport protein (StAR) rather than a steroidogenic enzyme. Second, because the defect compromises all steroid synthesis. Thus, there are no problems due to excessive mineralocorticoids or androgens. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement (and in the absence of other intervention), gonadal function and fertility cannot be preserved.[citation needed]
Diagnosis
In terms of diagnosis of this condition, gene sequencing can be done.[7]
Management
Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting congenital adrenal hyperplasias: 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.[citation needed]
Female patients
XX females with lipoid CAH may need estrogen replacement at or after puberty. Active intervention has been used to preserve the possibility of fertility and conception in lipoid CAH females.[8] In a case report in 2009, a woman with late onset lipoid CAH due to StAR deficiency underwent hormone replacement therapy in combination with an assisted fertility technique, intracytoplasmic sperm injection.[9] This led to ovulation and with implantation of the in vitro fertilized egg, a successful birth.[citation needed]
Male patients
Most XY children are so undervirilized that they are raised as girls. The testes are uniformly nonfunctional and undescended; they are removed when the diagnosis is made due to the risk of cancer development in these tissues.[10]
Epidemiology
Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.[11]
See also
- Inborn errors of steroid metabolism
- Congenital adrenal hyperplasia
- Adrenal insufficiency
- Disorders of sexual development
- ambiguous genitalia
- Steroidogenic acute regulatory protein
- Cholesterol side-chain cleavage enzyme
- Cholesterol, sex hormone, and corticosteroid
References
- ^ "Congenital lipoid adrenal hyperplasia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 14 April 2019.
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