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Congenital Adrenal Hyperplasia

INTRODUCTION
Background: The term congenital adrenal hyperplasia encompasses several autosomal recessive disorders that share complete or partial deficiency of an enzyme involved in cortisol or aldosterone synthesis. All disorders of this group share the common feature of a deficiency or relative defect in cortisol or aldosterone synthesis resulting in some degree of cortisol and/or aldosterone deficiency.

Pathophysiology: The clinical manifestations of the disease relate to the degree of cortisol and/or aldosterone deficiency and, in some cases, to the accumulation of precursor adrenocortical hormones. These precursors cause abnormalities such as virilization or hypertension when present in supraphysiologic concentrations. The phenotype depends on which particular protein is affected and the severity of the mutation or degree of deletion of the particular gene encoding for the protein involved in steroidogenesis. The phenotype can vary from clinically inapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease, which is expressed in adolescence or adulthood (nonclassical adrenal hyperplasia), to severe disease resulting in adrenal insufficiency in infancy, with or without virilization and salt wasting (classical adrenal hyperplasia). Adrenal hyperplasia due to a deficiency of 21-hydroxylase activity is divided clinically into a simple virilizing form and a salt wasting form.

Many of the enzymes involved in cortisol and aldosterone syntheses are cytochrome p450 proteins designated CYP. CYP21 refers to 21-hydroxylase, CYP11B1 refers to 11-beta-hydroxylase, and CYP17 refers to 17-alpha-hydroxylase.

Frequency:

  • In the US: The most common form of congenital adrenal hyperplasia is due to 21-hydroxylase (CYP21) deficiency. This deficiency accounts for more than 90% of cases of adrenal hyperplasia. Mutations or partial deletions of CYP21 are common with an estimated frequency ratio as high as 1:3 in individuals in selected populations (ie, Ashkenazi Jews) to 1:7 in New York City. Estimated incidence is 1 per 60 individuals in the general population. Two copies of an abnormal gene are required for disease to occur and not all mutations and partial deletions result in disease.

    Nonclassic adrenal hyperplasia may occur with a frequency ratio as high as 1:27 to 1:100. Classic adrenal hyperplasia because of severe deletions and loss of CYP21 function occurs with an overall incidence of 1 per 13,000 to 1 per 16,000. Congenital adrenal hyperplasia caused by 11-beta-hydroxylase deficiency accounts for 5-8% of all patients with congenital adrenal hyperplasia.

  • Internationally: 11-beta-hydroxylase deficiency is observed more commonly in persons of Moroccan or Iranian Jewish descent. Other forms of congenital adrenal hyperplasia are far less common.

Mortality/Morbidity: The morbidity of the various forms of adrenal hyperplasia is best understood in the context of the steroidogenic pathway used by the adrenal glands and gonads. By analyzing the location of the enzyme deficiency, the accumulation of precursor hormones, and the physiological action of those hormones, the clinical phenotype can be understood.

  • Severe forms of congenital adrenal hyperplasia are potentially fatal if unrecognized and untreated because of the severe cortisol and aldosterone deficiency that result in salt wasting, hyponatremia, hyperkalemia, dehydration, and hypotension. Females with some forms of adrenal hyperplasia (ie, CYP21 deficiency, CYP11B1, partial 3-beta-hydroxysteroid-dehydrogenase deficiency) have ambiguous genitalia at birth (classical virilizing adrenal hyperplasia) or subsequently become virilized in childhood (simple virilizing adrenal hyperplasia) or in adolescence and adulthood (nonclassical virilizing adrenal hyperplasia). Males with CYP21 deficiency generally are not diagnosed in the neonatal period because their genitalia are normal. If the defect is severe resulting in salt wasting, these male infants will be seen at 1-4 weeks of age because of failure to thrive, recurrent vomiting, dehydration, and shock. Some infants are misdiagnosed initially with gastroenteritis or pyloric stenosis.
  • Hyponatremia and hyperkalemia should raise the possibility of adrenal insufficiency. Children with simple virilizing 21-hydroxylase or 11-hydroxylase deficiencies have early pubic hair, phallic enlargement, and accelerated growth.
  • Males with steroidogenic acute regulatory (StAR) deficiency, classical 3-beta-hydroxysteroid-dehydrogenase deficiency, or CYP17 deficiency generally have ambiguous genitalia or female genitalia because of inadequate testosterone production in the first trimester of fetal life. A female with CYP17 deficiency will appear phenotypically female at birth but fail to develop breasts and menstruate in adolescence because of inadequate estradiol production.
  • Two forms of adrenal hyperplasia (CYP11B1 deficiency and CYP17 deficiency) result in hypertension. Hypertension occurs because of the accumulation of supraphysiologic concentrations of deoxycorticosterone. This weak mineralocorticoid has little consequence at physiological concentrations, but results in sodium retention and hypertension at the supraphysiological concentrations that occur in the presence of CYP11B1 deficiency or CYP17 deficiency. One form of adrenal hyperplasia results in isolated aldosterone deficiency without affecting the synthesis of cortisol or sex steroids. This occurs because of a defect in enzyme activities that variously have been termed CMO I, CMO II, 18-hydroxylase and 18-hydroxycorticosterone dehydrogenase but is currently thought to represent one protein termed aldosterone synthetase or CYP11B2.

Race: Congenital adrenal hyperplasia occurs among all races. Congenital adrenal hyperplasia secondary to CYP21 deficiency is particularly common among the Yupik Eskimos.

Sex: Since all forms of congenital adrenal hyperplasia are autosomal recessive disorders, both sexes are affected equally.

CLINICAL

History: The clinical phenotype depends upon the nature and severity of the enzyme deficiency. 21-hydroxylase deficiency (CYP21) is the most common form. Approximately 50% of patients with classic congenital adrenal hyperplasia from CYP21 deficiency have salt wasting due to inadequate aldosterone synthesis. Females with this disorder usually are recognized at birth because of ambiguous genitalia, but males have normal genitalia and are not diagnosed until later, often with a salt wasting crisis. Females with less severe forms of 21-hydroxylase deficiency (simple virilizing adrenal hyperplasia) are diagnosed later in childhood with precocious pubic hair and/or clitoromegaly, often accompanied by accelerated growth and skeletal development. Those individuals with mild deficiencies of the enzyme present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirsutism and infertility (nonclassical adrenal hyperplasia).

  • Males with CYP21 deficiency generally are unrecognized at birth because their genitalia are normal. These individuals come to medical attention either at a few weeks of life with salt wasting resulting in dehydration, hypotension, hyponatremia and hyperkalemia, or later in childhood because of early pubic hair and/or phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation.

     

  • Males or females with CYP11 deficiency may present in early infancy (second or third week of life) with a salt loss crisis. This occurs in spite of the fact that these children usually develop hypertension and /or hypokalemic alkalosis. This has been explained by the relative inability of the elevated 11-DOC levels to replace the defective levels of aldosterone, a phenomenon that disappears with the progression of age and the gradual decreased dependency of the infant from aldosterone.
  • Infants with StAR deficiency (lipoid adrenal hyperplasia) usually have signs of adrenal insufficiency (eg, poor feeding, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia). Some patients do not receive medical attention until late infancy. Males with this form of adrenal hyperplasia have female or ambiguous genitalia. Females have normal female genitalia. Curiously, females who survive do develop breasts and menstruate at puberty.
  • Other forms of adrenal hyperplasia are characterized by disordered genital development in utero, lack of development of secondary sexual characteristics, or hypertension. For example, females with CYP17 deficiency rarely are identified at birth, but come to medical attention later in life because of hypertension or failure to develop secondary sexual characteristics at puberty. Males with this disorder have ambiguous or female genitalia. In the latter case, individuals may be raised as females and come to medical attention later in life because of hypertension or lack of breast development.
  • Patients with aldosterone deficiency of any etiology may have dehydration, hyponatremia, and hyperkalemia, especially with the stress of illness.

Physical: Physical findings are dependent on the nature and severity of the deficient enzyme activity. Deficiencies of enzyme activity involved in cortisol synthesis result in elevations in concentrations of adrenocorticotropic hormone (ACTH) that often causes hyperpigmentation. This hyperpigmentation may be subtle and is observed best in the genitalia and areolae. In virilizing forms (deficiencies of CYP21, CYP11B1, and 3-beta hydroxysteroid dehydrogenase) females have ambiguous genitalia at birth that ranges from complete fusion of the labioscrotal folds and a phallic urethra to only clitoromegaly and partial fusion of the labioscrotal folds. In less severe forms, genitalia may be normal at birth, but early pubic hair and clitoromegaly (often accompanied by tall stature) may appear in childhood. In more mild forms, excess facial or body hair often appears.

  • Males with CYP21 deficiency have normal genitalia, but may develop signs of dehydration at 1-4 weeks of life if they are salt wasting. They may have no problems in infancy but develop a salt wasting crisis with illness during childhood or simply have precocious pubic hair, phallic enlargement, and accelerated growth and skeletal maturation in childhood.
  • Ambiguous genitalia or female genitalia are observed in males with deficiencies of 3-beta-hydroxysteroid dehydrogenase, CYP17, and StAR.
  • High blood pressure and sometimes hypokalemia may be found in individuals with CYP11B1 deficiency and CYP17 deficiency. These findings are due to the accumulation of the mineralocorticoid desoxycorticosterone.

Causes: The defects causing congenital adrenal hyperplasia are autosomal recessive disorders caused by a deficient activity of a protein involved in cortisol and/or aldosterone synthesis. In most cases, this disorder is due to a mutation or deletion of the gene that codes for the protein involved. When both genes carry the same mutation or deletion, the condition is homozygous. When the 2 affected genes carry different mutations or deletions, the patient is said to be a compound heterozygote. Carriers or heterozygotes that carry only one abnormal gene are asymptomatic.

  • Many of the genes involved in cortisol and aldosterone synthesis code for cytochrome p450 proteins, designated CYP. The best-studied gene is the 21-hydroxylase gene (CYP21, CYP21B). The 21-hydroxylase gene lies on chromosome 6p21.3 among genes that code for proteins determining human leukocyte antigen (HLA) types. The gene for 21-hydroxylase has a pseudogene (CYP21P, CYP21A) 30 kilobases (kb) away from CYP21 that is 98% homologous in structure to CYP21 but is rendered inactive due to minor differences in the gene. The proximity of CYP21P with CYP21 is thought to predispose the CYP21 to crossovers in meiosis between CYP21 and CYP21P, resulting in loss of gene function.

     

  • Other defects occur because of gene deletions or mutations. Among abnormalities of CYP21, approximately 95 % are thought to be due to recombinations with CYP21P, 20% are thought to represent deletions, and 70% point mutations. The phenotype depends on the function of the less severely affected gene because that determines the level of enzyme activity. In general, genotype-phenotype correlations are strong, although exceptions occur. Because aldosterone secretion is approximately 1000-fold less than cortisol secretion, the enzyme activity required for aldosterone synthesis is less than that required for cortisol synthesis. Therefore, only patients with the most severe loss of function of CYP21 have salt wasting.
  • The 11-beta-hydroxylase gene (CYP11B1) resides on chromosome 8q21. No pseudogene for CYP11B1 exists, and no HLA association exists. CYP11B1 catalyzes the conversion of 11-deoxycortisol to cortisol in the glucocorticoid pathway and the conversion of deoxycorticosterone to corticosterone in the mineralocorticoid pathway. A neighboring gene codes for CYP11B2 or aldosterone synthetase, which catalyzes the conversion of corticosterone to aldosterone in the zona glomerulosa. Mutations and deletions of CYP11B2 gene result in diminished aldosterone synthesis. Therefore individuals with CYP11B2 deficiency develop hyponatremia, hyperkalemia and dehydration.

     

  • Sexual differentiation occurs normally since sex steroid and cortisol synthesis are not impaired. The genes for CYP11B1 and CYP11B2 share 95% sequence homology for coding sequences. Nonetheless, gene conversion from chromosomal crossover at meiosis does not appear to play a major role in the mutations and deletions that render either gene inactive.
  • Two tissue forms of 3-beta-hydroxysteroid dehydrogenase have been described. Type I occurs primarily in the adrenal and gonad, while type II occurs primarily in the placenta and liver. The genes for both forms reside on chromosome 1p13. The classic form of 3-beta-hydroxysteroid-dehydrogenase deficiency results from mutations or deletions in the gene for the adrenal form of the enzyme.

     

  • Some patients appear to have nonclassic forms of this disease as evidenced by symptoms and signs of virilization later in life. These symptoms include oligomenorrhea, infertility, and abnormal ratios of precursors to product (ie, increased ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of dehydroepiandrosterone to androstenedione). These patients have not been shown to have mutations or deletions of any of the genes that code for adrenal 3-beta-hydroxysteroid dehydrogenase. The molecular basis for this disorder remains undefined. Considerable overlap between this condition and polycystic ovary disease exists in clinical and hormonal findings. Some of these patients benefit from suppression of adrenal steroidogenesis with dexamethasone.
  • 17-alpha-hydroxylase activity and 17,22-desmolase activities are thought to be due to a single protein (CYP17) with separate enzymatic activity sites.
  • Recently, patients with lipoid adrenal hyperplasia, which was originally thought to be due to deficiency of CYP450 scc enzyme activity, have been shown to have mutations in a gene that codes for steroidogenic acute regulatory protein (StAR). This protein appears to be involved in the transport of cholesterol across the mitochondrial membrane where it then can be acted upon by CYP450 scc, which converts cholesterol to pregnenolone and then is processed in the various steroidogenic tissues into cortisol, aldosterone, or sex steroids. Thus, a deficiency of StAR results in a global steroid deficiency state. 46 XY individuals with this disorder have female external genitalia. 46 XX individuals have normal female genitalia. Both develop signs of adrenal insufficiency with onset from early infancy to 6 months of life.

     

  • Curiously, females with this disorder who have survived as the result of early replacement of glucocorticoids and mineralocorticoid have developed breasts and spontaneous nonovulatory menses at puberty. This occurrence has led to the theory that some steroidogenesis is possible independent of StAR. Researchers postulate that the accumulation of cholesterol esters within steroidogenic cells, which results from StAR deficiency, is toxic to the steroidogenic cells, eventually resulting in loss of both StAR dependent and StAR independent steroidogenesis. According to this theory, ovarian function is preserved because steroidogenesis does not occur until puberty, and then steroidogenesis occurs in only one follicle at a time allowing preservation of StAR independent steroidogenesis.

Other Problems to be Considered:

Bilateral adrenal hemorrhage
Cryptorchidism
Defects in testosterone synthesis
Mixed gonadal dysgenesis
Polycystic ovary disease
Pseudohypoaldosteronism
Renal salt wasting

WORKUP

Lab Studies:

  • The diagnosis of congenital adrenal hyperplasia depends upon the demonstration of inadequate production of cortisol and/or aldosterone in the presence of accumulation of excess concentrations of precursor hormones. For example, the distinguishing characteristic of 21-hydroxylase deficiency is a very high serum concentration of 17-hydroxyprogesterone (usually exceeding 1000 ng/dL) and urinary pregnanetriol (metabolite of 17-hydroxyprogesterone) in the presence of clinical features suggestive of the disease (eg, a female with ambiguous genitalia, evidence of salt wasting, clitoromegaly, precocious pubic hair, excessive growth, premature phallic enlargement in the absence of testicular enlargement, hirsutism, oligomenorrhea, female infertility).

     

  • Likewise, 11-beta-hydroxylase deficiency is indicated by excess concentrations of 11-deoxycortisol and desoxycorticosterone or by an elevation in the ratio of 24-hour urinary tetrahydrocompound S (metabolite of 11-deoxycortisol) to tetrahydrocompound F (metabolite of cortisol). Both are accompanied by elevated 24-hour urinary 17-ketosteroids, the urinary metabolites of adrenal androgens.
  • 3-beta-hydroxysteroid dehydrogenase deficiency is indicated by an abnormal ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and dehydroepiandrosterone to androstenedione.
  • Salt wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone concentrations, hyponatremia, hyperkalemia, and elevated plasma renin activity indicating hypovolemia. In contrast, hypertensive forms of adrenal hyperplasia (11-beta-hydroxylase deficiency and 17-alpha-hydroxylase deficiency) are associated with suppressed plasma renin activity and often hypokalemia.
  • Subtle forms of adrenal hyperplasia (as in nonclassical forms of 21-hydroxylase deficiency and nonclassical 3-beta-hydroxysteroid dehydrogenase deficiency) often require a Cortrosyn (synthetic corticotropin) stimulation test in order to demonstrate the abnormal accumulation of precursor steroids. Nomograms are available for interpreting the results in the chapter on the adrenal cortex by New and Rapaport in Pediatric Endocrinology (Sperling).

Imaging Studies:

  • Imaging studies of the adrenal gland generally are not useful in the evaluation of patients suspected of having adrenal hyperplasia. A CT scan of the adrenal gland can be useful, however, to exclude the possibility of bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure without ambiguity of the genitalia or other clues of adrenal hyperplasia.
  • A pelvic ultrasound may be performed in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies, which are sometimes found in other conditions that may result in ambiguous genitalia (eg, mixed gonadal dysgenesis, Denys-Drash syndrome).
  • A urogenitogram often is helpful to define the anatomy of the internal genitalia.
  • A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth. Patients who have these symptoms from adrenal hyperplasia have advanced skeletal maturation.

Other Tests:

  • A karyotype is essential in the evaluation of the infant with ambiguous genitalia in order to establish the chromosomal sex.
  • Genetic testing rarely is necessary to demonstrate the diagnosis of classical forms of adrenal hyperplasia, but is essential in the prenatal diagnosis of adrenal hyperplasia.

Histologic Findings: Histologic features of congenital adrenal hyperplasia are simply hyperplasia of the adrenal cortex. Lipoid deposits within the adrenal cortical cells characterize lipoid adrenal hyperplasia from a deficiency of StAR. Lipoid deposits are thought to represent cholesterol esters that have accumulated from the inability of the cell to transport cholesterol into the mitochondria.

With salt wasting, there is hypertrophy of the juxtaglomerular apparatus of the kidney, the source of increased PRA.

TREATMENT

Medical Care: Infants with ambiguous genitalia should be observed closely for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues are abnormal weight loss or lack of expected weight gain. Electrolyte abnormalities generally take from a few days to 3 weeks to appear because the placenta maintains the fetal electrolytes in utero. In mild forms of salt wasting adrenal hyperplasia, salt wasting may not become apparent until the child is stressed by an illness.

  • Patients with dehydration, hyponatremia, or hyperkalemia who are suspected of having a salt wasting form of adrenal hyperplasia should receive an intravenous bolus of normal saline (20 mL/kg or 450 mL/m2) over the first hour as needed to restore intravascular volume and blood pressure. This dosage may be repeated if the blood pressure remains low. Dextrose must be given if the patient is hypoglycemic and must be included in the rehydration fluid after the bolus dose to prevent hypoglycemia. Once samples are obtained for electrolytes, blood sugar, cortisol, aldosterone, and 17-hydroxyprogesterone concentrations, the patient should be treated with glucocorticoids based on the suspicion of adrenal insufficiency rather than waiting for confirmatory studies, because this may be life preserving.
  • Once stabilized, treat all patients who have adrenal hyperplasia with chronic glucocorticoid and/or aldosterone replacement depending upon what enzyme is involved and whether cortisol and/or aldosterone synthesis is affected.
  • Another approach currently under investigation is the combined use of glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), and flutamide (an androgen blocker to reduce virilization).

Surgical Care: Infants with ambiguous genitalia require surgical evaluation and, if needed, plans for corrective surgery.

  • The traditional approach to the female with ambiguous genitalia due to adrenal hyperplasia is clitoral recession early in life, followed by vaginoplasty after puberty. Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.
  • Bilateral adrenalectomies have been suggested in the management of virilizing forms of adrenal hyperplasia in order to prevent further virilization and advancement of skeletal maturation. Currently, this approach is experimental and should only be considered in the context of a controlled study.

Consultations:

  • An endocrinologist should be consulted when adrenal insufficiency is suspected.
  • An experienced surgeon is required if genitalia are ambiguous or inconsistent with genetic sex and corrective surgery is contemplated.
  • A genetics consultation is useful in establishing the genetic defect causing the disorder. For parents contemplating a subsequent pregnancy, genetic counseling for prenatal diagnosis and treatment of this disorder is important.

Diet: Patients with congenital adrenal hyperplasia should be on an unrestricted diet. Patients should have ample access to salt, because salt wasting is common in some forms of the disease. Infants who have salt wasting generally benefit from supplementation with 2-4 g of NaCl per day added to their formula. Caloric intake may need to be monitored and restricted if excess weight gain occurs because glucocorticoids stimulate appetite.

Activity: Activity restriction is not necessary provided appropriate glucocorticoid and mineralocorticoid therapy is instituted.

MEDICATION

Short-term medical therapy

In the hypotensive patient, 0.9% sodium chloride (normal saline) must be given (450 mL/m2 or 20 mL/kg IV) rapidly over the first hour, followed by a continuos IV infusion of 3200 mL/m2/d or 200 mL/kg/100 cal of estimated resting energy expenditure as normal saline or half normal saline to restore intravascular volume. Dextrose also must be provided.

If the patient is hypoglycemic, 2-4 mL of dextrose 10% (D10W) will correct the hypoglycemia. Dextrose 5% (D5W) must be provided to prevent further hypoglycemia or prevent hypoglycemia from occurring if the patient is not hypoglycemic. Potassium is not needed for patients with salt wasting forms of adrenal hyperplasia because these patients usually are hyperkalemic. Patients with 11-hydroxylase and 17-alpha-hydroxylase deficiency, however, may be hypokalemic and require potassium. Once appropriate diagnostic studies are obtained or the results are known, glucocorticoid and/or mineralocorticoid therapy may be instituted.

In patients who are sick and have signs of adrenal insufficiency, therapy should consist of stress doses of hydrocortisone (50-100 mg/m2 or 1-2 mg/kg IV as an initial dose followed by 50-100 mg/m2/d IV divided q6h). Comparable stress doses are 10-20 mg/m2 IV/IM of methylprednisolone and 1-2 mg/m2 of dexamethasone. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects; thus, if the patient is hypovolemic, hyponatremic, or hyperkalemic, large doses of hydrocortisone (double or triple the stress doses mentioned above) are preferred.

Currently, no parenteral form of mineralocorticoid is available in the United States, but if the patient has good GI function, administer fludrocortisone 0.1-0.2 mg PO.
 

Long-term medical therapy
 

The goal of therapy of adrenal hyperplasia is the replacement of glucocorticoid and mineralocorticoid to prevent signs of adrenal insufficiency and to prevent the accumulation of precursor hormones that cause virilization. Adequate glucocorticoid replacement should prevent excessive concentrations of ACTH from stimulating the adrenal to produce abnormal concentrations of adrenal androgens that result in further virilization. In the growing child with adrenal insufficiency, chronic glucocorticoid replacement must be balanced to prevent symptoms of adrenal insufficiency while still allowing the child to grow at a normal rate and prevent symptoms of glucocorticoid excess. Dosage must be tailored to each patient, but generally runs in the range of 10-25 mg/m2/d PO of hydrocortisone divided in 2-3 doses.

Hydrocortisone is available in tablets of 5, 10, and 20 mg. Hydrocortisone is recommended in the pediatric population because of its lower potency that permits easier titration of appropriate doses. Unfortunately, hydrocortisone suspension (Cortef solution) is no longer available in the United States.

Prednisone, prednisolone, or even dexamethasone may be used. Prednisone comes in a suspension of 1 mg/mL and prednisolone comes in a solution of 5 or 15 mg/5 mL. The estimated equivalencies are (from Harriet Lane Handbook):

    1 mg prednisone = 4 mg hydrocortisone
    1 mg prednisolone = 5 mg hydrocortisone
    1 mg dexamethasone = 50 mg hydrocortisone

These forms of glucocorticoid have the advantage of having longer half-lives than hydrocortisone and, therefore, require twice a day dosing or even once a day dosing (dexamethasone), which often aids compliance. Because of the increased potency, however, growth suppression and other signs of glucocorticoid excess are common.
Administer fludrocortisone 0.05-0.2 mg/d PO to patients with mineralocorticoid deficiency. Administer 2-5 g/d NaCl to infants to counteract salt wasting. Older children usually can scavenge adequate salt to provide for their needs and may lose their salt wasting tendencies as they mature. The dose of glucocorticoid is adjusted clinically (absence of symptoms of glucocorticoid deficiency and normal growth) and by periodically measuring the concentrations of precursor hormones. For example, in 21-hydroxylase deficiency, keeping plasma concentrations of 17-hydroxyprogesterone in the 200-500 ng/dL range and androstenedione in the normal physiologic range is desirable.

Plasma ACTH concentrations are of little help in adjusting doses of glucocorticoid for patients with primary adrenal insufficiency. Symptoms of salt craving, blood pressure, plasma renin activity, and electrolytes are helpful in adjusting the dose of fludrocortisone. High blood pressure with suppressed PRA should prompt a reduction in fludrocortisone dose.

Stress/illness:

One of the important physiological responses to stress is an increase in cortisol production, mediated by ACTH. Patients with adrenal insufficiency of whatever etiology are unable to mount this response and must be administered stress doses of glucocorticoid. In the patient with a minor illness (fever <38°C), the dose of hydrocortisone should be at least doubled. For patients with more severe illness (fever >38°C), the dose of glucocorticoid should be tripled. If the patient is vomiting or listless, they should be given parenteral glucocorticoid (hydrocortisone 50-75 mg/m2 IM/IV or equivalent of methylprednisolone or dexamethasone). Because hydrocortisone succinate has a short duration of action, the dose must be repeated every 6-8 h at a daily dose of 50-100 mg/m2/d until the patient is well.

All patients with adrenal insufficiency must have injectable glucocorticoid available and the caretaker must be instructed in its use and importance. No contraindications of glucocorticoid or mineralocorticoid replacement exist when it is needed and few drug-drug interactions exist.
 

Drug Category: Glucocorticoids -- The purpose of glucocorticoid therapy in the treatment of congenital adrenal hyperplasia is to (1) replace the body's requirement for glucocorticoids under normal conditions and during stress and (2) suppress ACTH secretion, which drives the adrenal gland to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia.

Drug Name
 		 Hydrocortisone (A-Hydrocort, Cortef, Hydrocort) -- The same as cortisol, the primary steroid hormone secreted by the adrenal zona fasciculata and reticularis. Drug of choice in children because it has a short half-life and less potential for growth suppression. It also has mineralocorticoid effect when given in large doses.
Adult Dose 25-35 mg/d PO/IV/IM divided in 2-3 doses;
Dose doubled or tripled under stress conditions
Pediatric Dose 10-15 mg/m2/d PO divided tid;
Dose doubled or tripled under stress conditions
Contraindications Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions Phenytoin, phenobarbital, ephedrine, mitotane, and rifampin may increase the hepatic clearance of corticosteroids; PT may be prolonged with coadministration with anticoagulants; potassium-depleting diuretics may enhance hypokalemia
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Live virus immunizations are well tolerated in physiologic replacement doses; for large doses, avoid live virus immunizations; regularly observe patients taking corticosteroids for potential development of iatrogenic Cushing syndrome; may cause growth suppression, closely monitor children for growth
Increases risk of severe infections; monitor for signs of adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Category: Mineralocorticoids -- Replacement is required for patients who have salt-wasting congenital adrenal hyperplasia. This treatment is necessary to replace the aldosterone that is insufficiently produced by the adrenal cortex.

Drug Name
 		 Fludrocortisone acetate (Florinef) -- Synthetic steroid with predominantly mineralocorticoid activity. Acts on the renal tubule to promote sodium retention in exchange for potassium or hydrogen ion. Through this mechanism, it maintains intravascular and extracellular volume. Available only in tablet form. For patients requiring parenteral mineralocorticoid therapy, high dose hydrocortisone must be used.
Tablet may be crushed for infants and children
Adult Dose 0.05-0.2 mg/d PO
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; systemic fungal infections; hypokalemia
Interactions Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause sodium retention, hypokalemia or hypertension, use cautiously in patient with hypertension or those on potassium-depleting diuretics or digoxin; taper dose gradually when therapy is discontinued

FOLLOW-UP

Further Outpatient Care:

  • Monitor patients with adrenal hyperplasia closely for adequacy of dosing of glucocorticoid and/or mineralocorticoid.
    • Too little glucocorticoid results in symptoms of adrenal insufficiency (eg, anorexia, nausea, vomiting, abdominal pain, asthenia) and will result in progressive virilization and advancement of skeletal maturation in virilizing forms.
    • Too much glucocorticoid results in excess weight gain, Cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.
    • Growth failure is one of the more sensitive indicators of excess exposure to glucocorticoids. Adult short stature is frequently the outcome in virilizing forms of adrenal hyperplasia due to the effect of uncontrolled adrenal androgens on skeletal maturation.

Deterrence/Prevention:

  • Prenatal diagnosis by amniocentesis or chorionic villus sampling has been successful in congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency, if a sibling with a known mutation/deletion has preceded the pregnancy. Because these disorders are consistent with normal development and survival, if treated, the choice of terminating an affected pregnancy is rare. The usual reason for doing prenatal diagnosis is as part of prenatal treatment.

     

  • Prenatal treatment of congenital adrenal hyperplasia appears to be somewhat successful in preventing the virilization of a female fetus from 21-hydroxylase deficiency. According to the protocol proposed by Carlson et al, the mother is treated with dexamethasone (20 mcg/kg/d divided in 3 doses) as soon as the pregnancy is recognized in an attempt to suppress fetal ACTH secretion and prevent the fetal adrenal gland from overproducing adrenal androgens.

     

  • Dexamethasone treatment is discontinued if chorionic villus sampling (at 8-12 wk) or amniocentesis (at 18-20 wk) indicates that the fetus is male or if genetic analysis indicates that the fetus is unaffected. Because only the female fetus is at risk of disfigurement from virilization, this strategy results in unnecessary treatment of 7 out of 8 fetuses. However, because virilization occurs within the first 12 weeks of gestation, if one waits until the sex and diagnosis of the fetus are known, the virilization of an affected female fetus already will have occurred. So far, this strategy has not resulted in an increase in fetal wastage or congenital malformations in treated pregnancies. It is associated with considerable maternal adverse effects during the pregnancy, however. Long-term follow-up studies are ongoing and are required to determine whether dexamethasone treatment in early pregnancy results in any long-term adverse effects.
  • Methodology has been developed to screen neonates for congenital virilizing adrenal secondary to 21-hydroxylase deficiency using measurements of 17-hydroxyprogesterone from heel blood samples collected on filter paper. Currently, 13 countries and 17 regional areas in the US screen neonates for this disorder. This approach has permitted early identification of newborns with this disorder. This strategy has prevented salt wasting crises in males who are unrecognized at birth, the identification of completely virilized females who may be mistaken for males with cryptorchidism, and the identification of patients of both sexes with simple virilizing adrenal hyperplasia, which enables early treatment before undue advancement in skeletal maturation. Whether politicians will deem these benefits worth the economic cost of screening to justify more global screening remains to be determined.

Complications:

  • Complications of congenital adrenal hyperplasia are common. Too little glucocorticoid results in adrenal insufficiency and further virilization in the virilizing forms. Complications of excessive administration of glucocorticoids include growth failure, obesity, striae, hypertension, hyperglycemia, and cataracts. The complications of excess mineralocorticoid administration are hypertension and hypokalemia.
  • Short stature is a frequent complication of virilizing forms of congenital adrenal hyperplasia. In general, patients end up being 1-2 standard deviations below estimated genetic potential. This results from exposure to excessive concentrations of adrenal androgens that cause rapid skeletal maturation or from excessive exposure to glucocorticoids that limit growth. Early puberty often is observed in children with advanced skeletal maturation and can contribute to the limitation in growth.
  • Females with virilizing forms of adrenal hyperplasia have a decreased fertility rate. The reasons for a decreased fertility rate are believed to be multifactorial, including abnormal genital anatomy, vaginal stenosis, and poor control of adrenal androgen production resulting in diminished ovulation. When pregnancy does occur, delivery generally must be by caesarian section because of vaginal stenosis or an androgenic pelvic girdle.
  • Males with uncontrolled congenital adrenal hyperplasia may develop masses within the testes, which are adrenal rests or adrenal tissue. This stems from the fact that the gonads and adrenal glands are derived from the same embryological anlage. Because the adrenal rests are under ACTH control, the adrenal rests enlarge when ACTH concentrations are elevated. The adrenal rests may cause discomfort and may be mistaken for testicular tumors resulting in unnecessary surgery. Furthermore, these rests may cause oligospermia or azoospermia and infertility.

Prognosis:

  • With adequate medical therapy and surgical therapy, the prognosis is good. However, problems with psychological adjustment are frequent, usually stemming from the genital abnormality that accompanies some forms of congenital adrenal hyperplasia.
  • Short stature and infertility are common.
  • Gender identity in females with virilizing adrenal hyperplasia usually is female provided the female gender assignment is made early in life, adequate medical and surgical support are provided, and the family and eventually the patient herself is provided with adequate education to understand the disease.
  • Early death may occur if patients are not provided with stress doses of glucocorticoid in times of illness, trauma, or surgery.

Patient Education:

  • Educate the caretakers and patients about the nature of the disease in order for them to understand the importance of replacement of the deficient adrenal cortical hormones.
  • Patients also must understand the need for additional glucocorticoids in times of illness and stress in order to avoid an adrenal crisis.
  • Patients must know the importance of IM injections of glucocorticoids and be educated in the technique of IM administration.

MISCELLANEOUS

Medical/Legal Pitfalls:

  • Education is essential for parents and affected children to understand the pathophysiology of the disease and the importance of glucocorticoid and mineralocorticoid replacement. As with all forms of adrenal insufficiency, the need for coverage with stress doses of glucocorticoids must be emphasized and reemphasized periodically because caretakers often are reluctant to provide stress doses when needed and are particularly reluctant to give injectable glucocorticoids when the patient is unable to take oral medication or is severely lethargic. Disastrous consequences can result. Encourage patients to wear medical alert identification tags stating that they are on glucocorticoids. Advise patients to seek medical help early if they are ill.
  • The care of infants with ambiguous genitalia is problematic because major decisions must be made for the child regarding gender assignment without the input of the child. Some intersex patient groups advocate that no decisions be made regarding gender assignment, and no surgery be performed until the child reaches adulthood and can participate in these momentous decisions. While this approach certainly would alleviate the parents or physician from the responsibility of making these decisions on behalf of the affected patient, it leaves the patient with an ambiguous gender assignment and role through childhood and exposes the child to further embarrassment of having ambiguous genitalia. In the author's opinion, this approach poses a greater risk to the eventual physical and psychological welfare of the patient. In addition, proper diagnosis allows the institution of proper therapy, which can prevent further undesirable consequences of the untreated disease.

Special Concerns:

  • Some patient groups, such as the Intersex Society of North America, have been vocal in criticizing the management (particularly the surgical management) of patients with congenital virilizing adrenal hyperplasia as well as other conditions that cause ambiguity of the genitalia. These groups are to be commended for attempting to educate the public about these conditions and to improve society's tolerance for intersex conditions. However, it is the author's concern that the vocality of such groups, some of which are composed of dissatisfied and mismanaged patients treated in an era of less sensitivity to the feelings of the child and less sophisticated genital reconstruction techniques, will tie the hands of physicians and parents who struggle to arrive at decisions that are in the best interest of the child born with this difficult problem.
 

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