Congenital Adrenal Hyperplasia and Related Disorders

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Chapter 570 Congenital Adrenal Hyperplasia and Related Disorders

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of cortisol biosynthesis (normal adrenal steroidogenesis is discussed in Chapter 568). Cortisol deficiency increases secretion of corticotropin (ACTH), which in turn leads to adrenocortical hyperplasia and overproduction of intermediate metabolites. Depending on the enzymatic step that is deficient, there may be signs, symptoms, and laboratory findings of mineralocorticoid deficiency or excess; incomplete virilization or premature puberty in affected males; and virilization or sexual infantilism in affected females (Figs. 570-1 and 570-2 and Table 570-1).

570.1 Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Etiology

More than 90% of congenital adrenal hyperplasia (CAH) cases are caused by 21-hydroxylase deficiency. This P450 enzyme (CYP21, P450c21) hydroxylates progesterone and 17-hydroxyprogesterone (17-OHP) to yield 11-deoxycorticosterone (DOC) and 11-deoxycortisol, respectively (see Fig. 568-1). These conversions are required for synthesis of aldosterone and cortisol, respectively. Both hormones are deficient in the most severe, “salt-wasting” form of the disease. Slightly less severely affected patients are able to synthesize adequate amounts of aldosterone but have elevated levels of androgens of adrenal origin; this is termed simple virilizing disease. These 2 forms are collectively termed classical 21-hydroxylase deficiency. Patients with nonclassical disease have relatively mildly elevated levels of androgens and may have signs of androgen excess after birth.

Genetics

There are 2 steroid 21-hydroxylase genes—CYP21P (CYP21A1P, CYP21A) and CYP21 (CYP21A2, CYP21B)—which alternate in tandem with 2 genes for the 4th component of complement (C4A and C4B) in the human leukocyte antigen (HLA) major histocompatibility complex on chromosome 6p21.3 between the HLA-B and HLA-DR loci. Many other genes are located in this cluster. CYP21 is the active gene; CYP21P is 98% identical in DNA sequence to CYP21 but is a pseudogene due to 9 different mutations. More than 90% of mutations causing 21-hydroxylase deficiency are recombinations between CYP21 and CYP21P. Approximately 20% are deletions generated by unequal meiotic crossing-over between CYP21 and CYP21P, whereas the remainder is nonreciprocal transfers of deleterious mutations from CYP21P to CYP21, a phenomenon termed gene conversion.

The deleterious mutations in CYP21P have different effects on enzymatic activity when transferred to CYP21. Several mutations completely prevent synthesis of a functional protein, whereas others are missense mutations (they result in amino acid substitutions) that yield enzymes with 1-50% of normal activity. Disease severity correlates well with the mutations carried by an affected individual; for example, patients with salt-wasting disease usually carry mutations on both alleles that completely destroy enzymatic activity. Patients are frequently compound heterozygotes for different types of mutations (i.e., 1 allele is less severely affected than the other), in which case the severity of disease expression is largely determined by the activity of the less severely affected of the 2 alleles.

Pathogenesis and Clinical Manifestations

Prenatal Androgen Excess

The most important problem caused by accumulation of steroid precursors is that 17-hydroxyprogesterone is shunted into the pathway for androgen biosynthesis, leading to high levels of androstenedione that are converted outside the adrenal gland to testosterone. This problem begins in affected fetuses by 8-10 wk of gestation and leads to abnormal genital development in females (see Figs. 570-1 and 570-2).

The external genitals of males and females normally appear identical early in gestation (Chapter 576). Affected females, who are exposed in utero to high levels of androgens of adrenal origin, have masculinized external genitalia (see Figs. 570-1 and 570-2). This is manifested by enlargement of the clitoris and by partial or complete labial fusion. The vagina usually has a common opening with the urethra (urogenital sinus). The clitoris may be so enlarged that it resembles a penis; because the urethra opens below this organ, some affected females may be mistakenly presumed to be males with hypospadias and cryptorchidism. The severity of virilization is usually greatest in females with the salt-losing form of 21-hydroxylase deficiency. The internal genital organs are normal, because affected females have normal ovaries and not testes and thus do not secrete antimüllerian hormone.

Prenatal exposure of the brain to high levels of androgens may influence subsequent sexually dimorphic behaviors in affected females. Girls tend to be interested in masculine toys such as cars and trucks and often show decreased interest in playing with dolls and demonstrate aggressive play behavior. Women may have decreased interest in maternal roles. There is an increased frequency of homosexuality in affected females. Nonetheless, most function heterosexually and do not have gender identity confusion or dysphoria. It is unusual for affected females to assign themselves a male role.

Male infants appear normal at birth. Thus, the diagnosis may not be made in boys until signs of adrenal insufficiency develop. Because patients with this condition can deteriorate quickly, infant boys are more likely to die than infant girls. For this reason, many states and countries have instituted newborn screening for this condition (see Newborn Screening, later).

Postnatal Androgen Excess

Untreated or inadequately treated children of both sexes develop additional signs of androgen excess after birth. Boys with the simple virilizing form of 21-hydroxylase deficiency often have delayed diagnosis because they appear normal and rarely develop adrenal insufficiency.

Signs of androgen excess include rapid somatic growth and accelerated skeletal maturation. Thus, affected patients are tall in childhood but premature closure of the epiphyses causes growth to stop relatively early, and adult stature is stunted (see Fig. 570-1). Muscular development may be excessive. Pubic and axillary hair may appear; and acne and a deep voice may develop. The penis, scrotum, and prostate may become enlarged in affected boys; however, the testes are usually prepubertal in size so that they appear relatively small in contrast to the enlarged penis. Occasionally, ectopic adrenocortical cells in the testes of patients become hyperplastic similarly to the adrenal glands, producing testicular adrenal rest tumors (Chapter 578). The clitoris may become further enlarged in affected females (see Fig. 570-1). Although the internal genital structures are female, breast development and menstruation may not occur unless the excessive production of androgens is suppressed by adequate treatment.

Similar but usually milder signs of androgen excess may occur in nonclassical 21-hydroxylase deficiency. In this attenuated form, cortisol and aldosterone levels are normal and affected females have normal genitals at birth. Males and females may present with precocious pubarche and early development of pubic and axillary hair. Hirsutism, acne, menstrual disorders, and infertility may develop later in life. However, many females and males are completely asymptomatic.

Laboratory Findings (See Table 570-1)

Patients with salt-losing disease have typical laboratory findings associated with cortisol and aldosterone deficiency, including hyponatremia, hyperkalemia, metabolic acidosis, and often hypoglycemia, but these abnormalities can take 10-14 days or longer to develop after birth. Blood levels of 17-hydroxyprogesterone are markedly elevated. However, levels of this hormone are high during the 1st 2-3 days of life, even in unaffected infants and especially if they are sick or premature. After infancy, once the circadian rhythm of cortisol is established, 17-hydroxyprogesterone levels vary in the same circadian pattern, being highest in the morning and lowest at night. Blood levels of cortisol are usually low in patients with the salt-losing type of disease. They are often normal in patients with simple virilizing disease but inappropriately low in relation to the ACTH and 17-hydroxyprogesterone levels. In addition to 17-hydroxyprogesterone, levels of androstenedione and testosterone are elevated in affected females; testosterone is not elevated in affected males because normal infant males have high testosterone levels compared with those seen later in childhood. Levels of urinary 17-ketosteroids and pregnanetriol are elevated but are now rarely used clinically because blood samples are easier to obtain than 24-hr urine collections. ACTH levels are elevated but have no diagnostic utility over 17-hydroxyprogesterone levels. Plasma levels of renin are elevated, and serum aldosterone is inappropriately low for the renin level. However, renin levels are high in normal infants in the 1st few weeks of life.

Diagnosis of 21-hydroxylase deficiency is most reliably established by measuring 17-hydroxyprogesterone before and 30 or 60 min after an intravenous bolus of 0.125-0.25 mg of cosyntropin (ACTH 1-24). Nomograms exist that readily distinguish normals and patients with nonclassical and classical 21-hydroxylase deficiency. Heterozygous carriers of this autosomal recessive disorder tend to have higher ACTH-stimulated 17-hydroxyprogesterone levels than genetically unaffected individuals, but there is significant overlap between subjects in these 2 categories. However, in infants with frank electrolyte abnormalities or circulatory instability, it may not be possible or necessary to delay treatment to perform this test, as levels of precursors will be sufficiently elevated on a random blood sample to make the diagnosis.

Differential Diagnosis

Intersex conditions are discussed more generally in Chapter 582. The initial step in evaluating an infant with ambiguous genitals is a thorough physical examination to define the anatomy of the genitals, locate the urethral meatus, palpate the scrotum or labia and the inguinal regions for testes (palpable gonads almost always indicate the presence of testicular tissue and thus that the infant is a genetic male), and look for any other anatomic abnormalities. Ultrasonography is helpful in demonstrating the presence or absence of a uterus and can often locate the gonads. A rapid karyotype (such as fluorescence in situ hybridization of interphase nuclei for X and Y chromosomes) can quickly determine the genetic sex of the infant. These results are all likely to be available before the results of hormonal testing and together allow the clinical team to advise the parents as to the genetic sex of the infant and the anatomy of internal reproductive structures. Injection of contrast medium into the urogenital sinus of female pseudohermaphrodites demonstrates a vagina and uterus, and most surgeons utilize this information to formulate a plan for surgical management.

Newborn Screening

Because 21-hydroxylase deficiency is often undiagnosed in affected males until they have severe adrenal insufficiency, all states in the USA and many other countries have instituted newborn screening programs. These programs analyze 17-hydroxyprogesterone levels in dried blood obtained by heel-stick and absorbed on filter paper cards; the same cards are screened in parallel for other congenital conditions such as hypothyroidism and phenylketonuria. Potentially affected infants are typically quickly recalled for additional testing (electrolytes and repeat 17-hydroxyprogesterone determination) at approximately 2 wk of age. Infants with salt-wasting disease often have abnormal electrolytes by this age but are usually not severely ill. Thus, screening programs are effective in preventing many cases of adrenal crisis in affected males. The nonclassical form of the disease is not reliably detected by newborn screening, but this is of little clinical significance because adrenal insufficiency does not occur in this type of 21-hydroxylase deficiency.

The main difficulty with current newborn screening programs is that to reliably detect all affected infants, the cutoff 17-hydroxyprogesterone levels for recalls are set so low that there is a very high frequency of false-positive results (i.e., the test has a low positive predictive value of approximately 1%). This problem is worst in premature infants. Positive predictive value can be improved by using cutoff levels based on gestational age, and by utilizing more specific 2nd-tier screening methods such as liquid chromatography followed by tandem mass spectrometry (LC-MS/MS).

Treatment

Glucocorticoid Replacement

Cortisol deficiency is treated with glucocorticoids. Treatment also suppresses excessive production of androgens by the adrenal cortex and thus minimizes problems such as excessive growth and skeletal maturation and virilization. This often requires larger glucocorticoid doses than are needed in other forms of adrenal insufficiency, typically 15-20 mg/m2/24 hr of hydrocortisone daily administered orally in 3 divided doses. Affected infants usually require dosing at the high end of this range. Double or triple doses are indicated during periods of stress, such as infection or surgery. Glucocorticoid treatment must be continued indefinitely in all patients with classical 21-hydroxylase deficiency but may not be necessary in patients with nonclassical disease unless signs of androgen excess are present. Therapy must be individualized. It is desirable to maintain linear growth along percentile lines; crossing to higher height percentiles may suggest undertreatment, whereas loss of height percentiles often indicates overtreatment with glucocorticoids. Overtreatment is also suggested by excessive weight gain. Pubertal development should be monitored by periodic examination, and skeletal maturation is evaluated by serial radiographs of the hand and wrist for bone age. Hormone levels, particularly 17-hydroxyprogesterone and androstenedione, should be measured early in the morning, before taking the morning medications, or at a consistent time in relation to medication dosing. In general, desirable 17-hydroxyprogesterone levels are in the high-normal range or several times normal; low-normal levels can usually be achieved only with excessive glucocorticoid doses.

Menarche occurs at the appropriate age in most girls in whom good control has been achieved; it may be delayed in girls with suboptimal control.

Children with simple virilizing disease, particularly males, are frequently not diagnosed until 3-7 yr of age, at which time skeletal maturation may be 5 yr or more in advance of chronological age. In some children, especially if the bone age is 12 yr or more, spontaneous gonadotropin-dependent puberty may occur when treatment is instituted, because therapy with hydrocortisone has suppressed production of adrenal androgens and stimulated release of pituitary gonadotropins if the appropriate level of hypothalamic maturation is present. This form of superimposed true precocious puberty may be treated with a gonadotropin hormone-releasing hormone analog such as leuprolide.

Males with 21-hydroxylase deficiency who have had inadequate corticosteroid therapy may develop adrenal rest testicular tumors, which usually regress with increased steroid dosage. Testicular MRI, ultrasonography, and color flow Doppler examination help define the character and extent of disease. Testis-sparing surgery for steroid-unresponsive tumors has been reported.

Mineralocorticoid Replacement

Patients with salt-wasting disease (i.e., aldosterone deficiency) require mineralocorticoid replacement with fludrocortisone. Infants may have very high mineralocorticoid requirements in the 1st few mo of life, usually 0.1-0.3 mg daily in 2 divided doses but occasionally up to 0.4 mg daily, and often require sodium supplementation (sodium chloride, 8 mmol/kg) in addition to the mineralocorticoid. Older infants and children are usually maintained with 0.05-0.1 mg daily of fludrocortisone. In some patients, simple virilizing disease may be easier to control with a low dose of fludrocortisone in addition to hydrocortisone even when these patients have normal aldosterone levels in the absence of mineralocorticoid replacement. Therapy is evaluated by monitoring of vital signs; tachycardia and hypertension are signs of overtreatment with mineralocorticoids. Serum electrolytes should be measured frequently in early infancy as therapy is adjusted. Plasma renin activity is a useful way to determine adequacy of therapy; it should be maintained in or near the normal range but not suppressed.

Additional approaches to improve outcome have been proposed but have not yet become the standard of care. These include an antiandrogen such as flutamide to block the effects of excessive androgen levels, and/or an aromatase inhibitor such as anastrozole, which blocks conversion of androgens to estrogen and thus retards skeletal maturation, a process that is sensitive to estrogens in both boys and girls. Aromatase inhibitors generally should not be used in pubertal girls because they will obviously retard normal puberty and may expose the ovaries to excessive levels of gonadotropins. Growth hormone, with or without LHRH agonists to retard skeletal maturation, has been suggested to improve adult height.

Surgical Management of Ambiguous Genitals

Significantly virilized females usually undergo surgery between 2-6 mo of age. If there is severe clitoromegaly, the clitoris is reduced in size, with partial excision of the corporal bodies and preservation of the neurovascular bundle; however, moderate clitoromegaly may become much less noticeable even without surgery as the patient grows. Vaginoplasty and correction of the urogenital sinus usually are performed at the time of clitoral surgery; revision in adolescence is often necessary.

Risks and benefits of surgery should be fully discussed with parents of affected females. There is limited long-term follow-up of functional outcomes in patients who have undergone modern surgical procedures, although it appears that there is frequent sexual dysfunction that increases in frequency and severity with the initial degree of genital virilization. Sex assignment of infants with disorders of sexual differentiation (including CAH) is usually based on expected sexual functioning and fertility in adulthood with early surgical correction of the external genitals to conform with the sex assignment. Confused psychosexual identity is not common with CAH. Lay and medical opponents of this practice for other intersex conditions state that it ignores any prenatally biased gender role predisposition and precludes the patient from having any decision as to his or her own preferred sexual identity and what surgical correction of the genitals should be performed. These individuals and groups say treatment should be aimed primarily at educating patient, family, and others about the medical condition, its treatment, and how to deal with the intersex condition. They propose that surgery should be delayed until the patient decides on what, if any, correction should be performed.

In adolescent and adult females with poorly controlled 21-hydroxylase deficiency (hirsutism, obesity, amenorrhea) bilateral laparoscopic adrenalectomy (with hormone replacement) may be an alternative to standard medical hormone replacement therapy, but patients treated in this way may be more susceptible to acute adrenal insufficiency if treatment is interrupted because the adrenal glands have been removed. Moreover, they may exhibit signs of elevated ACTH levels such as abnormal pigmentation.

Prenatal Treatment

Besides genetic counseling, the main goal of prenatal diagnosis is to facilitate appropriate prenatal treatment of affected females. Mothers with pregnancies at risk are given dexamethasone, a steroid that readily crosses the placenta, in an amount of 20 µg/kg prepregnancy maternal weight daily in 2 or 3 divided doses. This suppresses secretion of steroids by the fetal adrenal, including secretion of adrenal androgens. If started by 6 wk of gestation, it ameliorates virilization of the external genitals in affected females. Chorionic villus biopsy is then performed to determine the sex and genotype of the fetus; therapy is continued only if the fetus is an affected female. DNA analysis of fetal cells isolated from maternal plasma for sex determination and CYP21 gene analysis may permit earlier identification of the affected female fetus. Children exposed to this therapy have slightly lower birthweights. Effects on personality or cognition, such as increased shyness, have been suggested but not consistently observed. At present there is insufficient information to determine whether there are any long-term risks, particularly in the males and unaffected females who derive no direct benefit from the treatment. Maternal side effects of prenatal treatment have included edema, excessive weight gain, hypertension, glucose intolerance, cushingoid facial features, and severe striae. Prenatal treatment is therefore carried out only under institutional protocols in some locales, but it is offered as an option outside the research setting by high-risk obstetricians in other communities.

Bibliography

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570.2 Congenital Adrenal Hyperplasia Due to 11β-Hydroxylase Deficiency

570.3 Congenital Adrenal Hyperplasia Due to 3β-Hydroxysteroid Dehydrogenase Deficiency

570.4 Congenital Adrenal Hyperplasia Due to 17-Hydroxylase Deficiency

570.5 Lipoid Adrenal Hyperplasia

570.6 Deficiency of P450 Oxidoreductase (Antley-Bixler Syndrome)

Etiology, Pathogenesis, and Clinical Manifestations

P450 oxidoreductase (POR, gene located on chromosome 7q11.3) is required for the activity of all microsomal cytochrome P450 enzymes (Chapter 568) including the adrenal enzymes CYP17 and CYP21. Thus, complete POR deficiency abolishes all microsomal P450 activity. This is embryonically lethal in mice and presumably in humans as well. Patients with mutations that decrease but do not abolish POR activity have partial deficiencies of 17-hydroxylase and 21-hydroxylase activities in the adrenals. Deficiency of 17-hydroxylase leads to incomplete masculinization in males; 21-hydroxylase deficiency may lead to virilization in females. Additionally, aromatase (CYP19) activity in the placenta is decreased, leading to unopposed action of androgens produced by the fetal adrenal. This exacerbates virilization of female fetuses and may virilize the mother of an affected fetus as well. Although it is puzzling that affected females could be virilized despite a partial deficiency in CYP17 (which is required for androgen biosynthesis), an alternative biosynthetic pathway may be utilized in which 17-hydroxyprogesterone is converted to 5α-pregnane-3α,17α-diol-20-one, a metabolite that is a much better substrate for the 17,20-lyase activity of CYP17 than the usual substrate, 17-hydroxypregnenolone (Chapter 568). The metabolite is then converted in several enzymatic steps to dihydrotestosterone, a potent androgen.

Because many other P450 enzymes are affected, patients often (but not invariably) have other congenital anomalies collectively referred to as Antley-Bixler syndrome. These include craniosynostosis; brachycephaly; frontal bossing; severe midface hypoplasia with proptosis and choanal stenosis or atresia; humeroradial synostosis; medial bowing of ulnas; long, slender fingers with camptodactyly; narrow iliac wings; anterior bowing of femurs; and malformations of the heart and kidneys. Studies of mutant mice suggest that the metabolic defects responsible for these anomalies include defective metabolism of retinoic acid, leading to elevated levels of this teratogenic compound, and deficient biosynthesis of cholesterol.

570.7 Aldosterone Synthase Deficiency

570.8 Glucocorticoid-Suppressible Hyperaldosteronism

Differential Diagnosis

This condition should be distinguished from primary aldosteronism due to bilateral hyperplasia or an aldosterone-producing adenoma (Chapter 572). Most cases of primary aldosteronism are sporadic although rare affected kindreds have been reported. Patients with primary aldosteronism may also have elevated levels of 18-hydroxycortisol and 18-oxocortisol, and these biochemical tests should be used cautiously to distinguish primary and glucocorticoid-suppressible aldosteronism. A therapeutic trial of dexamethasone may be helpful if aldosterone secretion is suppressed, and genetic testing should identify the hybrid gene of glucocorticoid-suppressible hyperaldosteronism if it is present.