Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia
Definition
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive genetic conditions that result from an abnormality in one of the enzymes required by the adrenal glands to convert cholesterol into cortisol, aldosterone, and androgens.
Description
The first likely description of congenital adrenal hyperplasia (CAH) occurred in 1865 when an anatomist named Luigi De Crecchio reported on a cadaver who had what appeared to be a penis with the urinary opening on its underside and undescended testicles. What was remarkable about this cadaver was that it also had a vagina, a uterus, fallopian tubes, ovaries, and very enlarged adrenal glands. From four years of age until his death, this person had lived his life as a male although at birth he was declared a female. He died in his 40s after many episodes of vomiting, diarrhea, and prostration. This genetic female with masculinized external genitals and abnormalities in regulating the amount of salt in her body had all the symptoms of a textbook case of a severe and untreated CAH.
Congenital adrenal hyperplasia (CAH), formerly called adrenogenital syndrome, results from an abnormality in one of the enzymes required by the adrenal glands to convert cholesterol into cortisol, aldosterone, and androgens such as testosterone. These three hormones are very necessary for normal health. Cortisol helps the body to cope with stress such as injury or illness, aldosterone helps to insure that the body retains normal amounts of salt, and androgens such as testosterone are involved in the production of masculine traits such as body hair and the development of male sex organs.
There are many different enzymes necessary for the normal production of cortisol, aldosterone, and testosterone. Each type of CAH results from a deficiency in one of these enzymes. One of the most important enzymes involved in the breakdown of cholesterol is 21-hydroxylase. 21-hydroxylase is involved in the conversion of cholesterol to cortisol and aldosterone but is not involved in the conversion of cholesterol to testosterone. Ninety to ninety-five percent of people with CAH have a deficiency or absence of 21-hydroxylase (21-hydroxylase deficiency).
A deficiency or absence of 21-hydroxylase (CAH21) results in the production of decreased levels of cortisol and aldosterone, which prompts the body to compensate by forcing the adrenal glands to increase the conversion of cholesterol. This does not result in significantly increased levels of cortisol and aldosterone, but does result in increased levels of testosterone, which is produced by another enzyme. Both men and women normally produce some testosterone, although men typically produce larger amounts of this hormone.
Increased levels of testosterone can result in premature puberty in males and females and can cause the absence of a menstrual period and increased amounts of body hair in women. Females who produce high levels of this hormone in utero can be born with masculinized external genitals. Decreased levels of cortisol can also result in increased levels of two other hormones called 17-hydroxyprogesterone and androstenedione. Increased levels of 17-hydroxyprogesterone in conjunction with decreased levels of aldosterone can result in an inability of the body to retain normal amounts of salt.
The three major types of 21-hydroxylase deficiency (CAH21) are: (1) the classic salt-losing form, (2) the classic non-salt-losing form, and (3) the non-classical form (later onset form). The classic forms of the disorder, if untreated, can result in premature puberty in boys and can cause girls to be born with an enlarged clitoris or external male genitals. Men and women with untreated classical CAH21 can have increased growth in childhood but short adult height. The salt-losing form of CAH21 results in reduced levels of salt in the body, which can sometimes result in an adrenal crisis. An adrenal crisis is a life threatening condition characterized by severe dehydration, very low blood pressure, and vomiting. The non-classic form, which is milder and has a later onset, can cause women to have an absence of menstruation and increased body hair and can cause a low sperm count in men.
Genetic profile
All types of CAH are autosomal recessive genetic conditions. An autosomal recessive condition is caused by a change in both genes of a pair. A person with CAH, has changes in both copies of the gene responsible for producing one of the enzymes involved in the breakdown of cholesterol. He or she has inherited one changed gene from his or her mother and one changed gene from his or her father. CAH21 results from changes in a gene, called CYP21, which creates the enzyme 21-hydroxylase, and is found on chromosome 6. When the CYP21 gene is changed it does not produce any 21-hydroxylase or it produces small amounts of this enzyme. There are a number of different types of gene changes that can result in reduced levels of 21-hydroxylase. The amount of 21-hydroxylase produced depends on the type and combination of CYP21 gene changes and partially determines the severity of CAH21.
Parents who have a child with CAH are called carriers, since they each possess one changed CAH gene and one unchanged CAH gene. Carriers usually do not have any symptoms since they have one unchanged gene that produces enough enzyme to prevent the symptoms of CAH. Each child born to parents who are both carriers for the same type of CAH, has a 25% chance of having CAH, a 50% chance of being a carrier, and a 25% chance of being neither a carrier nor affected with CAH disease.
Demographics
Approximately one in 10,000 infants is born with CAH, making it the most common disorder of the adrenal glands. CAH affects both females and males of all ethnic backgrounds. CAH21 is the most common form of CAH affecting 90–95% of people with CAH. Approximately one in 60 people are carriers for CAH21.
Signs and symptoms
The type of symptoms experienced by a person with CAH depends on their particular enzyme deficiency. CAH can cause congenital masculinization of the female external genitals or can cause feminization of the male genitals. CAH does not, however, affect the internal sexual organs of either males or females. CAH can cause women to have an absence of menstrual periods and increased body hair and is associated with premature puberty in both males and females. In some cases CAH can result in an inability of the body to retain normal amounts of salt.
CAH21 has a range of symptoms and the severity of the disorder is partially related to the amount of 21-hydroxylase that the body produces. The three major types of 21-hydroxylase deficiency (CAH21) are: (1) the classic salt-losing form, (2) the classic non-salt-losing form, and (3) the non-classical form (later onset form).
Classic salt-losing form of CAH21
The classic salt-losing form is the most severe form of CAH21 and results when very little or no 21-hydroxylase is produced. Untreated girls may be mistaken for boys at birth since they are typically born with fairly masculinized external genitals. Their internal sexual organs are, however, normal. Males with untreated CAH21 have normal external genitals but may experience premature puberty. Signs of puberty such as pubic hair, enlarged penis, deepened voice, and increased muscle strength can occur long before normal puberty and can sometimes occur as early as two to three years of age. This form of CAH21, if untreated, results in a loss of salt that can trigger an adrenal crisis. An adrenal crisis is a life-threatening condition characterized by severe dehydration, very low blood pressure, weakening of the heart muscles, and vomiting. The adrenal crisis typically occurs by six to twelve weeks. On occasion, salt loss is not noticed until precipitated by an infection in early childhood. This form of CAH21, if untreated, can also cause increased growth in childhood but short adult height in men and women.
Classical non-salt-losing form of CAH21
The classical non-salt-losing form of CAH21 results when a low amount of 21-hydroxylase is produced. In this form of CAH21 enough enzyme is present to prevent abnormally low levels of salt in the body and to prevent an adrenal crisis. Girls are born with slightly masculinized external genitals such as an enlarged clitoris and a partial fusion of the labia. If untreated, they may also experience early puberty and the lack of a menstrual period. Untreated boys have normal genitals but may have premature puberty. This form of CAH21, can also cause increased growth in childhood but short adult height in men and women.
Non-classical form of CAH21
The non-classical form is the mildest form of CAH21 and results from mildly decreased levels of 21-hydroxylase. Males and females with this form of CAH21 appear normal at birth and do not exhibit a salt deficiency. Untreated women may have an increase in body hair, irregular or absent menstrual periods, and/or cysts on their ovaries. Many men do not have any symptoms even if untreated. Some men and woman have short stature, severe acne, and decreased fertility.
Diagnosis
Diagnostic testing
Most forms of CAH can be diagnosed by measuring the amount of specific hormones in a urine sample. The type of hormone that is found in excess amounts in the urine depends on the type of CAH. CAH21 can be diagnosed by measuring the amount of 17-hydroxyprogester-one in a urine sample since people with CAH21 typically have elevated amounts of this hormone in their urine.
CAH21 is however, best diagnosed through a blood test called an ACTH (adrenocorticotropic hormone) stimulation test. ACTH is a hormone that stimulates the adrenal glands to convert cholesterol to cortisol. The ACTH stimulation test measures the amount of 17-hydroxyprogesterone in the blood before and after stimulation with ACTH. People with CAH21 have an exaggerated production of 17-hydroxyprogesterone after stimulation with ACTH. The ACTH stimulation test can usually identify what type of CAH21 a person is affected with.
Once a biochemical diagnosis of CAH is made, DNA testing may be recommended. DNA testing is available for some but not all types of CAH. Detection of a CYP21 gene alteration in a person with CAH21 can confirm an uncertain diagnosis and can help facilitate prenatal diagnosis and carrier testing of relatives. Some people with CAH21 may possess DNA changes that are not detectable through DNA testing.
Carrier testing
A person who has a relative with CAH or parents who have a child with CAH21 should consider undergoing carrier testing. Carriers for CAH21 can sometimes be identified through the ACTH stimulation test, although DNA testing is more accurate and is usually the recommended test. If possible, DNA testing should be first performed on the family member who is affected with CAH21. If a change in the CYP21 gene is detected, then carrier testing can be performed in relatives such as siblings and parents, with an accuracy of greater than 99%. If the affected relative does not possess detectable CYP21 gene changes, then DNA carrier testing will be inaccurate and should not be performed. In these cases ACTH stimulation testing of the potential carrier can be considered. If DNA testing of the affected relative cannot be performed, DNA carrier testing of family members can still be performed but will only identify approximately 95% of carriers.
Carrier testing should also be considered by someone who has a partner who is a carrier or is affected with CAH. DNA testing, which identifies approximately 95% of carriers for CAH21, is the recommended test for people who choose to undergo carrier testing but who do not themselves have a family history of CAH21.
Prenatal testing
If both parents are carriers for the same type of CAH or one parent is a carrier for CAH and one parent is affected with the same type of CAH, then prenatal testing should be considered. Prenatal testing is available for CAH21 and some of the other types of CAH. DNA testing is the recommended method of prenatal testing for CAH21 but it can only be performed if both parents have detectable mutations (gene changes) in CYP21. Prenatal testing cannot always identify what type of CAH21 a fetus has.
Some parents are known to be carriers for CAH21 since they already have a child with CAH21, yet they do not possess CYP21 gene changes that are detectable through DNA testing. Prenatal diagnosis can be performed in these cases by measuring the amount of 17-hydroxyprogesterone in the amniotic fluid, obtained from an amniocentesis . This type of prenatal testing can only detect the salt-losing form of CAH21.
Prenatal testing is especially important for mothers who are undergoing dexamethasone therapy to help prevent their daughters from being born with masculine genitalia. Although treatment must be started before prenatal testing can be performed, treatment can be discontinued if the baby is found to be a male or female who does not have CAH21.
Newborn screening
Many states offer newborn screening for CAH21. If newborn screening is available, hospitals in that state will automatically screen for CAH21 by measuring the amount of 17-hydroxyprogesterone in a drop of blood obtained from a newborn baby. More precise testing should be done if the initial test indicates that the infant has CAH21.
Treatment and management
Medications
Most people with CAH are treated with cortisol-like medications and in most cases this therapy is life-long. The goal of treatment is to return cortisol, aldosterone, and testosterone to near normal levels. People with the salt-losing and non-salt-losing forms of CAH21 are treated with injections of cortisol-like steroid medications or oral steroid medications. People with the salt-losing form are also given a form of oral aldosterone. Babies with the salt-losing form of CAH21 need to have salt added to their formula or breast milk. Children and adults do not need a salt supplement provided they have a high salt diet. An adrenal crisis is treated by intravenous administration of fluids containing sugars and salt. People with the non-classical form of CAH21, who require treatment, are treated with oral steroids. Medical therapy achieves hormonal balance most of the time, but CAH patients can have periods of fluctuating hormonal control. These fluctuations often require modifications in the amount of steroid required for treatment.
Some people with the salt-losing form of CAH21 are resistant to standard therapy. In 2001, the National Institutes of Health began conducting clinical trials determining the efficacy of a new combination drug treatment for CAH21. This experimental therapy involves treatment with a combination of four medications—flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone. The goal of these trials is to see whether this type of medical therapy is able to effectively treat CAH21 and still allow treated individuals to obtain a normal adult stature. Preliminary results are encouraging, but further research trials are necessary before the safety and effectiveness of this therapy is fully known.
Surgery
Adrenalectomy, a surgical procedure to remove the adrenal glands, is a more radical treatment for people with the salt-losing form of CAH21 who have little or no enzyme activity. This surgery allows people with CAH21 to be treated with lower dose steroids.
Girls born with masculinized genitals may undergo a surgery to create female genitals. This surgery is often performed at about six to twelve weeks of age. Sometimes an initial surgery is performed at that time followed by a surgery to correct the opening to the vagina when the girl becomes sexually active. Some people believe that any genital surgery should be delayed until the individual is old enough to decide whether they want the surgery.
Prenatal treatment
Some mothers who are at risk for having a child with CAH21 choose to take a type of steroid called dexamethasone while they are pregnant. This treatment can often prevent the masculinization of external genitals in female fetuses. To be fully effective this treatment needs to be started at approximately five to six weeks of gestation prior to the formation of the external genitals. Treatment can be stopped if prenatal testing finds that the baby is male or is an unaffected female, otherwise treatment continues until birth. Although this treatment does not appear to have many adverse effects on the fetus, the long-term risks are not known. The mother may, however, experience side effects such as weight gain, fluid accumulation, sugar intolerance, high blood pressure, gastrointestinal problems, and mood swings.
Prognosis
If appropriately treated, the prognosis for CAH and particularly CAH21 is good and most people have a normal life span. The prognosis for patients with the salt-losing form of CAH21 is, however, dependent on early identification and treatment. Some women and men with CAH 21, even if treated, have a short adult stature and may have decreased fertility. Women surgically treated for masculinized genitals may experience physical and/or psychological difficulties with sexual intercourse. They may also experience gender confusion and sexual identity difficulties.
Resources
BOOKS
"Congenital Adrenal Hyperplasia." In The Metabolic and Molecular Basis of Inherited Disease. Edited by C. R. Scriver, et al. New York: McGraw Hill, 1995.
"Fetal Adrenal Development." In Williams Obstetrics. 20th ed. Stamford, CT: Appleton & Lange, 1997.
PERIODICALS
New, Maria, and Robert Wilson. "Steroid Disorders in Children: Congenital Adrenal Hyperplasia and Apparent Mineralocorticoid Excess." Proceedings of the National Academy of Science (USA) 96, no. 2 (October 1999): 12790–97.
Speiser, P. W. "Prenatal Treatment of Congenital Adrenal Hyperplasia." The Journal of Urology 162 (August 1999): 594–36.
Speiser, P.W., et al. "A Multicenter Study of Women with Nonclassical Congenital Adrenal Hyperplasia: Relationships Between Genotype and Phenotype." Molecular Genetics and Metabolism 71, no. 3 (November 2000): 527–34.
ORGANIZATIONS
Ambiguous Genitalia Support Network. PO Box 313, Clements, CA 95227-0313. (209) 727-0313. Fax: (209) 727-0313. [email protected]. <http://www.stepstn.com>.
Congenital Adrenal Hyperplasia <http://congenitaladrenalhyperplasia.org>.
National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. (516) 487-4992. <http://medhlp.netusa.net/www/nadf.htm>.
WEBSITES
McKusick, Victor. "Adrenal Hyperplasia, Congenital, Due to 21-hydroxylase Deficiency." Online Mendelian Inheritance in Man. <http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?201910>. (February 16, 2001).
Speiser, Phyllis W. "New Developments in the Treatment and Diagnosis of Congenital Adrenal Hyperplasia." National Adrenal Diseases Foundation. (June 16, 2005.) <http://www.medhelp.org/nadf/nadf5.htm>.
Lisa Andres, MS, CGC
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia
Definition
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive genetic conditions that result from an abnormality in one of the enzymes required by the adrenal glands to convert cholesterol into cortisol, aldosterone, and androgens.
Description
The first likely description of congenital adrenal hyperplasia (CAH) occurred in 1865 when an anatomist named Luigi De Crecchio reported on a cadaver who had what appeared to be a penis with the urinary opening on its underside and undescended testicles. What was remarkable about this cadaver was that it also had a vagina, a uterus, fallopian tubes, ovaries and very enlarged adrenal glands. From four years of age until his death, this person had lived his life as a male although at birth he was declared a female. He died in his 40s after many episodes of vomiting, diarrhea, and prostration. This genetic female with masculinized external genitals and abnormalities in regulating the amount of salt in her body had all the symptoms of a textbook case of a severe and untreated CAH.
Congenital adrenal hyperplasia (CAH), formerly called adrenogenital syndrome, results from an abnormality in one of the enzymes required by the adrenal glands to convert cholesterol into cortisol, aldosterone, and androgens such as testosterone. These three hormones are very necessary for normal health. Cortisol helps the body to cope with stress such as injury or illness, aldosterone helps to insure that the body retains normal amounts of salt, and androgens such as testosterone are involved in the production of masculine traits such as body hair and the development of male sex organs.
There are many different enzymes necessary for the normal production of cortisol, aldosterone, and testosterone. Each type of CAH results from a deficiency in one of these enzymes. One of the most important enzymes involved in the breakdown of cholesterol is 21-hydroxylase. 21-hydroxylase is involved in the conversion of cholesterol to cortisol and aldosterone but is not involved in the conversion of cholesterol to testosterone. Ninety to ninety-five percent of people with CAH have a deficiency or absence of 21-hydroxylase (21-hydroxylase deficiency).
A deficiency or absence of 21-hydroxylase (CAH21) results in the production of decreased levels of cortisol and aldosterone, which prompts the body to compensate by forcing the adrenal glands to increase the conversion of cholesterol. This does not result in significantly increased levels of cortisol and aldosterone, but does result in increased levels of testosterone, which is produced by another enzyme. Both men and women normally produce some testosterone, although men typically produce larger amounts of this hormone.
Increased levels of testosterone can result in premature puberty in males and females and can cause the absence of a menstrual period and increased amounts of body hair in women. Females who produce high levels of this hormone in utero can be born with masculinized external genitals. Decreased levels of cortisol can also result in increased levels of two other hormones called 17-hydroxyprogesterone and androstenedione. Increased levels of 17-hydroxyprogesterone in conjunction with decreased levels of aldosterone can result in an inability of the body to retain normal amounts of salt.
The three major types of 21-hydroxylase deficiency (CAH21) are: (1) the classic salt-losing form, (2) the classic non-salt-losing form, and (3) the non-classical form (later onset form). The classic forms of the disorder, if untreated, can result in premature puberty in boys and can cause girls to be born with an enlarged clitoris or external male genitals. Men and women with untreated classical CAH21 can have increased growth in childhood but short adult height. The salt-losing form of CAH21 results in reduced levels of salt in the body, which can sometimes result in an adrenal crisis. An adrenal crisis is a life threatening condition characterized by severe dehydration, very low blood pressure, and vomiting. The nonclassic form, which is milder and has a later onset, can cause women to have an absence of menstruation and increased body hair and can cause a low sperm count in men.
Genetic profile
All types of CAH are autosomal recessive genetic conditions. An autosomal recessive condition is caused by a change in both genes of a pair. A person with CAH, has changes in both copies of the gene responsible for producing one of the enzymes involved in the breakdown of cholesterol. He or she has inherited one changed gene from his or her mother and one changed gene from his or her father. CAH21 results from changes in a gene, called CYP21, which creates the enzyme 21-hydroxylase, and is found on chromosome 6. When the CYP21 gene is changed it does not produce any 21-hydroxylase or it produces small amounts of this enzyme. There are a number of different types of gene changes that can result in reduced levels of 21-hydroxylase. The amount of 21-hydroxylase produced depends on the type and combination of CYP21 gene changes and partially determines the severity of CAH21.
Parents who have a child with CAH are called carriers, since they each possess one changed CAH gene and one unchanged CAH gene. Carriers usually do not have any symptoms since they have one unchanged gene that produces enough enzyme to prevent the symptoms of CAH. Each child born to parents who are both carriers for the same type of CAH, has a 25% chance of having CAH, a 50% chance of being a carrier, and a 25% chance of being neither a carrier nor affected with CAH disease.
Demographics
Approximately one in 10,000 infants is born with CAH, making it the most common disorder of the adrenal glands. CAH affects both females and males of all ethnic backgrounds. CAH21 is the most common form of CAH affecting 90–95% of people with CAH. Approximately one in 60 people are carriers for CAH21.
Signs and symptoms
The type of symptoms experienced by a person with CAH depends on their particular enzyme deficiency. CAH can cause congenital masculinization of the female external genitals or can cause feminization of the male genitals. CAH does not, however, affect the internal sexual organs of either males or females. CAH can cause women to have an absence of menstrual periods and increased body hair and is associated with premature puberty in both males and females. In some cases CAH can result in an inability of the body to retain normal amounts of salt.
CAH21 has a range of symptoms and the severity of the disorder is partially related to the amount of 21-hydroxylase that the body produces. The three major types of 21-hydroxylase deficiency (CAH21) are: (1) the classic salt-losing form, (2) the classic non-salt-losing form, and (3) the non-classical form (later onset form).
Classic salt-losing form of CAH21
The classic salt-losing form is the most severe form of CAH21 and results when very little or no 21-hydroxylase is produced. Untreated girls may be mistaken for boys at birth since they are typically born with fairly masculinized external genitals. Their internal sexual organs are, however, normal. Males with untreated CAH21 have normal external genitals but may experience premature puberty. Signs of puberty such as pubic hair, enlarged penis, deepened voice, and increased muscle strength can occur long before normal puberty and can sometimes occur as early as two to three years of age. This form of CAH21, if untreated, results in a loss of salt that can trigger an adrenal crisis. An adrenal crisis is a life-threatening condition characterized by severe dehydration, very low blood pressure, weakening of the heart muscles, and vomiting. The adrenal crisis typically occurs by six to twelve weeks. On occasion, salt loss is not noticed until precipitated by an infection in early childhood. This form of CAH21, if untreated, can also cause increased growth in childhood but short adult height in men and women.
Classical non-salt-losing form of CAH21
The classical non-salt-losing form of CAH21 results when a low amount of 21-hydroxylase is produced. In this form of CAH21 enough enzyme is present to prevent abnormally low levels of salt in the body and to prevent an adrenal crisis. Girls are born with slightly masculinized external genitals such as an enlarged clitoris and a partial fusion of the labia. If untreated, they may also experience early puberty and the lack of a menstrual period. Untreated boys have normal genitals but may have premature puberty. This form of CAH21, can also cause increased growth in childhood but short adult height in men and women.
Non-classical form of CAH21
The non-classical form is the mildest form of CAH21 and results from mildly decreased levels of 21-hydroxylase. Males and females with this form of CAH21 appear normal at birth and do not suffer from a deficiency of salt. Untreated women may have an increase in body hair, irregular or absent menstrual periods, and may have cysts on their ovaries. Many men do not have any symptoms even if untreated. Some men and woman have short stature, severe acne, and decreased fertility.
Diagnosis
Diagnostic testing
Most forms of CAH can be diagnosed by measuring the amount of specific hormones in a urine sample. The type of hormone that is found in excess amounts in the urine depends on the type of CAH. CAH21 can be diagnosed by measuring the amount of 17-hydroxyprogesterone in a urine sample since people with CAH21 typically have elevated amounts of this hormone in their urine.
CAH21 is however, best diagnosed through a blood test called an ACTH (adrenocorticotropic hormone) stimulation test. ACTH is a hormone that stimulates the adrenal glands to convert cholesterol to cortisol. The ACTH stimulation test measures the amount of 17-hydroxyprogesterone in the blood before and after stimulation with ACTH. People with CAH21 have an exaggerated production of 17-hydroxyprogesterone after stimulation with ACTH. The ACTH stimulation test can usually identify what type of CAH21 a person is affected with.
Once a biochemical diagnosis of CAH is made, DNA testing may be recommended. DNA testing is available for some but not all types of CAH. Detection of a CYP21 gene alteration in a person with CAH21 can confirm an uncertain diagnosis and can help facilitate prenatal diagnosis and carrier testing of relatives. Some people with CAH21 may possess DNA changes that are not detectable through DNA testing.
Carrier testing
A person who has a relative with CAH or parents who have a child with CAH21 should consider undergoing carrier testing. Carriers for CAH21 can sometimes be identified through the ACTH stimulation test, although DNA testing is more accurate and is usually the recommended test. If possible, DNA testing should be first performed on the family member who is affected with CAH21. If a change in the CYP21 gene is detected, then carrier testing can be performed in relatives such as siblings and parents, with an accuracy of greater than 99%. If the affected relative does not possess detectable CYP21 gene changes, then DNA carrier testing will be inaccurate and should not be performed. In these cases ACTH stimulation testing of the potential carrier can be considered. If DNA testing of the affected relative cannot be performed, DNA carrier testing of family members can still be performed but will only identify approximately 95% of carriers.
Carrier testing should also be considered by someone who has a partner who is a carrier or is affected with CAH. DNA testing, which identifies approximately 95% of carriers for CAH21, is the recommended test for people who choose to undergo carrier testing but who do not themselves have a family history of CAH21.
Prenatal testing
If both parents are carriers for the same type of CAH or one parent is a carrier for CAH and one parent is affected with the same type of CAH, then prenatal testing should be considered. Prenatal testing is available for CAH21 and some of the other types of CAH. DNA testing is the recommended method of prenatal testing for CAH21 but it can only be performed if both parents have detectable mutations (gene changes) in CYP21. Prenatal testing cannot always identify what type of CAH21 a fetus has.
Some parents are known to be carriers for CAH21 since they already have a child with CAH21, yet they do not possess CYP21 gene changes that are detectable through DNA testing. Prenatal diagnosis can be performed in these cases by measuring the amount of 17-hydroxyprogesterone in the amniotic fluid, obtained from an amniocentesis . This type of prenatal testing can only detect the salt-losing form of CAH21.
Prenatal testing is especially important for mothers who are undergoing dexamethasone therapy to help prevent their daughters from being born with masculine genitalia. Although treatment must be started before prenatal testing can be performed, treatment can be discontinued if the baby is found to be a male or female who does not have CAH21.
Newborn screening
Many states offer newborn screening for CAH21. If newborn screening is available in your state, then hospitals in that state will automatically screen for CAH21 by measuring the amount of 17-hydroxyprogesterone in a drop of blood obtained from a newborn baby. More precise testing should be done if the initial test indicates that an infant has CAH21.
Treatment and management
Medications
Most people with CAH are treated with cortisol-like medications and in most cases this therapy is life-long. The goal of treatment is to return cortisol, aldosterone, and testosterone to near normal levels. People with the salt-losing and non-salt-losing forms of CAH21 are treated with injections of cortisol-like steroid medications or oral steroid medications. People with the salt-losing form are also given a form of oral aldosterone. Babies with the salt-losing form of CAH21 need to have salt added to their formula or breast milk. Children and adults do not need a salt supplement provided they have a high salt diet. An adrenal crisis is treated by intravenous administration of fluids containing sugars and salt. People with the non-classical form of CAH21, who require treatment, are treated with oral steroids. Medical therapy achieves hormonal balance most of the time, but CAH patients can have periods of fluctuating hormonal control. These fluctuations often require modifications in the amount of steroid required for treatment.
Some people with the salt-losing form of CAH21 are resistant to standard therapy. As of 2001, the National Institutes of Health is conducting clinical trials determining the efficacy of a new combination drug treatment for CAH21. This experimental therapy involves treatment with a combination of four medications—flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone. The goal of these trials is to see whether this type of medical therapy is able to effectively treat CAH21 and still allow treated individuals to obtain a normal adult stature. Preliminary results are encouraging, but further research trials are necessary before the safety and effectiveness of this therapy is fully known.
Surgery
Adrenalectomy, a surgical procedure to remove the adrenal glands, is a more radical treatment for people with the salt-losing form of CAH21 who have little or no enzyme activity. This surgery allows people with CAH21 to be treated with lower dose steroids.
Girls born with masculinized genitals may undergo a surgery to create female genitals. This surgery is often performed at about six to twelve weeks of age. Sometimes an initial surgery is performed at that time followed by a surgery to correct the opening to the vagina when the girl becomes sexually active. Some people believe that any genital surgery should be delayed until the individual is old enough to decide whether they want the surgery.
Prenatal treatment
Some mothers who are at risk for having a child with CAH21 choose to take a type of steroid called dexamethasone while they are pregnant. This treatment can often prevent the masculinization of external genitals in female fetuses. To be fully effective this treatment needs to be started at approximately five to six weeks of gestation prior to the formation of the external genitals. Treatment can be stopped if prenatal testing finds that the baby is male or is an unaffected female, otherwise treatment continues until birth. Although this treatment does not appear to have many adverse effects on the fetus, the long-term risks are not known. The mother may, however, experience side effects such as weight gain, fluid accumulation, sugar intolerance, high blood pressure, gastrointestinal problems, and mood swings.
Prognosis
If appropriately treated, the prognosis for CAH and particularly CAH21 is good and most people have a normal lifespan. The prognosis for patients with the salt-losing form of CAH21 is, however, dependent on early identification and treatment. Some women and men with CAH 21, even if treated, have a short adult stature and may have decreased fertility. Women surgically treated for masculinized genitals may experience physical and/or psychological difficulties with sexual intercourse. They may also experience gender confusion and sexual identity difficulties.
Resources
BOOKS
"Congenital Adrenal Hyperplasia." In The Metabolic and Molecular Basis of Inherited Disease. Edited by C. R. Scriver, et al. New York: McGraw Hill, 1995.
"Fetal Adrenal Development." In Williams Obstetrics. 20th ed. Stamford, CT: Appleton & Lange, 1997.
PERIODICALS
New, Maria, and Robert Wilson. "Steroid Disorders in Children: Congenital Adrenal Hyperplasia and Apparent Mineralocorticoid Excess." Proceedings of the NationalAcademy of Science (USA) 96, no. 2 (October 1999): 12790–97.
Speiser, P. W. "Prenatal Treatment of Congenital Adrenal Hyperplasia." The Journal of Urology 162 (August 1999): 594–36.
Speiser, P.W., et al. "A Multicenter Study of Women with Nonclassical Congenital Adrenal Hyperplasia: Relationships Between Genotype and Phenotype." Molecular Genetics and Metabolism 71, no. 3 (November 2000): 527–34.
ORGANIZATIONS
Ambiguous Genitalia Support Network. PO Box 313, Clements, CA 95227-0313. (209) 727-0313. Fax: (209) 727-0313. [email protected]. <http://www.stepstn.com>.
Congenital Adrenal Hyperplasia <http://congenitaladrenalhyperplasia.org>.
National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. (516) 487-4992. <http://medhlp.netusa.net/www/nadf.htm>.
WEBSITES
McKusick, Victor. "Adrenal Hyperplasia, Congenital, Due to 21-hydroxylase Deficiency." Online Mendelian Inheritance in Man.<http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?201910>. (February 16 2001).
National Adrenal Diseases Foundation. "New Developments in the Treatment and Diagnosis of Congenital Adrenal Hyperplasia." <http://www.medhelp.org/222/nadf5.htm>. (May 28 1998).
Lisa Andres, MS, CGC
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia
Definition
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.
Description
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.
Demographics
CAH, a genetic disorder, is the most common adrenal gland disorder in infants and children, occurring in one in 10,000 total births worldwide.
Causes and symptoms
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.
When to call the doctor
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.
Diagnosis
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.
Treatment
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-like 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 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 like 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.
Prognosis
CAH can be controlled and successfully treated in most patients as long as they remain on drug therapy.
Prevention
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-like 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.
Parental concerns
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.
KEY TERMS
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.
Resources
BOOKS
Congenital Adrenal Hyperplasia: A Medical Dictionary, Bibliography, and Annotated Research Guide. San Diego, CA: Icon Group International, 2004.
PERIODICALS
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.
ORGANIZATIONS
American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007–1098. Web site: <www.aap.org/>.
National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. Web site: <www.medhelp.org/nadf/>.
WEB SITES
"Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: A Guide for Patients and Their Families." Johns Hopkins Children's Center. Available online at <www.hopkinsmedicine.org/pediatricendocrinology/cah/> (accessed December 8, 2004).
Judith Sims
Jennifer Sisk
Congenital Adrenal Hyperplasia
Congenital Adrenal Hyperplasia
Definition
CAH is a genetic disorder characterized by a deficiency in the hormones cortisol and aldosterone and an over-production of the hormone androgen, which is present at birth and affects sexual development.
Description
Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency in which the enzyme that produces two important adrenal steroid hormones, cortisol and aldosterone, is deficient. Because cortisol production is impeded, the adrenal gland instead overproduces androgens (male steroid hormones). 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; patients will be tall as children and short as adults. Females develop male characteristics, and males experience premature sexual development.
In its most severe form, called salt-wasting CAH, 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 mild form of CAH that occurs later in childhood or young adult life in which patients have partial enzyme 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. It affects both females and males. It is also called adrenogenital syndrome.
Causes and symptoms
CAH is an inherited disorder. It is a recessive disease, 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% risk of producing an affected child.
In females, CAH produces an enlarged clitoris at birth 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. 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.
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 arrhythmia.
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.
Diagnosis
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.
Treatment
The goal of treatment for CAH is to return the androgen levels to normal. This is usually accomplished through drug therapy, although surgery is an alternative. Lifelong treatment is required.
Drug therapy consists of a cortisol-like steroid medication called a glucocorticoid. Oral hydrocortisone is prescribed for children, and prednisone or dexamethasone is prescribed for older patients. For patients with salt-wasting CAH, fludrocortisone, which acts like aldosterone (the missing hormone), is also prescribed. Infants and small children may also receive salt tablets, while older patients are told to eat salty foods. Medical therapy achieves hormonal balance most of the time, but CAH patients can have periods of fluctuating hormonal control that lead to increases in the dose of steroids prescribed. Side effects of steroids include stunted growth. Steroid therapy should not be suddenly stopped, since adrenal insufficiency results.
Patients 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. CAH patients with the milder form of the disorder are usually effectively treated with hydrocortisone or prednisone, if they need medical treatment at all.
Females with CAH who have masculine external genitalia require surgery to reconstruct the clitoris and/or vagina. This is usually performed between the ages of one and three.
An experimental type of drug therapy—a three-drug combination, with an androgen blocking agent (flutamide), an aromatase inhibitor (testolactone), and low dose hydrocortisone—is currently 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. Today, it is recommended for CAH patients 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 1 in (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.
KEY TERMS
Adrenal glands— The two endocrine glands located above the kidney that secrete hormones and epinephrine.
Aldosterone— A hormone secreted by the adrenal glands that is important for maintaining salt and water balance in the body.
Androgens— Steroid hormones that cause masculinization.
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.
Hormone— A chemical messenger produced by the endocrine glands or certain other cells. Hormones are usually carried in the blood stream and regulate some metabolic activities.
Steroids— Hormones, including aldosterone, cortisol, and androgens, derived from cholesterol that share a four-ring structure.
Prognosis
CAH can be controlled and successfully treated in most patients as long as they remain on drug therapy.
Prevention
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 for about 10 years. 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-like 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, including a child who has CAH, should seek genetic counseling. Genetic testing during pregnancy can provide information on the risk of having a child with CAH.
Resources
ORGANIZATIONS
American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (847) 434-4000.
National Adrenal Diseases Foundation. 510 Northern Boulevard, Great Neck, NY 11021. (516) 487-4992. 〈http://medhlp.netusa.net/www/nadf.htm〉.
OTHER
The Johns Hopkins Children's Center. "Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency." 〈http://www.med.jhu.edu/pedendo/cha/printable.html〉.