Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

K E Y T E R M S

Amelogenesis imperfecta—A hereditary dental defect characterized by discoloration of the teeth.

Cones—Receptor cells that allow the perception of colors.

Nystagmus—Involuntary, rhythmic movement of the eye.

Photophobia—An extreme sensitivity to light.

Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve.

Rod—Photoreceptor that is highly sensitive to low levels of light and transmits images in shades of gray.

Prognosis

Studies of individuals thought to have cone-rod dystrophy reveal that central vision loss begins in the first decade of life with the onset of night blindness occurring sometime after age 20. Little visual function remains after the age of 50. There is no cure for this syndrome.

Resources

BOOKS

McKusick, Victor A. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. 12th ed. Baltimore: Johns Hopkins University Press, 1998.

Yanoff, Myron, and Jay S. Duker. Ophthalmology. St. Louis: Mosby, 2000.

PERIODICALS

Downes, Susan M., et al. “Autosomal Dominant Cone and Cone-Rod Dystrophy With Mutations in the Guanylate Cyclase Activator 1A Gene-Encoding Guanylate Cyclase Activating Protein-1.” Archives of Ophthalmology 119, no. 1 (2001): 96–105.

ORGANIZATIONS

American Academy of Ophthalmology. PO Box 7424, San Francisco, CA 94120-7424. [phone]. http://www

.eyenet.org .

Association for Macular Diseases, Inc. 210 East 64th St., New York, NY 10021. [phone]. [e-mail]://[e-mail] .

Foundation Fighting Blindness. Executive Plaza 1, 11350 McCormick Rd, Suite 800, Hunt Valley, MD 21031. [phone]. [e-mail]. http://www.blindness

.org .

National Eye Institute. 31 Center Dr., Bldg. 31, Rm 6A32, MSC 2510, Bethesda, MD 20892-2510. [phone]. [e-mail]. http://www.nei.nih.gov .

	Retinitis Pigmentosa International. 23241 Ventura Blvd., Suite	Congenital
	117, Woodland Hills, CA 91364. [phone] or (800)
	344-4877. [e-mail]. http://www.rpinternational
	.org .
	WEBSITES	adrenal
	Foundation Fighting Blindness:
	http://www.blindness.org/html/science/wcord2.html .
	Retina Foundation of the Southwest.	hyperplasia
	http://www.retinafoundation.org/eyeinfo2.html .
	Southeastern Eye Center. http://www.southeasterneyecenter
	.com/cases/bulls_eye.htm .

L. Fleming Fallon, Jr, MD, DrPH

I 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 testos-

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terone 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 21hydroxylase. 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 21hydroxylase 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 21hydroxylase that the body produces. The three major

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K E Y T E R M S

Adrenal gland—A triangle-shaped endocrine gland, located above each kidney, that synthesizes aldosterone, cortisol, and testosterone from cholesterol. The adrenal glands are responsible for salt and water levels in the body, as well as for protein, fat, and carbohydrate metabolism.

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Carrier—A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Carrier testing—Testing performed to determine if someone possesses one changed copy and one unchanged copy of a particular gene.

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Congenital—Refers to a disorder that is present at birth.

Deoxyribonucleic acid (DNA)—The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

Diagnostic testing—Testing performed to determine if someone is affected with a particular disease.

DNA testing—Analysis of DNA (the genetic component of cells) in order to determine changes in genes that may indicate a specific disorder.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Hormone—A chemical messenger produced by the body that is involved in regulating specific bodily functions such as growth, development, and reproduction.

In utero—While in the uterus; before birth.

Labia—Lips of the female genitals.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Prenatal testing—Testing for a disease such as a genetic condition in an unborn baby.

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-hydrox- ylase 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

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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 21hydroxylase. 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-hydroxyproges- terone 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-hydrox- yprogesterone 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 17hydroxyprogesterone 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.

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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-los- ing 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 medica- tions—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-los- ing 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

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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. [phone]. Fax: [phone]. [e-mail]. http://www.stepstn.com .

Congenital Adrenal Hyperplasia

http://congenitaladrenalhyperplasia.org .

National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. [phone]. 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 contractural arachnodactyly see

Beals syndrome

Congenital familial hypertrophic synovitis see Arthropathy-camptodactyly syndrome

I Congenital heart disease

Definition

Congenital heart disease, also called congenital heart defect, includes a variety of malformations of the heart or its major blood vessels that are present at the birth of a child.

Description

Congenital heart disease occurs when the heart or blood vessels near the heart do not develop properly before birth. Some infants are born with mild types of congenital heart disease, but most need surgery in order to survive. Patients who have had surgery are likely to experience other cardiac problems later in life.

Most types of congenital heart disease obstruct the flow of blood in the heart or the nearby vessels, or cause an abnormal flow of blood through the heart. Rarer types of congenital heart disease occur when the newborn has only one ventricle, when the pulmonary artery and the aorta come out of the same ventricle, or when one side of the heart is not completely formed.

Patent ductus arteriosus

Patent ductus arteriosus refers to the opening of a passageway—or temporary blood vessel (ductus)—to carry the blood from the heart to the aorta before birth, allowing blood to bypass the lungs, which are not yet functional. The ductus should close spontaneously in the first few hours or days after birth. When it does not close in the newborn, some of the blood that should flow through the aorta then returns to the lungs. Patent ductus arteriosus is common in premature babies, but rare in full-term babies. It has also been associated with mothers who had German measles (rubella) while pregnant.

Hypoplastic left heart syndrome

Hypoplastic left heart syndrome, a condition in which the left side of the heart is underdeveloped, is rare, but it is the most serious type of congenital heart disease. With this syndrome, blood reaches the aorta, which pumps blood to the entire body, only from the ductus, which then normally closes within a few days of birth. In hypoplastic left heart syndrome, the baby seems normal at birth, but as the ductus closes, blood cannot reach the aorta and circulation fails.

Obstruction defects

When heart valves, arteries, or veins are narrowed, they partly or completely block the flow of blood. The most common obstruction defects are pulmonary valve stenosis, aortic valve stenosis, and coarctation of the aorta. Bicuspid aortic valve and subaortic stenosis are less common.

Stenosis is a narrowing of the valves or arteries. In pulmonary stenosis, the pulmonary valve does not open properly, forcing the right ventricle to work harder. In aortic stenosis, the improperly formed aortic valve is nar-

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rowed. As the left ventricle works harder to pump blood through the body, it becomes enlarged. In coarctation of the aorta, the aorta is constricted, reducing the flow of blood to the lower part of the body and increasing blood pressure in the upper body.

A bicuspid aortic valve has only two flaps instead of three, which can lead to stenosis in adulthood. Subaortic stenosis is a narrowing of the left ventricle below the aortic valve, which limits the flow of blood from the left ventricle.

Septal defects

When a baby is born with a hole in the septum (the wall separating the right and left sides of the heart), blood leaks from the left side of the heart to the right, or from a higher pressure zone to a lower pressure zone. A major leakage can lead to enlargement of the heart and failing circulation. The most common types of septal defects are atrial septal defect, an opening between the two upper heart chambers, and ventricular septal defect, an opening between the two lower heart chambers. Ventricular septal defect accounts for about 15% of all cases of congenital heart disease in the United States.

Cyanotic defects

Heart disorders that cause a decreased, inadequate amount of oxygen in blood pumped to the body are called cyanotic defects. Cyanotic defects, including truncus arteriosus, total anomalous pulmonary venous return, tetralogy of Fallot, transposition of the great arteries, and tricuspid atresia, result in a blue discoloration of the skin due to low oxygen levels. About 10% of cases of congenital heart disease in the United States are tetralogy of Fallot, which includes four defects. The major defects are a large hole between the ventricles that allows oxygenpoor blood to mix with oxygen-rich blood, and narrowing at or beneath the pulmonary valve. The other defects are an overly muscular right ventricle and an aorta that lies over the ventricular hole.

In transposition (reversal of position) of the great arteries, the pulmonary artery and the aorta are reversed, causing oxygen-rich blood to re-circulate to the lungs while oxygen-poor blood goes to the rest of the body. In tricuspid atresia, the baby lacks a triscupid valve and blood cannot flow properly from the right atrium to the right ventricle.

Other defects

Ebstein’s anomaly is a rare congenital syndrome that causes malformed tricuspid valve leaflets, which allow blood to leak between the right ventricle and the right

K E Y T E R M S

Aorta—The main artery located above the heart which pumps oxygenated blood out into the body. Many congenital heart defects affect the aorta.

Congenital—Refers to a disorder which is present at birth.

Cyanotic—Marked by bluish discoloration of the skin due to a lack of oxygen in the blood. It is one of the types of congenital heart disease.

Ductus—The blood vessel that joins the pulmonary artery and the aorta. When the ductus does not close at birth, it causes a type of congenital heart disease called patent ductus arteriosus.

Electrocardiograph (ECG, EKG)—A test used to measure electrical impulses coming from the heart in order to gain information about its structure or function.

Hypoplastic—Incomplete or underdevelopment of a tissue or organ. Hypoplastic left heart syndrome is the most serious type of congenital heart disease.

Neuchal translucency—A pocket of fluid at the back of an embryo’s neck visible via ultrasound that, when thickened, may indicate the infant will be born with a congenital heart defect.

Septal—Relating to the septum, the thin muscle wall dividing the right and left sides of the heart. Holes in the septum are called septal defects.

Stenosis—The constricting or narrowing of an opening or passageway.

atrium. It also may cause a hole in the wall between the left and right atrium. Treatment often involves repairing the tricuspid valve. Ebstein’s anomaly may be associated with maternal use of the psychiatric drug lithium during pregnancy.

Brugada syndrome is another rare congenital heart defect that appears in adulthood and may cause sudden death if untreated. Symptoms, which include rapid, uneven heart beat, often appear at night. Scientists believe that Brugada syndrome is caused by mutations in the gene SCN5A, which involves cardiac sodium channels.

Infants born with DiGeorge sequence can have heart defects such as a malformed aortic arch and tetralogy of Fallot. Researchers believe DiGeorge sequence

disease heart Congenital

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An angiogram showing a hole in the heart of a young patient. (Photo Researchers, Inc.)

is most often caused by mutations in genes in the region 22q11.

Marfan syndrome is a connective tissue disorder that causes tears in the aorta. Since the disease also causes excessive bone growth, most Marfan syndrome patients are over six-feet-tall. In athletes, and others, it can lead to sudden death. Researchers believe the defect responsible for Marfan syndrome is found in gene FBN1, on chromosome 15.

Genetic profile

Scientists have made much progress in identifying some of the genes that are responsible for congenital heart defects, but others remain a mystery. When possible, genetic testing can help families determine the risk that their child will be born with a heart defect.

Demographics

About 32,000 infants are born every year with congenital heart disease, which is the most common birth defect. About half of these patients will require medical treatment. More than one million people with heart defects are currently living in the United States.

Signs and symptoms

In most cases, the causes of congenital heart disease are unknown. Genetic and environmental factors, and

lifestyle habits can all be involved. The likelihood of having a child with a congenital heart disease increases if the mother or father, another child, or another relative had congenital heart disease or a family history of sudden death. Viral infections, such as German measles, can produce congenital heart disease. Women with diabetes and phenylketonuria also are at higher risk of having children with congenital heart defects. Many cases of congenital heart disease result from the mother’s excessive use of alcohol or illegal drugs, such as cocaine, while pregnant. The mother’s exposure to certain anticonvulsant and dermatologic drugs during pregnancy can also cause congenital heart disease. There are many genetic conditions, such as Down syndrome, which affect multiple organs and can cause congenital heart disease.

Symptoms of congenital heart disease in general include: shortness of breath, difficulty feeding in infancy, sweating, cyanosis (bluish discoloration of the skin), heart murmur, respiratory infections that recur excessively, stunted growth, and limbs and muscles that are underdeveloped.

Symptoms of specific types of congenital heart disease are as follows:

•Patent ductus arteriosus: quick tiring, slow growth, susceptibility to pneumonia, rapid breathing. If the ductus is small, there are no symptoms.

•Hypoplastic left heart syndrome: ashen color, rapid and difficult breathing, inability to eat.

•Obstruction defects: cyanosis (skin that is discolored blue), chest pain, tiring easily, dizziness or fainting, congestive heart failure, and high blood pressure.

•Septal defects: difficulty breathing, stunted growth. Sometimes there are no symptoms.

•Cyanotic defects: cyanosis, sudden rapid breathing or unconsciousness, and shortness of breath and fainting during exercise.

Diagnosis

Echocardiography and cardiac magnetic resonance imaging are used to confirm congenital heart disease when it is suggested by the symptoms and physical examination. An echocardiograph will display an image of the heart that is formed by sound waves. It detects valve and other heart problems. Fetal echocardiography is used to diagnose congenital heart disease in utero, usually after 20 weeks of pregnancy. Between 10 and 14 weeks of pregnancy, physicians also may use an ultrasound to look for a thickness at the nuchal translucency, a pocket of fluid in back of the embryo’s

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neck, which may indicate a cardiac defect in 55% of cases. Cardiac magnetic resonance imaging, a scanning method that uses magnetic fields and radio waves, can help physicians evaluate congenital heart disease, but is not always necessary. Physicians may also use a chest x ray to look at the size and location of the heart and lungs, or an electrocardiograph (ECG), which measures electrical impulses to create a graph of the heart beat.

Treatment and management

Congenital heart disease is treated with drugs and/or surgery. Drugs used include diuretics, which aid the baby in excreting water and salts, and digoxin, which strengthens the contraction of the heart, slows the heartbeat, and removes fluid from tissues.

Surgical procedures seek to repair the defect as much as possible and restore circulation to as close to normal as possible. Sometimes, multiple surgical procedures are necessary. Surgical procedures include: arterial switch, balloon atrial septostomy, balloon valvuloplasty, Damus-Kaye-Stansel procedure, Fontan procedure, pulmonary artery banding, Ross procedure, shunt procedure, and venous switch or intra-atrial baffle.

Arterial switch, to correct transposition of the great arteries, involves connecting the aorta to the left ventricle and connecting the pulmonary artery to the right ventricle. Balloon atrial septostomy, also done to correct transposition of the great arteries, enlarges the atrial opening during heart catheterization. Balloon valvuloplasty uses a balloon-tipped catheter to open a narrowed heart valve, improving the flow of blood in pulmonary stenosis. It is sometimes used in aortic stenosis. Transposition of the great arteries can also be corrected by the Damus-Kaye-Stansel procedure, in which the pulmonary artery is cut in two and connected to the ascending aorta and the farthest section of the right ventricle.

For tricuspid atresia and pulmonary atresia, the Fontan procedure connects the right atrium to the pulmonary artery directly or with a conduit, and the atrial defect is closed. Pulmonary artery banding, narrowing the pulmonary artery with a band to reduce blood flow and pressure in the lungs, is used for ventricular septal defect, atrioventricular canal defect, and tricuspid atresia. Later, the band can be removed and the defect corrected with open-heart surgery.

To correct aortic stenosis, the Ross procedure grafts the pulmonary artery to the aorta. For tetralogy of Fallot, tricuspid atresia, or pulmonary atresia, the shunt procedure creates a passage between blood vessels, sending blood into parts of the body that need it. For transposition

of the great arteries, venous switch creates a tunnel inside the atria to re-direct oxygen-rich blood to the right ventricle and aorta and venous blood to the left ventricle and pulmonary artery.

When all other options fail, some patients may need a heart transplant. Children with congenital heart disease require lifelong monitoring, even after successful surgery. The American Heart Association recommends regular dental check-ups and the preventive use of antibiotics to protect patients from heart infections, or endocarditis. Since children with congenital heart disease have slower growth, nutrition is important. Physicians may also limit their athletic activity.

Prognosis

The outlook for children with congenital heart disease has improved markedly in the past two decades. Many types of congenital heart disease that would have been fatal can now be treated successfully. Research on diagnosing heart defects when the fetus is in the womb may lead to future treatment to correct defects before birth. Promising new prevention methods and treatments include genetic screening and the cultivation of cardiac tissue in the laboratory that could be used to repair congenital heart defects.

Resources

BOOKS

Mayo Clinic Heart Book. New York: William Morrow and Company, 2000.

Wild, C. L., and M. J. Neary. Heart Defects in Children: What Every Parent Should Know. Chronimed Publishing, Minneapolis, 2000.

Williams, R. A. The Athlete and Heart Disease. Lippincott Williams & Wilkins, Philadelphia, 1999.

PERIODICALS

“Coping with Congenital Heart Disease in Your Baby.”

American Family Physician 59 (April 1, 1999): 1867. Hyett, Jon, et. al. “Using fetal nuchal translucency to screen for

major congenital cardiac defects at 10-14 weeks: popula- tion-based cohort study.” Lancet 318 (January 1999): 8185.

ORGANIZATIONS

American Heart Association. 7272 Greenville Ave., Dallas, TX 75231-4596. [phone] or [phone]. inquire @heart.org. http://www.americanheart.org .

Congenital Heart Disease Information and Resources. 1561 Clark Dr., Yardley, PA 19067. http://www.tchin.org .

Texas Heart Institute Heart Information Service. PO Box 20345, Houston, TX 77225-0345. [phone].http://www.tmc.edu/thi/his.html .

Melissa Knopper

disease heart Congenital

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Congenital hypothyroid syndrome

I Congenital hypothyroid syndrome

Definition

Congenital hypothyroid syndrome is a condition in which a child is born with a deficiency in thyroid gland activity or thyroid hormone levels.

Description

The thyroid gland is a small gland in the front of the neck that secretes thyroid hormones called thyroxine (T4) and triiodothyronine (T3) into the bloodstream. Some of the T4 is converted into T3 by the liver and kidney. These thyroid hormones help regulate a great number of processes. A deficiency in the level of these hormones can affect the brain, heart, muscles, skeleton, digestive tract, kidneys, reproductive function, blood cells, other hormone systems, heat production, and energy metabolism.

In most cases of congenital hypothyroidism, the thyroid gland is either completely absent or severely underdeveloped. Sometimes thyroid tissue is located in ectopic, or abnormal, locations along the neck.

Other abnormalities can lead to congenital hypothyroidism including:

•abnormal synthesis of thyroid hormones;

•abnormal synthesis of thyroid-stimulating hormone (TSH) or thyrotropin-releasing hormone (TRH), which are regulatory hormones that affect the production of thyroid hormones;

•abnormal response to thyroid hormones, TSH or TRH;

•inadvertent administration of harmful drugs or substances to the pregnant mother, possibly resulting in temporary congenital hypothyroidism in the newborn;

•dietary deficiency of iodine, a raw component vital to the manufacture thyroid hormones.

Genetic profile

Most causes of congenital hypothyroidism are not inherited. Some abnormalities in thyroid hormone synthesis (TSH synthesis), or the response to TSH, are inherited in autosomal recessive fashion. This means that both parents have one copy of the changed (mutated) gene but do not have the condition. Abnormal response to thyroid hormone may be an autosomal dominant condition, meaning that only one parent has to pass on the gene mutation in order for the child to be affected with the syndrome.

K E Y T E R M S

Congenital—Refers to a disorder which is present at birth.

Ectopic—Tissue found in an abnormal location.

Hypothyroid—Deficiency in thyroid gland activity or thyroid hormone levels.

Jaundice—Yellowing of the skin or eyes due to excess of bilirubin in the blood.

Levothyroxine—A form of thyroxine (T4) for replacement of thyroid hormones in hypothryoidism.

Myxedema—Swelling of the face, hands, feet, and genitals due to hypothyroidism.

Scintigraphy—Injection and detection of radioactive substances to create images of body parts.

Thyroxine (T4)—Thyroid hormone.

Triiodothyronine (T3)—Thyroid hormone.

Demographics

Congenital hypothyroidism occurs in one in every 4,000 newborns in the United States. It is twice as common in girls as in boys. The condition is less common in African Americans and more common in Hispanics and Native Americans.

Signs and symptoms

The signs and symptoms of congenital hypothyroidism are difficult to observe because the mother passes along some of her thyroid hormones to the fetus during pregnancy. Even if the newborn is completely lacking a thyroid gland, it may not be obvious in the early stages of life. Ectopic thyroid tissue may also provide enough thyroid hormones for a short period of time.

Rarely, the affected newborn will exhibit jaundice (yellow skin), noisy breathing, and enlarged tongue. If hypothyroidism continues undetected and untreated, the infant may gradually demonstrate feeding problems, constipation, sluggishness, sleepiness, cool hands and feet, and failure to thrive. Other signs include protruding abdomen, slow pulse, enlarged heart, dry skin, delayed teething, and coarse hair. Affected children may also have myxedema, which is swelling of the face, hands, feet, and genitals. Hypothyroidism eventually leads to marked retardation in physical growth, mental development, and sexual maturation.

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