Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders characterized by impaired cortisol synthesis
CAH results from mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids or sex steroids from cholesterol by the adrenal glands.
One of the most common autosomal recessive disorders.
Its incidence varies geographically.
Congenital adrenal hyperplasia in its classic form is particularly common in Native Americans and Yupik Eskimos with an incidence of 1-2%.
Among American Caucasians, the incidence of the classic form is approximately 1/15,000.
It is potentially life-threatening in the severe form and may be asymptomatic or cause female infertility in its mild form.
Most cases of CAH involve excessive or deficient production of sex steroids.
CAH can alter development of primary or secondary sex characteristics in some affected infants, children or adults.
The most common type of CAH is 21-hydroxylate deficiency.
Symptoms of CAH:
Excessive urination of sodium,
Early, delayed, or absent puberty
Usual onset before birth
Glucocorticoids, mineralocorticoids, androgens, estrogens.
The clinical presentation of each form of CAH is depends to a large extent on the underlying enzyme defect, it precursor retention and deficient products.
Classical presentation is during infancy.
Non-classical forms appear in late childhood.
With classic CAH there are into two forms: salt-wasting and simple-virilizing.
The presentation varies with the degree of mineralocorticoid deficiency present.
Because all CAH patients lose salt to some degree presentations may overlap.
In 75% of cases of severe enzyme deficiency, insufficient aldosterone production leads to salt wasting, failure to thrive, and potentially fatal hypovolemia and shock.
Salt losing CAH is related to the increased risk of early neonatal morbidity and death.
CAH in newborn female is characterized by the abnormal development of the external genitalia, which has varying degrees of virilization.
Late onset congenital adrenal hyperplasia is also a mild or non-classic form, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic.
This non-classic form may appear in late childhood and may lead to accelerated growth, premature sexual maturation, acne and secondary polycystic ovary syndrome.
The non-classic form adult males, is suggested by balding and infertility.
The non-classic form is characterized by mild subclinical impairment of cortisol synthesis, yet the serum cortisol level is usually normal.
Symptoms of CAH vary with the form of CAH and the gender of the patient.
Findings of CAH can include:
Due to inadequate mineralocorticoids-
Vomiting due to salt-wasting, leading to dehydration
Due to excess androgens: virilization with elongated clitoris and phallic like structure.
Ambiguous genitalia, in some infants.
Early pubic hair and rapid growth in childhood.
Precocious puberty or failure of puberty to occur.
Excessive facial hair, virilization, and/or menstrual irregularity in adolescence.
Infertility due to anovulation.
Enlarged clitoris and shallow vagina.
Due to insufficient androgens and estrogens:
Undervirilization in males, which can result in apparently female external genitalia
In females, hypogonadism can cause sexual infantilism, abnormal pubertal development, infertility, and other reproductive system abnormalities
CAH is associated with a specific defective gene, the most common of which involves the gene for 21-hydroxylase.
This defective gene is present in 95% of cases, and is located on chromosome 6p21.3 as part of the HLA complex.
21-hydroxylase deficiency results from a mutation with two highly homologous near-copies in series consisting of an active gene (CYP21A2) and an inactive pseudogene (CYP21A1P).
About 5% of cases of CAH are due to defects in the gene encoding 11-hydroxylase and consequent 11-hydroxylase deficiency.
The degree of enzyme inefficiency produced by the specific alleles varies with each patient.
When there are severe degrees of enzyme inefficiency, it produces changes in the fetus and in prenatal or perinatal life.
Lesser degrees of enzyme inefficiency are associated with excessive or deficient sex hormone effects in childhood or adolescence.
Thebmildest forms of CAH interfere with ovulation and fertility in adults.
With classical CAH female infants with have ambiguous genitalia.
Ambiguous genitalia is due to exposure to high concentrations of androgens in utero.
As noted above, CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (44+XX).
Less severe CAH affected females may present with early pubarche.
Young women with CAH may present with symptoms of polycystic ovarian syndrome.
At birth males with classic CAH generally have no signs, but some may have hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone (MSH), and possible penile enlargement.
Age of diagnosis of males with CAH depends on the severity of aldosterone deficiency.
Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia, while those with non-salt-wasting disease present later with signs of virilization.
In classic 21-hydroxylase deficiency, laboratory studies will show:
Hypoglycemia due to hypocortisolism.
Hyponatremia due to hypoaldosteronism.
In 11-hydroxylase deficiency, 11-deoxycorticosterone is produced in excess retaining sodium at the expense of potassium.
Patients with 11-hydroxylase deficiency do not show salt wasting and instead have hypertension/water retention and sometimes hypokalemia.
Classic 21-hydroxylase deficiency typically causes 17?-hydroxyprogesterone blood levels to >242 nmol/L.
Salt-wasting patients tend to have higher 17?-hydroxyprogesterone levels than non-salt-wasting patients.
Cortisol, the adrenal steroid hormone is required for normal endocrine function.
Cortisol production begins in the second month of fetal life.
Poor cortisol production is a hallmark of most forms of CAH.
Inefficient cortisol production results in rising levels of ACTH.
This increased ACTH stimulation induces hyperplasia and overactivity of the steroid-producing cells of the adrenal cortex.
The defects causing adrenal hyperplasia are congenital.
Depending upon which enzyme is unavailable, there is a reduced production of androgens, which in turn can lead to increased production of other molecules, due to a buildup of precursors.
Cortisol deficiency in CAH is usually partial.
Cortisol deficiency in CAH is usually not the most serious problem for an affected person.
Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol.
The abnormal production of these three classes of hormones produce the most important problems for people with CAH., as enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH.
CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same clinical challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.
Currently, every child born is screened for 21-hydroxylase CAH at birth.
The test is for elevated levels of 17-hydroxyprogesterone enables early detection of CAH.
Newborns detected early enough can be placed on medication and live a relatively normal life.
The screening process, however, is characterized by a high false positive rate, with 200 unaffected newborns requiring clinical and laboratory follow-up for every true case of CAH.
Treatment: to replenish insufficient adrenal hormones and suppress excess precursors.
Treatment of all forms of CAH may include: supplying glucocorticoids to reduce hyperplasia and overproduction of androgens or mineralocorticoids, providing replacement mineralocorticoid and extra salt if the person is deficient, providing replacement testosterone or estrogens at puberty if the person is deficient, other treatments optimize growth by delaying puberty or delaying bone maturation.
If CAH is caused by the deficiency of the 21-hydroxylase enzyme, then treatment aims to normalize levels of main substrate of the enzyme – 17-Hydroxyprogesterone.