Konjenital Adrenal Hiperplazi Nedir?
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasias (CAH) are a group of heritable disorders associated with an inability or deficiency in the ability to produce cortisol. In affected individuals, the disease begins early in gestation and leads to disease that is manifest at birth.
Without cortisol, there is a failure of negative feedback and excessive secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the anterior pituitary.
Continued secretion of ACTH causes unremitting stimulation of the adrenal cortex, leading to hyperplasia (an increase in the number of cells in that tissue).
In the most common cases, adrenal hyperplasia also involves a deficiency in aldosterone, which results in mild to severe loss of body sodium. In some individuals, the disorder also involves overproduction of adrenal androgens, which, in affected females, often results prenatal virilization with an ambiguous or male- external genital tract at birth.
Mutations in at least five different genes can result in adrenal hyperplasia, all of which are transmitted as autosomal recessive traits.
CAH Due to 21-Hydroxylase Deficiency
Greater than 90% of the cases of CAH are the result of deficiency in the enzyme steroid 21-hydroxylase. Absolute or partial deficiency in this enzyme leads to two problems:
- Deficiency in production of cortisol and aldosterone: Aldosterone is necessary for normal retention of sodium by the kidney, and in its absense, a “salt wasting” disorder occurs.
- Shunting of steroid precursors to form androgens: In the absence of 21-hydroxylase, concentrations of 17-hydroxyprogesterone increase substantially and is converted to androgens including testosterone and dihydrotestosterone. The resulting secretion of relative large quantities of androgens early in life leads to virilization of female fetuses and abnormal development in male children.
Incidence and Clinical Presentation
CAH due to 21-hydroxylase deficiency is seen in roughly 1 of every 15,000 live births worldwide; it is a relatively common disorder in humans. Clinically, it is seen in three primary manifestations:
- Simple virilizing form: Excessive prenatal production of androgens in affected females results in masculinization of the reproductive tract to a point that the sex of the newborn is not clear (“ambiguous genitalia”) or appears male-. Affected males are usually normal at birth. In both sexes, linear growth in childhood is accelerated, but the epiphyses fuse early, leading to short stature. The simple virilizing form of CAH is seen in approximately 25% of those with 21-hydroxylase deficiency.
- Salt-wasting form: Roughly 75% patients are unable to synthesize adequate amounts of aldosterone, which is essential for sodium homeostasis. Such individuals lose large amounts of sodium in urine, which leads to potentially fatal electrolyte and water imbalance. Individuals with severe deficiency usually present with “adrenal crisis” between 1 and 4 weeks of age; signs are often non-specific, but can include poor appetite, vomiting and failure to grow. Replacement therapy is mandatory in such patients.
- Non-classical form: This form of the disease is mild and usually manifest as some type of androgen excess later in life. Aldosterone deficiency is not usually observed.
The 21-hydroxylase enzyme is encoded by the CYP21 gene. More than 50 different mutations of CYP21 have been identified, of which about 15 account for a large majority of 21-hydroxylase cases.
Most mutations appear to be the result of a recombination between CYP21 and a pseudogene (CYP21P).
One consequence of this multitude of mutations is that there is considerable variability in the clinical presentation of disease, ranging from severe salt-wasting or virilizing disease to milder syndromes. This disorder is seen as a simple autosomal recessive trait.
Diagnosis and Prenatal ScreeningMost commonly, 21-hydroxylase deficiency is first suspected in a newborn infant with “ambiguous genitalia”.
Finding elevated blood levels of 17-hydroxyprogesterone, in conjuction with ultrasound examination of the abdomen and genital tract usually leads to a rapid diagnosis.
Disorders that must be differentiated in such cases include true hermaphorditism, pseudohermaphroditism and certain types of sex chromosome abnormalities, none of which should have high concentrations of 17-hydroxyprogesterone.
All patients with CAH, regardless of form, are treated with glucocorticoid replacment therapy. This not only alleviates glucocorticoid (i.e.
cortisol) deficiency, but more importantly, provides negative feedback to suppress ACTH secretion and prevent continued adrenal stimulation.
As a result, excessive 17-hydroxyprogesterone is not available as a substrate for excessive androgen production.
Patients with the salt-wasting form of deficiency must also receive mineralocorticoid therapy to normalize the abnormalities in sodium balance associated with aldosterone deficiency.
Prenatal treatment of the mother with glucocorticoids can prevent or reduce that the virilizing effects of fetal 21-hydroxylase deficiency. This procedure has been used in cases where couples have previously had a child with virilizing CAH.In such cases, it is known that both parents are carriers, and since only female children require prenatal treatment, the probability that the current fetus is affected is 1 in 8. Treatment of the mother with glucocorticoids must begin at 6 to 7 weeks of gestation, at which time it is almost never known whether the fetus is affected.
Hence, in 7 of 8 cases, the fetus does not actually require therapy. The long term effect and safety of this procedure is poorly defined.
A number of surigical procedures have been developed to correct the genital abnormalities of girls with the virilizing form of CAH. These procedures are complicated by concerns about when the surgery should be performed, gender identity of the patient and other factors.
CAH Due to Other Mutations
Mutations in four genes other than CYP21 are recognized to cause forms of CAH. Three of these induce a deficiency in enzymes involved in steroidogenesis. The fourth involves the steroid acute-regulatory protein (StAR), which is promotes transport of cholesterol into mitochondria.
|11-β-hydroxylase||~1 in 100,000 livebirths||Females virilized; salt-wasting is rare|
|17-α-hydroxylase||rare||Males virilized; females fail to achieve puberty. Salt-wasting not observed.|
|3-β-hydroxysteroid dehydrogenase||rare||Males virilized; female virilization mild. Salt-wasting may be seen.|
|aldosterone synthase||rare||Cortisol concentrations normal and virilization not seen. Salt-wasting occurs.|
|StAR||rare||Males virilized; females fail to achieve puberty. Salt-wasting occurs.|
References and Reviews
- Lee H: CYP21 mutations and congenital adrenal hyperplasia. Clin Genetics 59:293-301, 2001.
- Meyer-Bahlburg HF: Gender and sexuality in classic congenital adrenal hyperplasia. Endocrin Metab Clinics North Amer 30:155-171, 2001.
- Ritzen EM: Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Seminars Neonatology 6:357-362, 2001.
- Spiser PW, White PC: Congenital adrenal hyperplasia. New Eng J Med 349:776,788, 2003.
- Therrell BL: Newborn screening for congenital adrenal hyperplasia. Endocrin Metab Clinics North Amer 30:15-30, 2001.
- White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21:245-291, 2000.
Advanced and Supplemental Topics
Send comments to Richard.Bowen@colostate.edu
Congenital Adrenal Hyperplasias, CAH
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The congenital adrenal hyperplasias (CAH) are a group of inherited disorders that result from loss-of-function mutations in one of several genes involved in adrenal steroid hormone synthesis.
In the virilizing forms of CAH the mutations result in impairment of cortisol production and the consequent accumulation of steroid intermediates proximal to the defective enzyme.
In the virilizing forms of CAH there is increased ACTH secretion which leads to elevated synthesis of adrenal androgens. In addition, there is adrenal cortical hyperplasia, the symptom that imparts the name to these disorders. All forms of CAH are inherited in an autosomal recessive manner.
There are two common and at least three rare forms of virilizing CAH. The common forms are caused by defects in either CYP21A2 (21-hydroxylase, also identified as just CYP21 or CYP21B) or CYP11B1 (11β-hydroxylase).
The majority of CAH cases (90-95%) are the result of defects in CYP21A2 with a frequency of between 1 in 5,000 and 1 in 10,000.
Three rare forms of virilizing CAH result from either defects in 3β-hydroxysteroid dehydrogenase (HSD3B2), placental aromatase (CYP19A1) or P450-oxidoreductase (POR).
The typical signs of virilizing CAH are reflective of the androgen excess as well as the mineralocorticoid and glucocorticoid deficiencies. In general, the degree to which a given mutation results in reduction of enzyme activity is correlated to the level of glucocorticoid and mineralocorticoid deficiency.
An additional CAH is caused by mutations that affect either the 17β-hydroxylase, 17,20-lyase or both activities encoded in the CYP17A1 gene. Un the virilizing forms of CAH, in individuals harboring CYP17A1 mutations that result in severe loss of enzyme activity there is absent sex steroid hormone production accompanied by hypertension resulting from mineralocorticoid excess.
Clinical Features of the CAHs
CYP21A2 deficiency: CAH resulting from deficiencies in the CYP21A2 gene represent the most commonly occurring forms (>95%) of the disease.
The majority of the mutations in CYP21A2 that result in CAH have been identified and the severity of the disorder can be correlated to specific mutations and the consequent effect of the mutation on enzyme activity.
Deficiencies in CYP21A2 result in decreased secretion and plasma concentration of cortisol. The reduced levels of cortisol result in a reduction in the negative feedback exerted by this hormone on the hypothalamic-pituitary axis.
The reduced negative feedback leads to increased secretion of corticotropin releasing hormone (CRH) and ACTH. The resultant high plasma concentrations of ACTH are responsible for the adrenocortical hyperplasia characteristic of this disorder.CAH resulting from CYP21A2 deficiencies is divided into three distinct clinical forms. The most severe enzyme impairment mutations result in the salt-losing form. Females with this form of the disease present at birth due to ambiguity in the external genitalia.
Males with the salt-losing form present with acute adrenal crisis shortly after birth or in early infancy.
Females who present with no acute adrenal crisis and only mild masculinization of the external genitalia and males who present with virilism early in life are considered be be suffering from the simple virilizing form of CAH.
The final clinical form of CAH manifests only in females at puberty or shortly thereafter with symptoms of mild excess androgen development resulting in hirsutism, amenorrhea, and infertility. This form of the disorder is referred to as the attenuated form or the late onset or nonclassic form.
The 21-hydroxylase gene (CYP21A2, CYP21, CYP21B) is located within the class III region of the major histocompatibility complex (MHC) on chromosome 6. There are in fact, two CYP21 genes within this MHC locus but one of the two is a pseudogene and is identified as CYP21P.
Older nomenclature identifies the CYP21P gene as the 21-hydroxylase A gene (or CYP21A1) and CYP21A2 as the 21-hydroxylase B gene. All 21-hydroxylase activity is synthesized from the mRNA encoded by the CYP21A2 gene. The CYP21A2 gene is located on chromosome 6p21.3 and is composed of 10 exons that generate two alternatively spliced mRNAs.
The encoded proteins from these two mRNAs are identified as steroid 21-hydroxylase isoform a (495 amino acids) and steroid 21-hydroxylase isoform b (465 amino acids).
Salt-losing CYP21A2 deficiency: In the salt-losing form of this disorder the degree of loss of enzyme activity is severe to complete. As a result of the level of enzyme deficiency the synthesis of cortisol is negligible.
Because CYP21A2 is also needed for the synthesis of aldosterone, which is a major hormone involved in Na+ retention by the kidney, there is excessive salt loss leading to hyponatremic dehydration which can be fatal if not treated.Although there is some aldosterone made, the level of salt loss exceeds the ability of the adrenal cortex to make sufficient aldosterone to compensate. The net result is an acute adrenal crisis. The near complete, or complete, loss in cortisol production results in loss of the normal cortisol-mediated feed-back inhibition of the hypothalamic-pituitary (CRH-ACTH) axis.
The excess ACTH release from the pituitary leads to maximal adrenal androgen secretion with the result being masculinization of the female genitalia. The first sign of CAH due to CYP21A2 deficiency is, in fact, the ambiguous female genitalia in neonates. The masculinization can be so extreme as to result in the fusion of the labia and the formation of a penile urethra.
Diagnosis of the salt-losing form of this disorder is made in females born with masculinized genitalia, who are of normal 46,XX karyotype, with marked elevation in plasma 17α-hydroxyprogesterone and androstenedione, as well as serum chemistry showing hyponatremia, hypochloremia and hyperkalemic acidosis.
Simple virilizing CYP21A2 deficiency: In the simple virilizing form of the disorder the deficiency in CYP21A2 is not complete or as severe as in the salt-losing form. As a result the adrenal cortex can compensate for salt loss with increased aldosterone synthesis and release.
In addition, although there is increased ACTH release there is near normal plasma cortisol levels and thus, there is no glucocorticoid deficit.
However, as in the salt-losing form the CRH-ACTH axis is hyperactive leading to excessive adrenal androgen synthesis with consequent masculinization of the female genitalia.
Attenuated CYP21A2 deficierncy: As the name of this form of disease implies, patients with the attenuated form exhibit only mild reductions in CYP21A2 activity. Symptoms associated with this form of the disorder manifest in females at puberty.
There are no signs of masculinization of the genitalia in females with this form of the disease.
Although females have relatively normal breast development, the androgen excess results in excessive body hair (hirsutism), amenorrhea and the development of small ovarian cysts.
Gene Reviews page on CYP21A2-deficient CAH
CYP11B1 deficiency: CAH due to deficiencies in 11β-hydroxylase (CYP11B1), although rare, are the second most commonly occurring forms of these disorders being found in approximately 5% of CAH patients. CYP11B1 deficiency was originally identified as a hypertensive form of CAH.
Deficiency of CYP11B1 activity in the zona fasciculata results in reductions in cortisol and corticosterone synthesis. In addition, the loss of negative feedback on the hypothalamic-pituitary axis leads to increased ACTH release with the consequent increase in production of deoxycorticosterone (DOC; 11-deoxycorticosterone), 11-deoxycortisol, and 18-hydroxy DOC.The hypertension seen in this form of CAH is due to the increased secretion of DOC which is a weak mineralocorticoid activating the aldosterone receptor in the kidney (mineralocorticoid receptor) resulting dysregulation in the renin-angiotensin-aldosterone system (RAAS).
Because there is hypersecretion of ACTH and a block in the normal pathway to corticosteroid synthesis there is an androgen excess similar to that seen in the CYP21A2 deficiency forms of CAH. As a result, females exhibit masculinized genitalia.
The CYP11B1 gene is located on chromosome 8q21 spanning 6.5kbp and composed of 11 exons that generate two alternatively spliced mRNAs encoding isoform 1 (503 amino acids) ans isoform 2 (437 amino acids). Both isoforms encoded by the CYP11B1 gene include a 24 amino acid mitochondrial localization signal.
HSD3B2 deficiency: CAH due to deficiencies in 3β-hydroxysteroid dehydrogenase represent less than 1% of all cases. When the deficiency is severe there is a near total absence of adrenal steroids.
Thus there are deficiencies in the glucocorticoids, mineralocorticoids, as well as adrenal androgens. The impaired corticosteroid synthesis results in symptoms of adrenal insufficiency that can be fatal if not treated during the neonatal period.
Several steroid precursors accumulate including pregneneolone and DHEA as well as their hydroxylated derivatives. Females with this disorder will present with slight fusion of the labia and an enlarged clitoris, while males present with ambiguous genitalia.
Correct diagnosis of this disorder can be made by measurement of the levels of DHEA, 17α-hydroxypregnenolone and 16α-hydroxy-DHEA in the urine and serum.
The HSD3B2 gene is located on chromosome 1p13.1 and is composed of 5 exons that generate two alternatively spliced mRNAs, both of which encode the same 372 amino acid protein.
POR deficiency: Cytochrome P450 oxidoreductase (POR) is a flavoprotein that donates electrons to all microsomal P450 enzymes. In the context of adrenal streroidogenesis, POR functions as the electron donor for CYP17A1, CYP21A2, and CYP19A1. Deficiencies in POR result in ambiguous genitalia in both males and females.
Some of the skeletal malformations resulting from POR deficiency resemble Antley-Bixler syndrome (ABS), however ABS is not associated with disordered steroidogenesis. These skeletal malformations include midface hypoplasia, low set ears, craniosynostosis (premature fusion of the cranial sutures), choanal atresia (blockage in the back of the nasal passage), and fusion of the arm bones.
CAH resulting from POR deficiencies are rare.The POR gene is located on chromosome 7q11.2 and is composed of 16 exons that encode a 680 amino acid protein.
Placental aromatase (CYP19A1) deficiency: The aromatase gene (also called estrogen synthetase) is expressed in ovaries, placenta, and extragonadal tissues such as adipose tissue, liver, brain, muscle, and hair follicles.
The activity of the enzyme is to convert androgens to estrogens. During fetal development the fetal adrenal glands secrete DHEA-S as the substrate for placental estrogen production. The loss of CYP19A1 activity results in decreased placental estrogen production and increased androgen precursors.
Female infants may have masculinized external genitalia.
The CYP19A1 gene is located on chromosome 15q21.1 spanning 70kbp and composed of 13 exons that generate two alternatively spliced mRNAs, both of which encode the same 503 amino acid enzyme.
CYP17A1 deficiency: The CYP17A1 enzyme catalyzes both the 17α-hydroxylase and 17,20-lyase (side-chain removal) reactions of adrenal steroidogenesis.
Similar to each of the above described CAH, the underlying clinical manifestations of CYP17A1 deficiency are due to the inability to produce normal levels of glucocorticoids with the consequences being a loss of the feedback inhibition of the hypothalamic-pituitary axis resulting in elevated ACTH secretion. However, symptoms in these patients are less severe than in other forms of CAH.
Patients with 17α-hydroxylase deficiency do not make cortisol but do produce large amounts of corticosterone. Corticosterone does bind the glucocorticoid receptor but with an affinity 1/100th that of cortisol. Deoxycorticosterone (DOC), which serves as the precursor to corticosterone, exhibits significant mineralocorticoid activity.
This fact explains the hypertension exhibited in 17α-hydroxylase deficient patients. A deficiency in the 17,20-lyase activity of CYP17A1 leads to loss of C-18 and C-19 steroids from C-21 precursors leading to impaired production of androgens and estrogens. Affected males have defective genital development in utero and present with ambiguous external genitalia at birth.
Development of female genitalia in utero does not require endogenous sex steroid production thus, affected females present at birth with normal external genitalia. However, female patients will present at puberty with infantile breasts, primary amenorrhea, absent or scant axillary and pubic hair, and hypogonadism.
The CYP17A1 gene is located on chromosome 10q24.3 and is composed of 8 exons encoding a 508 amino acid enzyme. Deficiency in CYP17A1 is extremely rare with more than 90% of reported cases having deficiency in the both the 17α-hydroxylase and 17,20-lyase activities or just 17α-hydroxylase. The remainder of reported cases have deficiency in only the 17,20-lyase activity.
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Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by a deficiency in the hormones cortisol and aldosterone and an over-production of the hormone androgen. CAH is present at birth and affects the sexual development of the child.
Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency in which 21-hydroxylase, the enzyme that produces two important adrenal steroid hormones, cortisol and aldosterone, is deficient. Because cortisol production is impeded, the adrenal gland over-produces androgens (male steroid hormones). CAH affects both females and males.
Females with CAH are born with an enlarged clitoris and normal internal reproductive tract structures. Males have normal genitals at birth. CAH causes abnormal growth for both sexes; those affected will be tall as children but short as adults because of early bone maturation.
Females develop male characteristics, and males experience premature sexual development.
In its most severe form, called salt-wasting (or salt-losing) CAH, where there is a total or near total deficiency of the 21-hydroxylase enzyme, a life-threatening adrenal crisis can occur if the disorder is untreated. Adrenal crisis can cause dehydration , shock, and death within 14 days of birth.
There is also a milder form of CAH in which children have partial 21-hydroxylase enzyme deficiencies (simple virilizing form).Another type of CAH is characterized by only a slight deficiency in production of the 21-hydroxylase enzyme (nonclassic or late-onset form), in which symptoms occurs later in childhood or during young adolescence .
CAH is also called adrenogenital syndrome or 21-hydroxylase deficiency.
CAH, a genetic disorder, is the most common adrenal gland disorder in infants and children, occurring in one in 10,000 total births worldwide.
CAH is an inherited recessive disorder, which means that a child must inherit one copy of the defective gene from each parent who is a carrier; when two carriers have children, each pregnancy carries a 25 percent risk of producing an affected child.
CAH is related to the deficiency of 21-hydroxylase, an enzyme that is required to transform cholesterol into cortisol. The 21-hydroxylase gene is made by a gene located on the short arm of chromosome 6.
This gene is located in an area of the chromosome that contains many other important genes whose products control immune function. Various mutations of the 21-hydroxylase gene result in various degrees of CAH (salt-losing form, simple-virilizing form, and the nonclassic form).
When 21-hydroxylase is deficient, this leads to a hyperfunction and increased size (hyperplasia) of the adrenals.
In females, CAH produces an enlarged clitoris at birth, with the urethral opening at the base (ambiguous genitalia, appearing more male than female) and masculinization of features as the child grows, such as deepening of the voice, facial hair, and failure to menstruate or abnormal periods at puberty .
The internal structures of the reproductive tract, including the ovaries, uterus, and fallopian tubes, are normal. Females with severe CAH may be mistaken for males at birth.In males, the genitals are normal at birth, but the child becomes muscular, the penis enlarges, pubic hair appears, and the voice deepens long before normal puberty, sometimes as early as two to three years of age. At puberty, the testes are small.
In the severe salt-wasting form of CAH, newborns may develop symptoms shortly after birth, including vomiting , dehydration, electrolyte (a compound such as sodium or calcium that separates to form ions when dissolved in water) changes, and cardiac arrhythmias. If not treated, this form of CAH can result in death within one to six weeks after birth.
In the mild form of CAH, which occurs in late childhood or early adulthood, symptoms include premature development of pubic hair, irregular menstrual periods, unwanted body hair, or severe acne . However, sometimes there are no symptoms, and children affected are diagnosed because of an affected relative.
Many cases of CAH will be detected at birth, but in milder cases, symptoms may not develop until later, at which time medical care should be obtained. For children with more severe cases of CAH, regular medical care is necessary to achieve desired treatment results.
CAH is diagnosed by a careful examination of the genitals and blood and urine tests that measure the hormones produced by the adrenal gland.
A number of states in the United States perform a hormonal test (a heel prick blood test) for CAH and other inherited diseases within a few days of birth. In questionable cases, genetic testing can provide a definitive diagnosis.
For some forms of CAH, prenatal diagnosis is possible through chronic villus sampling in the first trimester and by measuring certain hormones in the amniotic fluid during the second trimester.
The goal of treatment for CAH is to return the androgen levels to normal. This is usually accomplished through drug therapy, although surgery may be an alternative for children with little or no enzyme activity. Lifelong treatment for CAH is required.Drug therapy consists of use of a cortisol- steroid medications called glucocorticoids.
Oral hydrocortisone is prescribed for younger children, and prednisone or dexamethasone is prescribed for older children. Side effects of steroids include stunted growth.
Steroid Adrenal cortical hyperplasia. The adrenal on the left is normal, the right shows hyperplasia.
(Photo Researchers, Inc.)
therapy should not be suddenly stopped, since adrenal insufficiency will result. Treatment results must be monitored carefully, because of large individual variations in enzyme deficiency in children with CAH.
For children with salt-wasting CAH, fludrocortisone (Florinef), which acts aldosterone (the missing hormone), is also prescribed.
Infants and small children may also receive salt tablets, while older children are encouraged to eat salty foods.
Serum electrolytes must be checked frequently, especially for children with salt-wasting CAH, to assure that normal levels of sodium and potassium are maintained.
Medical therapy achieves hormonal balance most of the time, but at times appropriate levels can be hard to maintain. CAH patients may have periods of fluctuating hormonal control that lead to increases in the dose of steroids prescribed. Sometimes these doses can become excessive as needs later decrease, leading to growth inhibition.
Increased doses may also be required when the child has a fever or a serious injury (a broken bone). If children are vomiting their oral medicine, have severe diarrhea , are unconscious, or cannot take anything by mouth before surgery, they may need to receive their medications by injections.Children with CAH should see a pediatric endocrinologist frequently. The endocrinologist will assess height, weight, and blood pressure, and order an annual x ray of the wrist (to assess bone age), as well as assess blood hormone levels. If they require medical treatment, CAH children with the milder form of the disorder are usually effectively treated with hydrocortisone or prednisone.
Females with CAH who have masculine external genitalia require surgery to reconstruct the clitoris and/or vagina. This is usually performed when the child is an infant. However, some doctors and parents believe that the best time for vaginal surgery is during adolescence.
An experimental type of drug therapy—a three-drug combination, with an androgen blocking agent (flutamide), an aromatase inhibitor (testolactone), and low dose hydrocortisone—was as of 2004 being studied by physicians at the National Institutes of Health. Preliminary results are encouraging, but it will be many years before the safety and effectiveness of this therapy is fully known.
Adrenalectomy, a surgical procedure to remove the adrenal glands, is a more radical treatment for CAH. It was widely used before the advent of steroids. In the early 2000s, it is recommended for CAH children with little or no enzyme activity and can be accomplished by laparoscopy.
This is a minimally invasive type of surgery done through one or more small one-inch (2.5 cm) incisions and a laparoscope, an instrument with a fiber-optic light containing a tube with openings for surgical instruments.
Adrenalectomy is followed by hormone therapy, but in lower doses than CAH patients not treated surgically receive.
CAH can be controlled and successfully treated in most patients as long as they remain on drug therapy.
Prenatal therapy, in which a pregnant woman at risk for a second CAH child is given dexamethasone to decrease secretion of androgens by the adrenal glands of the female fetus, has been in use since 1994.This therapy is started in the first trimester when fetal adrenal production of androgens begins but before prenatal diagnosis is done that would provide definitive information about the sex of the fetus and its disease status.
This means that a number of fetuses are exposed to unnecessary steroid treatment in order to prevent the development of male- genitals in female fetuses with CAH. Several hundred children have undergone this treatment with no major adverse effects, but its long-term risks are unknown.
Since there is very little data on the effectiveness and safety of prenatal therapy, it should only be offered to patients who clearly understand the risks and benefits and who are capable of complying with strict monitoring and follow-up throughout pregnancy and after the child is born.
Parents with a family history of CAH or who have a child with CAH should seek genetic counseling. Genetic testing during pregnancy can provide information on the risk of having a child with CAH.
Because children with CAH may not always be able to administer their own treatment (because they are too young or they are unconscious), parents are encouraged to make sure that the child with CAH wears a medical identification bracelet or necklace (Medic-Alert) stating that the child takes glucocorticoids and possibly Florinef. This notifies medical personnel to administer stress doses of medicines if needed.
When taking a child with CAH for emergency care, parents are advised to refer to the condition by its full name rather than CAH.
This is because this rare disease could be confused with another condition that shares the same initials: chronic active hepatitis. The parents should inform medical personnel if the child has salt-wasting CAH.
It is also recommended that parents have a letter or information prepared concerning CAH and care needed so that this can be given to a new doctors who may treat the child.Parents should be sensitive to the psychological aspects of the disease and obtain counseling for children with CAH. Topics of concern might include an understanding of the disease, the life-long requirement for medication, genital surgery, and sexuality.
Adrenal glands —A pair of endocrine glands (glands that secrete hormones directly into the bloodstream) that are located on top of the kidneys. The outer tissue of the glands (cortex) produces several steroid hormones, while the inner tissue (medulla) produces the hormones epinephrine (adrenaline) and norepinephrine.
Aldosterone —A hormone secreted by the adrenal glands that is important for maintaining salt and water balance in the body.
Androgens —Hormones (specifically testosterone) responsible for male sex characteristics.
Congenital —Present at birth.
Cortisol —A steroid hormone secreted by the adrenal cortex that is important for maintenance of body fluids, electrolytes, and blood sugar levels. Also called hydrocortisone.
Hormone —A chemical messenger secreted by a gland or organ and released into the bloodstream. It travels via the bloodstream to distant cells where it exerts an effect.
Hyperplasia —A condition where cells, such as those making up the prostate gland, rapidly divide abnormally and cause the organ to become enlarged.
Steroids —Hormones, including aldosterone, cortisol, and androgens, that are derived from cholesterol and that share a four-ring structural characteristic.
Congenital Adrenal Hyperplasia: A Medical Dictionary, Bibliography, and Annotated Research Guide. San Diego, CA: Icon Group International, 2004.
Gmyrek, Glenn A., et al. “Bilateral Laparoscopic Adrenalectomy as a Treatment for Classic Congenital Adrenal Hyperplasia Attributable to 21-Hydroxylase Deficiency.” Pediatrics 109 (February 2002): 28.
American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007–1098. Web site: http://www.aap.org/.
National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. Web site: http://www.medhelp.org/nadf/.
“Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: A Guide for Patients and Their Families.” Johns Hopkins Children's Center. Available online at http://www.hopkinsmedicine.org/pediatricendocrinology/cah/ (accessed December 8, 2004).
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How is CAH diagnosed?
In the United States and many other countries, newborns are screened for CAH with a blood test from a heel prick right after birth (referred to as newborn screening). Diagnosis in infancy or later also may include:
- A history and physical examination
- Blood test
- Genetic test
Sometimes, when there is a known family history of CAH, a fetus is diagnosed before birth. Experimental prenatal treatment of CAH is controversial experimental, and experts recommend it be done only in the context of an approved clinical trial (a research study that involves people).
What are the different types of CAH?
The genetic defect in CAH leads to abnormal Steroid 21-hydroxylase enzyme, (a protein that causes a chemical change in the body) activity in the adrenal glands, that are is needed for proper function. CAH can be severe (classic) or mild (non-classic).
Classic CAH is usually diagnosed in infancy or early childhood and is the most severe type and can be life-threatening.
In one form of classic CAH, called “salt-wasting” (meaning the body has trouble keeping the right amount of salt in the blood), the adrenal glands do not make enough cortisol and aldosterone. If not found and treated, classic CAH can cause shock, coma, and death.
In another form of classic CAH, called non-salt wasting; the loss of enzyme activity shortage is less severe.
Signs and Symptoms of Classic CAH
In many cases, female infants are diagnosed at birth, because they have ambiguous genitalia (external sex organs that resemble male genitals). However, they still have normal internal female organs (ovaries and uterus).
A male infant with classic CAH usually appears normal at birth, although he may have an enlarged penis. After infancy, boys with classic CAH grow rapidly and show signs of early puberty.
If infants are not diagnosed at birth, they may have shown weight loss, frequent vomiting, dehydration, diarrhea, changes in body chemistry, shock, heart problems, coma and can be life-threatening.
Treatment of Classic CAH
The goals of treatment are to ensure proper hormone levels and promote normal growth, and sexual development and sexual function. Patients with classic CAH should have a team of health care providers, including specialists in pediatric endocrinology, pediatric urologic surgery, mental health care provider, and genetics.
Individuals with classic CAH are treated with medications called glucocorticoids to replace the cortisol their bodies can't make.
Extra glucocorticoids may be needed during times of stress, such as when a patient is sick with an infection.
Individuals with classic CAH, especially those with the salt-wasting form, also need medicines called mineralocorticoids to replace the aldosterone they can’t make. Newborns also may need sodium chloride (salt) supplements.Surgery can correct ambiguous genitalia in girls. Parents may choose to delay surgery until the child is old enough to help make the decision. Thus, genital reconstructive surgery should incorporate the shared decisions and values of parents, patients, surgeons, endocrinologists, mental health providers, and support groups.
Individuals with CAH should be monitored according to conventional guidelines for monitoring healthy individuals. It is important that children with CAH and caregivers seek mental health treatment to address any CAH-related psychosocial concerns. An important goal of CAH therapy is improved mental health monitoring and quality of life.
Un classic CAH, the non-classic form is mild and not life threatening. Recent estimates suggest that this form of CAH is common, with an overall frequency of approximately 1 in 200 individuals. Signs and symptoms might not (or never) appear until childhood or adulthood.
Signs and Symptoms of Non-Classic CAH
Signs and symptoms in both males and females include:
- Early development of armpit and pubic hair
- Early or severe acne
- Infertility or decreased fertility
Adolescent girls and adult women also may have:
- Masculine characteristics such as facial hair and a deep voice
- Infrequent or absent menstrual periods
Treatment of Non-classic CAH
Some patients have no symptoms and require no treatment. Others need low-dose glucocorticoids (which might help with fertility) but might not need life-long treatment.
What Does the Future Hold for People With CAH?
With proper care, people with either type of CAH can live long and healthy lives. In the meantime, researchers continue to explore better ways to diagnose and treat this condition.
Questions to ask your healthcare team:
- What kind of CAH does my child (or do I) have?
- What are the options for treatment for my child (or for me)?
- What are the risks and benefits of each of the treatment options?
- Should I see a pediatric endocrinologist (or an endocrinologist)?
- Should I (or my child) have genetic testing for carrier identification of CAH?
Developed for patients Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency, an Endocrine Society Clinical Practice Guideline