Medical Management of CAH: Transition from Childhood to Adulthood

by Phyllis W. Speiser, M.D.

As most readers of this newsletter know, congenital adrenal hyperplasia (CAH) is a group of inherited disorders caused by inborn errors in the natural production of essential steroid hormones by the adrenal glands. The most common form, (CAH-21), is a result of low or absent activity of the 21-hydroxylase enzyme. The classic type of CAH-21 is present in about 1 in 10,000 to 1 in 15,000 live births worldwide, and about 75% of these patients suffer from salt-wasting and potentially deadly adrenal insufficiency. The other 25% of classic CAH-21 patients, called simple virilizers, have a non-salt-wasting form recognized by genital ambiguity in affected females, and by signs of androgen (male hormone) excess in later childhood. Nonclassic CAH-21 is the mild form of the disorder, detected in up to 1-3% of certain populations. The mild form of CAH-21 may be mistaken for early adrenarche (the increase in the production of androgens by the adrenal cortex that normally occurs at ages 8-9), a generally benign form of early pubic hair development in younger children. It may also be mistaken for polycystic ovarian syndrome with unwanted facial and body hair, irregular menstrual periods, and acne in young women. Nonclassic CAH is not life-threatening, and is not usually associated with genital ambiguity. This article will address issues relating to transition of CAH care from the pediatric age group to the adult.

Issues of concern to the pediatric endocrinologist, pediatrician, and young CAH family include making sure the diagnosis is correct, getting timely medical treatment, understanding when surgical intervention may be indicated, obtaining genetic counseling, and monitoring growth. With the transition from childhood to adolescence to adult care, growth and puberty remain important, but additional new concerns develop. Among such issues are psychosexual adaptation and reproduction.

Growth: Although children with CAH grow too rapidly, they may finish growth prematurely, so that adult height is shorter than average. Balancing medical treatment to maintain appropriate blood hormone levels is often complicated in CAH. Untreated or inadequately treated children grow rapidly and may not reach their height potential, but on the other hand, those treated with excessive medication doses suffer growth retardation. Since over-zealous medical treatment is a major cause of poor growth, it is important to treat CAH children with the lowest dose effective in maintaining adrenocortical hormones in a reasonable range. Optimal levels of these hormones will change with age and sex. Although the topic of growth inhibition by excessive treatment has been studied in infants and young children, there has been no careful study of whether less stringent control at puberty is effective in promoting maximal growth. There is still only very scant information about experimental treatment regimens and how they alter adult height among CAH patients. For instance, some children have been treated with low-dose conventional therapy in addition to two other oral drugs: an aromatase inhibitor and an androgen receptor blocker.

Another experimental treatment program involves standard medication combined with daily injections of growth hormone and monthly injections of Lupron, a gonadotropin-releasing hormone (GnRH) analog that suppresses puberty. Clearly, these experimental regimens are complex and would be difficult to manage for many patients. Thus, such regimens are not the current standard of care. The heights of individuals with nonclassic CAH are not significantly different from family heights, and thus they would seldom be candidates for extreme forms of height-enhancing treatment.

Puberty: Puberty may occur early, late, or on time in CAH patients. Since pubertal hormones contribute to growth and height attainment, it is important for puberty to be properly timed. A child whose hormone levels are poorly controlled may grow rapidly, then abruptly stop growing. Girls who are inadequately treated tend to have delayed onset of their menstrual periods. In some cases, additional treatment may be necessary to induce periods. Boys should be examined for normal pubertal development, as well. One particular concern in boys is the development of testicular masses due to poor hormonal control (see below, Reproductive function in CAH males).

Psychosexual development: Girls with classic CAH, especially salt-wasters, express more typical male play in childhood, are more physically aggressive, and show less interest in infants and maternal nurturing compared with other girls. Yet despite this early atypical female behavior, most CAH girls express female-typical gender identity (that is, they are girls in their own minds) and show heterosexual orientation. Only in very rare cases have CAH women decided to undergo sex change, negating their sex of rearing. Gender-atypical behavior has not been observed in CAH males. Psychological support from professionals experienced in treating gender-related problems should be sought by families on an as-needed basis. This is particularly important at the time of diagnosis in severely affected females, and in adolescence, especially if genital surgery is performed. It is important to know that overt psychiatric disturbances are not common among CAH patients.

Reproductive function in CAH women: Reproductive problems for women with CAH usually become apparent in adolescent women who have poor hormonal control. Some patients have a clinical picture similar to polycystic ovarian syndrome, with multiple ovarian cysts, irregular menstrual bleeding, excess facial and body hair, and acne. Adrenalectomy may be considered when medical therapies are unsuccessful in achieving adrenal suppression in severely affected CAH women. In some cases, this may allow conception and fertility. Adrenalectomized patients must still be followed with medical treatment since they are prone to adrenal crisis and death if lifelong glucocorticoid treatment is interrupted.

Reproductive function in nonclassic CAH is more consistently normal. In fact, many cases of mild 21-hydroxylase deficiency, both male and female, go undiagnosed for lack of clinically important symptoms. At present, there is no test to predict which individuals affected with nonclassic CAH will progress and suffer adverse consequences of their hormonal imbalance.

Pregnancy outcome in women with CAH: A recent review found that up to about 80% of simple virilizers and 60% of salt-wasters can bear children. French investigators found that about 50% of women affected with nonclassic CAH became pregnant before the diagnosis of mild 21-hydroxylase deficiency was made, without receiving any specific treatment. Among the other 50%, those who desired pregnancy conceived during hydrocortisone treatment; and only one in twenty women required additional treatment with Clomid, a standard fertility drug, to conceive. Despite high levels of maternal testosterone (male hormone) during pregnancy, unaffected female offspring, even of classic CAH mothers, show no genital ambiguity. This is because the placental aromatase enzyme prevents maternal testosterone from reaching the fetus.

Reproductive function in CAH males: Impaired reproductive function is less frequent among men with classic CAH compared with affected women. Most CAH males are able to father children, or at least have adequate sperm counts. Low sperm counts, observed in both classic and nonclassic CAH, do not preclude fertility. Testicular adrenal rests (also referred to as “testicular tumors of adrenogenital syndrome”), may occur in CAH males, especially if they are inadequately treated salt-wasters. For this reason, it is recommended that by adolescence all CAH boys have careful testicular examinations and a baseline testicular sonogram. The preferred treatment consists of effective adrenal hormone suppression. Male infertility and testicular adrenal rest tumors are uncommon in nonclassic CAH.

Other problems associated with CAH: The incidence of adrenal masses increases with age, and is higher in CAH than in the general population. Most adrenal masses associated with CAH are benign.

Medical treatment: With the completion of growth, CAH patients may be managed with more potent glucocorticoids (for instance, prednisone or dexamethasone, rather than hydrocortisone). These drugs are not often used routinely in children because of their greater tendency to cause growth suppression. Treatment during pregnancy requires special consideration, depending on whether one is treating the mother with classic CAH (where hydrocortisone or prednisone are used), or a potentially affected fetus (where dexamethasone is used because it crosses the placenta intact). Patients treated for nonclassic CAH before or during the child-bearing years may not require treatment throughout adult life, if symptoms abate. Patients on long-term prednisone and dexamethasone should be carefully monitored for potential development of excess weight gain, hypertension, and high blood glucose. Some patients may be able to reduce or discontinue fludrocortisone (Florinef®) in later childhood or adolescence. The reason for this is not entirely understood, but may relate to increasing salt consumption with age, and to better conservation of salt by the mature body. There are other treatments for CAH women that supplement glucocorticoid therapy. These include cosmetic hair removal, topical and oral anti-acne medications, and drugs that either reduce production (e.g., oral contraceptives) or block action (e.g., flutamide or cyproterone, not approved for this use in the U.S.) of male hormones.

Surgical treatment: In the past, surgical correction of genital ambiguity was considered an emergency to be repaired, at least in part, before the infant was discharged from the hospital, or in the first few months of life. Current thinking and practice are evolving to allow the families to play a greater decision-making role in situations that do not require immediate attention. In some centers, a concerted surgical repair may be performed in a single stage in early life, while others will delay vaginal reconstruction until nearer the time a girl is mature enough to become sexually active. The decision of whether, when, and what type of genital surgery is desirable needs to be decided by the family and/or patient, experienced surgeons, and endocrinologist; surgery is not necessary in many cases.

Genetic counseling: The diagnosis of CAH is most often made on clinical grounds and on the basis of hormone measurements. Genetic counseling is useful in helping the family understand the implications of the diagnosis. There are several circumstances when genetic testing is important, especially, prenatal diagnosis and newborn screening with questionable results. Another common situation arises when a woman has been told she has “CAH” and is treated with glucocorticoids, but the hormonal measurements upon which the diagnosis was made are either unavailable or in doubt. Since hormonal diagnosis is unreliable during or immediately following glucocorticoid treatment or during pregnancy, genetic testing is a viable alternative. Genetic testing may also be done for those who have been diagnosed with nonclassic CAH who wish to know whether they carry a classic trait or allele. The estimated risk of a nonclassic CAH parent and a partner of unknown genetic status of having a child affected with classic CAH is about 1 in 1,000. Since this overall risk is relatively low compared with the 1 in 8 risk to a couple who have already produced a child with classic CAH, prenatal treatment and invasive prenatal diagnosis seem unwarranted, especially now that newborn screening is performed in most states.

Carriers or Heterozygotes: Family members often wish to know their risk of transmitting CAH. Parents of a child with CAH have a 50% (1 in 2) risk of transmitting the CAH trait to offspring, and this risk is the same in each successive pregnancy. Thus, there is a 25% (1 in 4) disease risk for each sibling of a CAH patient born to the same parents. Carriers of a single CAH trait do not usually suffer from any significant symptoms or hormone imbalance, and are consequently not candidates for hormonal replacement therapy.

Classic CAH is a congenital disease with far-reaching ramifications in childhood, adolescence and adult life. Much progress has been made in understanding various aspects of CAH, but several areas remain to be studied. Nonclassic CAH is of variable severity, and should only be treated in cases with overt clinical evidence of androgen excess. Whereas treatment duration is lifelong in classic disease, this is not necessarily so for the nonclassic disorder. Patients, parents and family members should be aware of the changing needs of CAH patients throughout life, and seek appropriate medical care.

Phyllis W. Speiser, M.D., a member of CARES Foundation’s Scientific and Medical Advisory Board, is Chief of the Division of Pediatric Endocrinology at Schneider Children’s Hospital in New Hyde Park, NY.