Causes, incidence, and risk factors

3. Causes, incidence, and risk factors   Congenital adrenal hyperplasia can affect both boys and girls. People with congenital adrenal hyperplasia lack of an enzyme needed by the adrenal gland to make the hormones cortisol and aldosterone. Without these hormones, the body produces more androgen, a type of male sex hormones. This causes early (or inappropriate) appearance of male characteristics. Newborn girls with this disorder have a swollen clitoris with the urethral opening at the base (ambiguous genitalia, often appearing more male than female). The internal structures of the female reproductive tract (ovaries, uterus, and fallopian tubes) are normal. As the female grows older, some features start to appear male, such as deepening of the voice, facial hair, and failure to menstruate at puberty. No obvious problems are seen in newborn males, but changes can be seen long before puberty normally occurs. The child becomes increasingly muscular, the penis enlarges, pubic hair appears, and the voice deepens. Boys may appear to enter puberty as early as 2-3 years of age. At puberty, the testes are small. Some forms of congenital adrenal hyperplasia are more severe and cause adrenal crisis in the newborn due to salt wasting. In this salt-losing form of congenital adrenal hyperplasia, newborns develop severe symptoms shortly after birth, including vomiting, dehydration, electrolyte changes, and cardiac arrhythmias. Untreated, this condition can lead to death within 1 to 6 weeks after birth. About 1 in 10,000 to 18,000 children are born with congenital adrenal hyperplasia.

4. Symptoms   • In girls: • Ambiguous genitalia • Early appearance of pubic and armpit hair • Excessive hair growth • Deep voice • Abnormal menstrual periods • Failure to menstruate • In boys: • Early development of masculine characteristics • Well-developed musculature • Enlarged penis • Small testes • Early appearance of pubic and armpit hair • Both boys and girls will be tall as children but significantly shorter than normal as adults

5. Complications   Adrenal crisis, including hyponatremia and shock (especially in newborns) Abnormal female external genitalia (internal organs are normal) Early development of male sexual characteristics Short adult stature despite early, rapid childhood growth Tumors of the testes in adult men High blood pressure Low blood sugar Side effects of corticosteroids used as treatment Prevention   Genetic counseling is indicated for parents with a family history of congenital adrenal hyperplasia (of any type) or a family with a child who has the condition. Prenatal diagnosis is available for some forms of congenital adrenal hyperplasia. Diagnosis is made in the first trimester by chorionic villus sampling and in the second trimester by measuring hormones such as 17-hydroxyprogesterone in the amniotic fluid. A newborn screening test is available for the most common form of congenital adrenal hyperplasia and can be done on heelstick blood (as part of the routine screenings done on newborns). This test is not yet widely available.

10. Incidence and Clinical Presentation CAH due to 21-hydroxylase deficiency is seen in roughly 1 of every 15,000 live births worldwide; it is a relatively common disorder in humans. Clinically, it is seen in three primary manifestations: Simple virilizing form: Excessive prenatal production of androgens in affected females results in masculinization of the reproductive tract to a point that the sex of the newborn is not clear ("ambiguous genitalia") or appears male-like. Affected males are usually normal at birth. In both sexes, linear growth in childhood is accelerated, but the epiphyses fuse early, leading to short stature. The simple virilizing form of CAH is seen in approximately 25% of those with 21-hydroxylase deficiency. Salt-wasting form: Roughly 75% patients are unable to synthesize adequate amounts of aldosterone, which is essential for sodium homeostasis. Such individuals lose large amounts of sodium in urine, which leads to potentially fatal electrolyte and water imbalance. Individuals with severe deficiency usually present with "adrenal crisis" between 1 and 4 weeks of age; signs are often non-specific, but can include poor appetite, vomiting and failure to grow. Replacement therapy is mandatory in such patients. Non-classical form: This form of the disease is mild and usually manifest as some type of androgen excess later in life. Aldosterone deficiency is not usually observed

12. Genetics The 21-hydroxylase enzyme is encoded by the CYP21 gene. More than 50 different mutations of CYP21 have been identified, of which about 15 account for a large majority of 21-hydroxylase cases. Most mutations appear to be the result of a recombination between CYP21 and a pseudogene (CYP21P). One consequence of this multitude of mutations is that there is considerable variability in the clinical presentation of disease, ranging from severe salt-wasting or virilizing disease to milder syndromes. This disorder is seen as a simple autosomal recessive trait. Diagnosis and Prenatal Screening Most commonly, 21-hydroxylase deficiency is first suspected in a newborn infant with "ambiguous genitalia". Finding elevated blood levels of 17-hydroxyprogesterone, in conjuction with ultrasound examination of the abdomen and genital tract usually leads to a rapid diagnosis. Disorders that must be differentiated in such cases include true hermaphorditism, pseudohermaphroditism and certain types of sex chromosome abnormalities, none of which should have high concentrations of 17-hydroxyprogesterone

13. Classical and nonclassical 21-OHD CAH are diagnosed by serum elevations of the hormone 17-hydroxyprogesterone before and after a 60-minute adrenocorticotropin (ACTH) stimulation test (Figure 3). Confirmation by molecular genetic analysis of the CYP21 gene is advised. Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line for all data points is shown.

14. Prenatal diagnosis : Prenatal diagnosis and treatment are available. Prenatal diagnosis is done by analysis of fetal DNA obtained by amniocentesis or chorionic villus sampling (CVS). Prenatal treatment with the drug dexamethasone prevents virilization of the genitalia of classically affected females and must be started prior to the 9th week of pregnancy, as outlined in the algorithm below (Figure 4). Figure 4. Algorithm for prenatal diagnosis and treatment of CAH.

15. Treatment All patients with CAH, regardless of form, are treated with glucocorticoid replacment therapy. This not only alleviates glucocorticoid (i.e. cortisol) deficiency, but more importantly, provides negative feedback to suppress ACTH secretion and prevent continued adrenal stimulation. As a result, excessive 17-hydroxyprogesterone is not available as a substrate for excessive androgen production. Patients with the salt-wasting form of deficiency must also receive mineralocorticoid therapy to normalize the abnormalities in sodium balance associated with aldosterone deficiency. Prenatal treatment of the mother with glucocorticoids can prevent or reduce that the virilizing effects of fetal 21-hydroxylase deficiency. This procedure has been used in cases where couples have previously had a child with virilizing CAH. In such cases, it is known that both parents are carriers, and since only female children require prenatal treatment, the probability that the current fetus is affected is 1 in 8. Treatment of the mother with glucocorticoids must begin at 6 to 7 weeks of gestation, at which time it is almost never known whether the fetus is affected. Hence, in 7 of 8 cases, the fetus does not actually require therapy. The long term effect and safety of this procedure is poorly defined A number of surigical procedures have been developed to correct the genital abnormalities of girls with the virilizing form of CAH. These procedures are complicated by concerns about when the surgery should be performed, gender identity of the patient and other factors.

23. SCREENING Infant females with CAH often come to medical attention because the disorder causes affected females to exhibit recognizable genital abnormalities and therefore receive prompt treatment for adrenal failure and salt-wasting. However, newborn males and females that, due to the extent of their genital abnormalities are miscast as males, show no other outward signs of the disorder and are sent home.  Newborn screening allows for these children to be identified as possibly having CAH before they go into adrenal crisis and present for urgent medical attention at a time when they are beyond resuscitation. A second diagnostic test then is ordered and the diagnosis of CAH either confirmed or denied. Current newborn testing is quite effective in identifying infants with the severe form of CAH, Classical Salt-Wasting CAH.  Some babies with Simple Virilizing CAH also are detected through this process.  It is rare that a child with Non-classical or Late-onset CAH will be picked-up through this type of testing.  To learn more about Non-classical CAH diagnosis, please visit our page on Genetic Testing. The majority of infants detected through newborn screening have Salt-wasting CAH. 

24. SCREENING Infant females with CAH often come to medical attention because the disorder causes affected females to exhibit recognizable genital abnormalities and therefore receive prompt treatment for adrenal failure and salt-wasting. However, newborn males and females that, due to the extent of their genital abnormalities are miscast as males, show no other outward signs of the disorder and are sent home.  Newborn screening allows for these children to be identified as possibly having CAH before they go into adrenal crisis and present for urgent medical attention at a time when they are beyond resuscitation. A second diagnostic test then is ordered and the diagnosis of CAH either confirmed or denied. Current newborn testing is quite effective in identifying infants with the severe form of CAH, Classical Salt-Wasting CAH.  Some babies with Simple Virilizing CAH also are detected through this process.  It is rare that a child with Non-classical or Late-onset CAH will be picked-up through this type of testing.  To learn more about Non-classical CAH diagnosis, please visit our page on Genetic Testing. The majority of infants detected through newborn screening have Salt-wasting CAH. 

25. Genetic Testing for CAH The polymerase chain reaction (PCR) is a common method used for genetic testing that can tell one gene apart from another. PCR can be thought of as a "genetic Xerox machine." By using PCR, the laboratory can make up to a million copies of a specific gene or piece of a gene from a DNA sample for studies.Some laboratories use a technique called a Southern blot. In this method, extracted DNA is cut at specific sites near or within the gene and pseudogene. A specially made piece of DNA, referred to as a probe, is used to detect the specific DNA pattern of the gene and pseudogene. A Southern blot will usually find large gene deletions and rearrangements. After a lab performs a Southern blot, it will also need to perform PCR and some other method, like sequencing, in order to find those smaller changes.PCR can also be used to distinguish the pseudogene and functional gene, and in most cases can determine the number of functional genes and pseudogenes a person has in their DNA without using the Southern blot technique. Unique landmarks outside the gene and pseudogene are used to separately copy and identify the gene, the pseudogene, as well as any rearranged copies of the gene and pseudogene that might be present.

28. In families where the diagnosis of CAH due to 21-hydroxylase deficiency has been proven but a mutation cannot be identified, another test called linkage can be used to determine if a relative has the mutation or if a pregnancy is affected. Linkage cannot be performed without testing multiple family members. At least both parents must be tested, as well as a previously born affected child. Unique genetic landmarks either within the gene or pseudogene, or close to, or "linked" to the CYP21A2 gene are used to identify and follow copies of the mutated gene causing CAH from generation to generation without actually knowing the exact mutation involved. Sequencing small areas of the pseudogene and functional gene can provide good genetic information for linkage analysis. Linkage can be used to predict whether or not a subsequent child will be affected with a high degree of accuracy. Because linkage does not test for the actual mutation, however, there is a small risk that the linked genetic landmark will become unlinked and thus an incorrect result will be obtained.

29. Who Might Consider Genetic Testing?Genetic testing can be used to confirm the diagnosis of CAH and identify the mutations present in a person who is suspected of having classic or non-classic CAH. For example, genetic testing can help confirm the diagnosis in infants that have a positive newborn screen for CAH. Adults with suspected CAH due to infertility problems or women who have symptoms of androgen excess might also have their diagnosis confirmed through genetic testing.Parents of a child with CAH may want to know the genetic alterations present in their affected child. This information can be used, early in pregnancy, to determine whether a subsequent child has CAH by testing the baby through amniocentesis or chorionic villus sampling. The information could help direct prenatal treatment with dexamethasone or help families and doctors anticipate and prepare for the birth of an affected child. Genetic information can also be used for preimplantation genetic diagnosis in future pregnancies in order to significantly reduce the chance of a having another child affected with CAH

30. Genetic testing can also be used to screen an unaffected person who has no family history of CAH to determine if they carry CAH. This can be especially useful for the partners of individuals who are either affected by CAH, or are known carriers of CAH, for the purpose of family planning and pregnancy management. If both members of a couple are known carriers, they can consider the option of starting dexamethasone treatment early in the pregnancy which would reduce the degree of masculinization of the female genitalia in an affected female infant.For couples that have no known personal or family history of CAH, but are currently pregnant with a female fetus that has ambiguous genitalia detected by prenatal ultrasound, genetic testing for CAH may be appropriate after other causes have been ruled out. The advance knowledge can help the family and physicians prepare for the medical, social and emotional issues related to the diagnosis and birth of an affected child.

31. Prenatal Testing for CAHPrenatal testing can be performed by two methods. Chorionic villus sampling (CVS) is a procedure that obtains fetal cells by sampling cells from the developing placenta. The procedure is usually done with ultrasound guidance to see the physical structures of the patient and fetus. CVS is typically offered at 10-12 weeks from the last known menstrual period. As with any prenatal procedure, CVS carries with it a small risk of miscarriage. The advantage of CVS is that the procedure takes place in the first trimester and genetic test results can be obtained early in the pregnancy. The cells obtained are taken to a laboratory and grown so that the DNA can ultimately be obtained and tested.

32. Prenatal Testing for CAHThe cells obtained are taken to a laboratory and grown so that the DNA can ultimately be obtained and tested.Amniocentesis is another technique that can be used to obtain a sample of fetal cells for genetic testing. This method is typically performed at 15-20 weeks from the last menstrual period. This procedure requires that a thin needle is passed through the abdomen, under ultrasound guidance, into the fluid filled sac that surrounds the fetus. A few tablespoons of the fluid are taken from the sac. This fluid contains cells from the baby that are then grown in a laboratory. As is the case with CVS, amniocentesis is not a risk-free procedure. With amniocentesis, there is a small risk of about 1 in 200 that the procedure will cause a miscarriage. The risks and benefits must be taken into consideration when considering prenatal testing. Your doctor and genetic counselor are good resources for additional information regarding these procedures.

33. Treatment Research has shown Congenital Adrenal Hyperplasia to be a spectrum disease. That is, a condition that manifests itself in varying degrees: the severe form being Classical Salt-wasting CAH and the mild form being Non-classical CAH with Simple-Virilizing CAH somewhere in between. In all cases, however, CAH is caused by an adrenal insufficiency resulting in impaired production of hormones. All individuals affected by Classical CAH require glucocorticoid (hydrocortisone, prednisone, dexamethasone) replacement therapy. Those with a salt-wasting component to their insufficiency also require mineralocorticoids (fludrocortisone and sodium). The following pages outline medication dose guidelines for all individuals with CAH as agreed upon by the leading pediatric endocrinologists in the United States and Europe in 2002. As always, this information is provided for your reference to help you better understand decisions made regarding medication dosing and in no way should be taken to be the provision or practice of medical, nursing or professional healthcare advice or services. This information should not be considered complete or exhaustive and should not be used in place of the visit, call, consultation or advice of your physician or other healthcare provider.

34. Dosing of Medications - from the Joint LWPES/ESPE 2002 CAH Consensus Statement(pages 4050-51, footnotes omitted): Optimal Glucocorticoids Dosing. During infancy, initial reduction of markedly elevated adrenal sex hormones may require up to 25 mg hydrocortisone (HC)/m 2 .d, but typical dosing is 10-15 mg/m 2.d divided three times daily. HC oral suspension is not recommended; divided or crushed tablets of HC should be used in growing children. ...HC is considered the first drug of choice. Excessive doses, especially during infancy, may causes persistent growth suppression, obesity and other Cushingoid features. Insufficient data exist to recommend higher morning or evening dosages. Whereas HC is preferred during infancy and childhood, long-acting glucocorticoids may be an option at or near completion of linear growth. Prednisone and prednisolone need to be given twice daily.…The dose (2-4 mg/m 2.d) should be approximately one-fifth the dose of HC. The dosage of Dexamethasone is 0.25-0.375 mg/m 2.d, given once daily. Monitoring of these more potent glucocorticoids should include BP, in addition to weight, and other clinical and laboratory variables. These steroids have minimal mineralocorticoid effect, compared with HC. In children with advanced bone age, such as boys with non-salt losing CAH, initiation of therapy may precipitate central precocious puberty, requiring treatment with a GnRH agonist.

35. Mineralocorticoid use. All classic CAH patients should be treated with fludrocortisone at diagnosis in the newborn period. Dosage requirements in early infancy range from 0.05-0.30 mg/d, whereas typical maintenance doses are 0.05-0.2 mg/d, depending on the sodium intake.…Sodium chloride supplements are often needed in infancy at 1-3gm/d(17-51mEq/d), distributed in several feedings. body surface area calculator for medications

36. Although it may seem that monitoring and testing in CAH is confusing, there are several approaches that can be used to adequately assess hormone production. It is also very important to emphasize that monitoring changes in physical growth and maturation is as important, if not more important, as the laboratory testing in CAH. Growth & Bone Density Monitoring growth and maturation in CAH.Growth and weight: The rate of growth provides very important clues about treatment in CAH. In general, with proper treatment the child with CAH should grow along the same percentile for height, which reflects the height of the parents. Between two years of age and puberty, the average child grows about 2-1/2 inches per year and gains 2-3 pounds for every inch of height gain. During infancy and puberty, rates of growth are even faster than during childhood. In general, a child will usually grow along the same percentile on growth charts from infancy though adolescence. Thus, height and weight need to be both monitored and plotted on standard growth charts to assess growth in CAH.

37. Looking at growth charts and following changes in height and weight, one can detect signs of over- and undertreatment. If glucocorticoid (hydrocortisone, prednisone, dexamethasone) doses are too high, growth will slow and weight will increase. It takes about 3-6 months to appreciate changes in growth rates (changes in height). Changes in weight, though, can be seen much sooner. Increases in weight, above and beyond that which are normally expected (more than 3 lbs per inch of growth; more than 7 lbs per year), can be a sign of overtreatment. Thus, it is very useful for families to monitor weight at home. For example, if the weight increases by more than one pound over 2-4 weeks after a dose change, it may be a sign that the dose is too high. Whereas slowing of growth can represent signs of overtreatment, increased growth can reflect undertreatment. With undertreatment, there is increased androgen production, which can stimulate growth. Undertreated children may therefore climb to higher height percentiles on growth charts.

38. The importance of regular follow-upTo assess physical changes in CAH and be able to respond to signs of over- or undertreatment in a timely manner, many practitioners will see individuals with CAH every 3-4 months. Because signs of over-treatment (facial roundness) can be subtle, it is preferable to see the same practitioner at each visit. There are physical signs that clinicians can see that suggest either over- or undertreatment. With overtreatment, the face can become round. With significant overtreatment, striae (purple "stretch-marks") can occur. Features of undertreatment include dark or "dirty"-looking knuckles caused by excessive ACTH secretion. Stomach pain and being excessively tired are also symptoms of undertreatment. The blood pressure can provide clues about mineralocorticoid (Florinef, fludrocortisone) treatment. If the blood pressure is elevated, this may indicate that the mineralocorticoid dose or salt supplementation is too high and should be reduced. Yet, if the dose is normal or too low, the blood pressure is normal. Signs of pubertal development are also monitored. In girls, one of the earliest signs of puberty is breast development. In boys, enlargement of the size of the testes is the earliest signs that puberty has started. If puberty begins less than seven years of age in girls and less than nine years of age in boys, it is said to be early or "precocious". Because the adrenal hormones can affect the pituitary gland, precocious puberty is seen in CAH and warrants attention.

39. The Usefulness of Bone AgesOne of the best tools for monitoring changes in physical maturation is the "bone age". The growth centers, which can be easily visualized with an x-ray of the hand, provide a wonderful marker of long-term androgen secretion. As children get older, the shape of the growth centers change and have characteristic appearances at each age. By comparing the size and shapes of the growth centers in the child's hand to those found in a book of standards, a "bone age" can be determined. Because there is variability from practitioner to practitioner in bone age interpretation, it is useful to have bone ages interpreted by the same individual. Also, some pediatric endocrinologists may be more experienced in interpreting bone ages than general radiologists. When there is excessive androgen secretion, the skeleton matures at a more rapid pace than usual. This will result in an advanced bone age. Thus, an undertreated child at 6 years of age may have a bone age of 9 years of age. Yet, if the bone age is within a year or so of the actual age, this suggests that treatment has been fine. The bone age also reflects hormone secretion over the preceding 6-12 months. Changes in the bone age may lag behind recent periods of excess androgen secretion. Many practitioners therefore obtain bone ages every 6 to 12 months.

40. Laboratory Testing Monitoring of Hormone Levels in CAHThe levels of adrenal hormones in the blood vary over the 24-hour day. Cortisol and androgen production is highest in the morning and lowest in the afternoon and evening. Hormone levels are also affected by medications. Following a dose of glucocorticoids, androgen levels will fall. Yet, as the medication wears off, hormone levels may rise excessively. Care must be taken to consider the time of day and the timing of doses when interpreting hormone levels. There are several different approaches that can be used to assess adrenal hormone production. Urine testing is a "gold standard" and can be used to measure hormone production throughout the day. Blood testing provides important information about hormone production and is preferred by many clinicians due to convenience. Testing of hormone levels several times a day using filter paper specimens has also been shown to be an effective monitoring tool, but is not widely available.

41. Laboratory Testing Blood TestingAssessing control from a single blood test is very commonly used due to its convenience. However, a single test may not always reflect if there is adequate control of adrenal gland activity. One also needs to consider the time of day and the timing of doses in interpreting blood levels. Some hormone levels are also better than others in assessing treatment. A number of hormones that reflect adrenal gland activity can be measured in the blood. These factors include ACTH, 17 hydroxyprogesterone (17 OHP), androstenedione, and testosterone. Electrolytes and renin are used to assess mineralocorticoid replacement. Of these different hormones, androstenedione and testosterone most closely match 24-hour 17 KS production and reflect adrenal androgen production. These hormones are especially useful in prepubertal children and females. Because testosterone levels rise in puberty in males, testosterone levels are not as useful in adolescent or adult males. In comparison with androstenedione and testosterone, 17 OHP levels can fluctuate widely and may be elevated even when there is good control. The pituitary hormone ACTH has been shown to provide a nice measure of control and is elevated 75% of the time when there is undertreatment.

42. Laboratory Testing Blood TestingFor children without CAH and who are not in puberty, average levels of androstenedione are 25 ng/dl, average levels of testosterone levels are 5 ng/dl, and average 17OHP levels are 50 ng/dl. During puberty, levels of these hormones rise. It is possible to achieve normal levels of these hormones in children with CAH. Yet, treating CAH to "normalize" all hormone levels, especially 17 OHP levels, can result in growth suppression and weight gain. Thus, many clinicians aim for androstenedione and testosterone levels that are normal or modestly (about 25%) above normal. Because 17 OHP levels can fluctuate widely and be elevated when there is adequate treatment, some clinicians will accept mid-day 17 OHP levels of 500-1000 ng/dl; others will aim for lower levels. Morning levels of 17 OHP, androstenedione, and testosterone are much higher than mid-day levels, especially when there is undertreatment. This occurrence reflects the general observation that adrenal glands become more active in the early morning hours and at a time when the medication from the day before is wearing off. It can therefore be very useful to obtain morning hormone levels. It has been recently shown that when there is good control of adrenal gland activity, 17 OHP levels are less than less than 600 ng/dl in the morning before medication is given and less than 200 ng/dl during the day. In undertreated individuals, 17 OHP levels average 10,000 ng/dl in the morning before the dose, and 5000 ng/dl during the day.

43. Laboratory Testing Blood TestingTo measure if the child is getting enough salt and/or fludrocortisone, renin and electrolyte levels are measured. An elevated renin levels indicates a need for more salt and/or fludrocortisone. A suppressed renin suggests that the dose of salt and/or fludrocortisone is too high. Filter Paper SpecimensWhereas a single blood test during the day can provide important insights into CAH control, they can sometimes be misleading. If a sample is obtained in an undertreated child a few hours after a dose of hydrocortisone has been given, levels of 17OHP can decrease. As the medication wears off, 17 OHP levels can increase dramatically. One can overcome potential pitfalls of obtaining once daily samples by obtaining filter-paper specimens over the course of the day. Children with diabetes check their blood sugar by finger stick 3-4 times a day to be able to properly dose insulin levels. Similarly, one can measure 17 OHP levels on filter paper specimens taken at different times of day. Thus, one can identify times of day when levels are high and others when levels are low and adjust doses accordingly. Filter paper 17OHP levels can be measured by state laboratories that perform newborn screening for CAH using filter-paper specimens.

44. Hormone Prepubertal Mid-Pubertal Pubertal and adult Blood testing   ACTH (pg/ml) 30 (10-60)30 (10-60)30 (10-60) Androstenedione(ng/dl)25 (8-50)70 (50-100)115 (70-200) 17 OHP (ng/dl)40 (3-100) 80 (10-150)100 (25-250)T estosterone (ng/dl)5 (3-10)    Males:150 (100-300)600 (300-1000)  Female:  25 (15-35)  30 (10-55)Urine testing17 Ketosteroids (mg/24 hr) 1.5 (0.2- 3) Males 5 (3-10) 15 (10-25)Female 3.5 (2.5-8) 10 (6-14)Pregnanetriol (mg/24 hr) 0.5 1.0 2.0 -In CAH, levels of androstenedione, testosterone and 17 ketosteroids that are normal or modestly (about 25%) above normal are acceptable. Because blood 17 OHP levels can vary widely in CAH, higher 17 OHP levels are acceptable, but are usually less than 1000 ng/dl with adequate treatment.-To convert ng/dl units to pmol/L, multiply androstenedione levels by 34, 17 OHP by 30, testosterone by 34.

45. CARES strongly recommends that no surgery be done until: 1) the child is medically stable; 2) the parents are fully informed of the risks and benefits; and 3) an expert surgeon is found. Ultimately, the decision about whether and when to perform surgery is intensely personal.  Whatever you choose, you must be comfortable and confident in your decision and your choice of surgeon.  Below are some frequently asked questions that may help guide you through the decision-making process.

46. How different are our daughter’s genitals from other female children?Your daughter may look different, but she has all of the female reproductive organs. She has a uterus, vagina and ovaries. She will be able to bear children. The degree of virilization (masculinization) affecting your daughter will be can be graded on a classification known as the Prader Scale.  Your daughter’s pediatric urologist or pediatric endocrinologist will be able to tell you what Prader Level she is. Typical Prader 4

47. What is the Prader Scale and what are the Prader Scale levels?The Prader Scale is a scoring system for grading the degrees of genital masculinization.  The Prader Scale starts at “0”, which is an unvirilized female, and ends at “5” which is a completely virilized female (a female who appears externally male at birth with the labial/scrotal sac empty since there are no testicles).  The picture below shows the Prader Virilization Scores. (From Speiser and White; Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency; Endocrine Reviews 21(3): 245-291; 2000)

48. When should surgery be performed?The decision of when to have surgery can be one of the hardest.  How can we be sure that we are doing the right thing?  There is no “right decision”.   There is only what is right for you and your daughter.  Gather as much information as you can, and work to make the best decision you can. The 2002 CAH Consensus Statement states, “[b]ased on recent clinical experience, the recommended time for surgery is at 2-6 months, although this is not universal practice.  It is important to note that surgery at this stage is technically easier than at later stages.” “Technically easier,” refers to how “easy” it is for the surgeon and to the benefits of faster healing in babies. Very young children tend to heal faster following surgery, and the surgery is easier because the area disturbed is smaller. Also, following surgery, babies not yet walking, crawling or standing are less likely to pull stitches out with their movement.  How do Adult Women with CAH Feel about the Timing of Surgery? Some adult women with CAH recommend that parents wait and allow the child to make the decision as an adult.  Some adult women with CAH recommend that parents wait until the child is old enough to be consulted about her desires for surgical reconstruction. Others are grateful that their parents made the decision for them early in life and that they did not have to deal with growing up with genital anomalies. 

49. What are the differences among reduction clitoroplasty, vaginoplasty and labioplasty?Genital reconstruction in CAH generally involves three separate procedures. These are often done at the same time when early surgery is chosen.  Clitoral reduction surgery (clitoroplasty) involves reducing the size of the clitoris by removing a portion of the erectile tissue.  If done properly, the nerve bundles are preserved and left intact.  The CAH Consensus Statement states that, “[s]urgery to reduce the clitoral size requires careful consideration.  Total removal of the clitoris should never be performed.  If clitoral reduction is elected, it is crucial to preserve the neurovascular bundle, the glans, and the preputial skin related to the glans.” Vaginoplasty involves rebuilding the vaginal area to improve functioning of the vagina and urethra.  This involves creating a vaginal opening on the perineum separate from the urethra. It is often done by moving the recessed vagina out to the perineum or can include complete separation of the vagina from urethra at the site of confluence.

50. Confluence in CAH: where the urethra and vagina meet. (courtesy RC Rink) Labioplasty is the construction of the labia majora and/or minora when absent or inadequate. Most children with CAH are lacking labia minora so they are created. The labia majora , while present often require repositioning.