AUTHOR INFORMATION

Section 1 of 12

Authored by Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook

Thomas A Wilson, MD, is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa

Edited by Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus, Department of Pediatrics, University of Florida College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry B Bercu, MD, Professor, Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Therapeutics, University of South Florida; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

Author's Email:	Thomas A Wilson, MD
Editor's Email:	Arlan L Rosenbloom, MD

eMedicine Journal, November 17 2006, VOLUME 7, Number 11

INTRODUCTION

Section 2 of 12

Background: The term congenital adrenal hyperplasia encompasses several autosomal recessive disorders, all of which involve a deficiency or relative defect in cortisol synthesis, aldosterone synthesis, or both that results in some degree of cortisol deficiency, aldosterone deficiency, or both.

Pathophysiology: Clinical manifestations of the disease are related to the degree of cortisol deficiency, aldosterone deficiency, or deficiency of both. In some cases, these manifestations reflect the accumulation of precursor adrenocortical hormones. These precursors, when present in supraphysiologic concentrations, cause abnormalities such as virilization or hypertension.

The phenotype depends on which protein is affected, the severity of the mutation, or the degree of deletion of the particular gene encoding for the protein involved in steroidogenesis. Two copies of an abnormal gene are required for disease to occur, and not all mutations and partial deletions result in disease. The phenotype can vary from clinically inapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease that is expressed in adolescence or adulthood (nonclassic adrenal hyperplasia) to severe disease that results in adrenal insufficiency in infancy with or without virilization and salt wasting (classic adrenal hyperplasia). The most common form of adrenal hyperplasia, due to a deficiency of 21-hydroxylase activity, is clinically divided into a simple virilizing form and a salt-wasting form.

Many of the enzymes involved in cortisol and aldosterone syntheses are cytochrome P450 (CYP) proteins. 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 CYP21 deficiency. This deficiency accounts for more than 90% of adrenal hyperplasia cases. Mutations or partial deletions that affect CYP21 are common, with estimated frequencies as high as 1 in 3 individuals in selected populations (eg, Ashkenazi Jews) to 1 in 7 individuals in New York City. The estimated prevalence is 1 case per 60 individuals in the general population.

  Nonclassic adrenal hyperplasia may occur with a frequency ratio as high as 1 per 27-100. Classic adrenal hyperplasia occurs with an overall prevalence of 1 case per 13,000-16,000 population. Congenital adrenal hyperplasia caused by 11-beta-hydroxylase deficiency accounts for 5-8% of all congenital adrenal hyperplasia cases.

• Internationally: 11-Beta-hydroxylase deficiency is most common 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 (see Image 1). The clinical phenotype can be understood by analyzing the location of the enzyme deficiency, the accumulation of precursor hormones, and the physiologic action of those hormones (see History).

• Severe forms of congenital adrenal hyperplasia are potentially fatal if unrecognized and untreated because of the severe cortisol and aldosterone deficiencies that result in salt wasting, hyponatremia, hyperkalemia, dehydration, and hypotension.

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

Sex: Because all forms of congenital adrenal hyperplasia are autosomal recessive disorders, both sexes are affected with equal frequency.

CLINICAL

Section 3 of 12

History: The clinical phenotype depends on 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 due to CYP21 deficiency have salt wasting due to inadequate aldosterone synthesis. Although presented below according to chromosomal sex, the sex of an infant with congenital adrenal hyperplasia is often initially unclear because of genital ambiguity.

• Clinical presentation in females


• • Females with severe forms of adrenal hyperplasia (eg, CYP21, CYP11B1, partial 3-beta-hydroxysteroid dehydrogenase deficiency) have ambiguous genitalia at birth due to excess adrenal androgen production in utero. This is often called classic virilizing adrenal hyperplasia.
  
  
  
  • Mild forms of 21-hydroxylase deficiency in females are identified later in childhood because of precocious pubic hair, clitoromegaly, or both often accompanied by accelerated growth and skeletal development due to excess postnatal exposure to adrenal androgens. This is called simple virilizing adrenal hyperplasia.
  
  
  
  • Milder deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. This is termed nonclassic adrenal hyperplasia.
  
  
  
  • Females with CYP17 deficiency appear phenotypically female at birth but does not develop breasts or menstruate in adolescence because of inadequate estradiol production. They may present with hypertension.
  
  
  
• Clinical presentation in males


• • CYP21 deficiency in males is generally not identified in the neonatal period because their genitalia are normal. If the defect is severe and results in salt wasting, these male neonates present at age 1-4 weeks because of failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock (classic salt-wasting adrenal hyperplasia). Patients with less severe deficiencies of 21-hydroxylase present later in childhood because of the early development of pubic hair, phallic enlargement, or both accompanied by accelerated linear growth and advancement of skeletal maturation (simple virilizing adrenal hyperplasia).
  
  
  
  • In male infants, the disease may be misdiagnosed as gastroenteritis or pyloric stenosis, with potentially disastrous consequences.
  
  
  
  • Males with steroidogenic acute regulatory (StAR) deficiency, classic 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.
  
  
  
• Other findings


• • Hyponatremia, hyperkalemia, and/or hypoglycemia suggests the possibility of adrenal insufficiency.
  
  
  
  • Children with simple virilizing 21-hydroxylase or 11-hydroxylase deficiency have early pubic hair, phallic enlargement, and accelerated linear growth and advanced skeletal maturation.
  
  
  
  • Two forms of adrenal hyperplasia (ie, CYP11B1 and CYP17 deficiency) result in hypertension due to the accumulation of supraphysiologic concentrations of deoxycorticosterone. This weak mineralocorticoid has little consequence at physiologic concentrations but causes sodium retention and hypertension at the supraphysiologic concentrations that occur in CYP11B1 or CYP17 deficiency. One form of adrenal hyperplasia results in isolated aldosterone deficiency without affecting the synthesis of cortisol or sex steroids. This form is due to a defect in enzymatic activities that have variously been termed CMO I, CMO II, 18-hydroxylase, or 18-hydroxycorticosterone dehydrogenase; however, it is currently thought to represent 1 protein called aldosterone synthetase, or CYP11B2.
  
  
  
  • Other forms of adrenal hyperplasia are characterized by disordered genital development in utero, lack of the development of secondary sexual characteristics, or hypertension. For example, CYP17 deficiency in females is rarely identified at birth, but they seek medical attention later in life because of hypertension or failure to develop secondary sexual characteristics at puberty. Male patients with this disorder have ambiguous or female genitalia and may be raised as girls and seek medical attention later in life because of hypertension or a lack of breast development.
  
  
  
  • Patients with aldosterone deficiency of any etiology may present with dehydration, hyponatremia, and hyperkalemia, especially with the stress of illness.
  
  
  
  • Male or female patients with CYP11 deficiency may present in the second or third week of life with a salt-losing crisis. However, these patients develop hypertension, hypokalemic alkalosis, or both later in life. This paradox is explained by resistance to mineralocorticoids in infancy and the inability of the elevated deoxycorticosterone levels to replace the deficient serum concentrations of aldosterone in infancy. Upon maturation, mineralocorticoid responsiveness increases, and the elevated concentrations of deoxycorticosterone are sufficient to cause sodium retention, potassium excretion, and hypertension.
  
  
  
  • 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. Male patients with this form of adrenal hyperplasia have female or ambiguous genitalia. Female patients have normal female genitalia. A curious observation is that girls who survive develop breasts and menstruate at puberty, suggesting preservation of ovarian steroidogenesis.
  
  
  

Physical: Physical findings depend on the nature and severity of the deficient enzyme activity (see Image 1).

• Deficiencies of enzyme activity involved in cortisol synthesis result in elevations in concentrations of corticotropic hormone (previously adrenocorticotropic hormone [ACTH]) that often causes hyperpigmentation. This hyperpigmentation may be subtle and is best observed in the genitalia and areolae.



• In virilizing forms (ie, deficiencies of CYP21, CYP11B1, and 3-beta-hydroxysteroid dehydrogenase), female patients have ambiguous genitalia at birth that ranges from complete fusion of the labioscrotal folds and a phallic urethra to only clitoromegaly, partial fusion of the labioscrotal folds, or both (see Images 2-3).


• • In relatively nonsevere forms, genitalia may be normal at birth, but early pubic hair and clitoromegaly (often accompanied by tall stature) may appear in childhood.
  
  
  
  • In mild forms, excess facial or body hair often appears.
  
  
  
• Male patients with CYP21 deficiency have normal genitalia but may develop signs of dehydration at 1-4 weeks of life if they have salt wasting or may have no problems in infancy but develop a salt-wasting crisis with illness during childhood (classic salt-wasting adrenal hyperplasia). Less severely affected males may present with precocious development of pubic hair, phallic enlargement, and accelerated growth and skeletal maturation in childhood (simple virilizing adrenal hyperplasia).



• Ambiguous genitalia or female genitalia are also observed in male patients with deficiencies of 3-beta-hydroxysteroid dehydrogenase, CYP17, and StAR.



• High blood pressure and, sometimes, hypokalemia may be found in individuals with CYP11B1 and CYP17 deficiency. These findings are due to the accumulation of the mineralocorticoid deoxycorticosterone.

Causes: The defects that cause congenital adrenal hyperplasia are autosomal recessive disorders due to deficient activity of a protein involved in cortisol synthesis, aldosterone synthesis, or both (see Image 1). In most cases, this disorder is due to a mutation or deletion of the gene that codes for the involved protein. 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 who carry only one abnormal gene are asymptomatic.

Many of the genes involved in cortisol and aldosterone synthesis code for CYP proteins. The best-studied gene is the 21-hydroxylase gene (CYP21, CYP21B). The 21-hydroxylase gene is located on chromosomal band 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 kb away from CYP21 that is 98% homologous in structure to CYP21; however, it is rendered inactive because of minor differences in the gene. The proximity of CYP21P with CYP21 is thought to predispose the CYP21 gene to crossovers in meiosis between CYP21 and CYP21P, resulting in loss of genetic 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% are point mutations. The phenotype depends on the function of the less severely affected gene than on the more severely affected one because the former 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, patients with only the most severe loss of function of CYP21 have salt wasting.

The 11-beta-hydroxylase gene (CYP11B1) is on chromosomal band 8q21. No pseudogene for CYP11B1 exists, and no HLA association is found. 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 the CYP11B2 gene result in diminished aldosterone synthesis. Therefore, individuals with CYP11B2 deficiency develop hyponatremia, hyperkalemia, and dehydration.

Sexual differentiation normally occurs because 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 are described. Type I occurs primarily in the adrenal and gonad, whereas type II occurs primarily in the placenta and liver. The genes for both forms reside on chromosomal band 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 relatively late in life. These symptoms include oligomenorrhea, infertility, and abnormal precursors-to-product ratios (ie, increased ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of dehydroepiandrosterone to androstenedione). These patients have not had mutations or deletions in any of the genes that code for adrenal 3-beta-hydroxysteroid dehydrogenase. The molecular basis for this disorder remains undefined. Clinical and hormonal findings of condition and polycystic ovary disease considerably overlap. Some patients benefit from suppression of adrenal steroidogenesis with dexamethasone.

17-Alpha-hydroxylase activity and 17,20-desmolase activities are thought to be due to a single protein (CYP17) with separate enzymatic activity sites.

Some patients with lipoid adrenal hyperplasia, which was originally thought to be due to deficiency of CYP450 scc enzyme activity, have had mutations in a gene that codes for StAR. This protein appears to be involved in the transport of cholesterol across the mitochondrial membrane, where CYP450 scc can act on it. This enzyme converts cholesterol to pregnenolone, which is then 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, and 46 XX individuals have normal female genitalia. Both develop signs of adrenal insufficiency with onset from early infancy to 6 months of life.

A curious observation is that females with this disorder who 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 may be independent of StAR. Researchers postulate that the accumulation of cholesterol esters in steroidogenic cells, which results from StAR deficiency, is toxic to the steroidogenic cells and eventually results in a 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 1 follicle at a time; this mechanism allows for the preservation of StAR-independent steroidogenesis.

Mutations in the gene coding for CYP oxidoreductase were recently found to cause deficiencies of several enzymes involved in steroidogenesis. CYP oxidoreductase facilitates electron transfer from nicotinamide adenine dinucleotide phosphate reduced form (NADPH) to the 21- and 17-hydroxylase enzymes required in steroidogenesis (Online Mendelian Inheritance in Man [OMIM] #201750 and #124015). Some individuals with these mutations have craniosynostosis and skeletal abnormalities known as the Antley-Bixler syndrome (OMIM #207410). However, mutations in the fibroblast growth factor receptor-2 can also cause the phenotypic picture of Antley-Bixler syndrome without problems in steroidogenesis.

DIFFERENTIALS

Section 4 of 12

3-Beta-Hydroxysteroid Dehydrogenase Deficiency
5-Alpha-Reductase Deficiency
Adrenal Hypoplasia
Adrenal Insufficiency
Ambiguous Genitalia and Intersexuality
Androgen Insensitivity Syndrome
Congenital Adrenal Hyperplasia
Cystic Fibrosis
Denys-Drash Syndrome
Failure to Thrive
Familial Glucocorticoid Deficiency
Fluid, Electrolyte, and Nutrition Management of the Newborn
Hyperkalemia
Hypokalemia
Hyponatremia
Pyloric Stenosis, Hypertrophic
Sexuality: Gender Identity
Sexuality: Sexual Orientation
Small-Bowel Obstruction
WAGR Syndrome

Other Problems to be Considered:

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

WORKUP

Section 5 of 12

Lab Studies:

• The diagnosis of congenital adrenal hyperplasia depends on the demonstration of inadequate production of cortisol, aldosterone, or both in the presence of accumulation of excess concentrations of precursor hormones. For example, the distinguishing characteristic of 21-hydroxylase deficiency is a high serum concentration of 17-hydroxyprogesterone (usually >1000 ng/dL) and urinary pregnanetriol (metabolite of 17-hydroxyprogesterone) in the presence of clinical features suggestive of the disease (eg, ambiguous genitalia [in a female patient], 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 deoxycorticosterone 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 levels of 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 (PRA), indicating hypovolemia. In contrast, hypertensive forms of adrenal hyperplasia (ie, 11-beta-hydroxylase deficiency, 17-alpha-hydroxylase deficiency) are associated with suppressed PRA and, often, hypokalemia.



• Subtle forms of adrenal hyperplasia (as in nonclassic forms of 21-hydroxylase deficiency and nonclassic 3-beta-hydroxysteroid dehydrogenase deficiency) often require a Cortrosyn (synthetic corticotropin) stimulation test to demonstrate the abnormal accumulation of precursor steroids. Nomograms are available for interpreting the results (New, 1996).

Imaging Studies:

• Imaging studies of the adrenal gland are generally not useful in the evaluation of patients with suspected adrenal hyperplasia. However, CT scanning of the adrenal gland can be useful to exclude bilateral adrenal hemorrhage in patients with signs of acute adrenal failure without ambiguity of the genitalia or other clues of adrenal hyperplasia.



• Pelvic ultrasonography may be performed in an infant with ambiguous genitalia to demonstrate 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).



• Urogenitography is often helpful to define the anatomy of the internal genitalia.



• A bone-age study is useful in evaluating a child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth. Patients who have these symptoms because of adrenal hyperplasia have advanced skeletal maturation.

Other Tests:

• A karyotype is essential in the evaluation of an infant with ambiguous genitalia to establish the patient’s chromosomal sex.



• Genetic testing is rarely necessary to diagnose classic forms of adrenal hyperplasia but is essential for the prenatal diagnosis of adrenal hyperplasia.

Lipoid deposits in the adrenal cortical cells characterize lipoid adrenal hyperplasia due to 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, hypertrophy of the juxtaglomerular apparatus of the kidney, the source of increased PRA, occurs.

TREATMENT

Section 6 of 12

Medical Care: Infants with ambiguous genitalia should be closely observed for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues include 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 an illness stresses the child.

• Patients with dehydration, hyponatremia, or hyperkalemia and a possible salt-wasting form of adrenal hyperplasia should receive an intravenous (IV) bolus of isotonic sodium chloride solution (20 mL/kg or 450 mL/m²) over the first hour, as needed, to restore their intravascular volume and blood pressure.


• • This dosage may be repeated if the blood pressure remains low.

  • Dextrose must be administered if the patient is hypoglycemic and must be included in the rehydration fluid after the bolus dose to prevent hypoglycemia.

  • After samples are obtained to measure electrolyte, blood sugar, cortisol, aldosterone, and 17-hydroxyprogesterone concentrations, the patient should be treated with glucocorticoids based on suspected adrenal insufficiency. Treatment should not be withheld while confirmatory results are awaited because it may be life preserving (see Medication).
  
  
  
• After the patient’s condition is stabilized, treat all patients who have adrenal hyperplasia with long-term glucocorticoid or aldosterone replacement (or both), depending on which enzyme is involved and on 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).



• Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropin-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone may partially improve the patient’s height.

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

• The traditional approach to the female patient with ambiguous genitalia due to adrenal hyperplasia is clitoral recession early in life followed by vaginoplasty after puberty.


• • Vocal groups of intersex patients (Intersex Society of North America) have recently challenged this approach.
  
  
  
  • Some female infants with adrenal hyperplasia have only mild virilization 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. This approach is experimental and should be considered only 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 consultation with a geneticist is useful in establishing the genetic defect causing the disorder. In 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 NaCl (2-4 g/d) 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 if appropriate glucocorticoid and mineralocorticoid therapy is given.

MEDICATION

Section 7 of 12

Short-term medical therapy

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

If the patient is hypoglycemic, 2-4 mL of dextrose 10% in water (D10W) should be administered to increase the blood sugar, followed by a continuous infusion of dextrose 5% in water (D5W). If the patient is not hypoglycemic, D5W should be administered to prevent hypoglycemia. Patients with salt-wasting forms of adrenal hyperplasia do not need potassium supplementation because they are usually hyperkalemic. However, patients with 11-hydroxylase and 17-alpha-hydroxylase deficiency may be hypokalemic and require potassium. After appropriate diagnostic studies are performed or after the results are known, glucocorticoid and/or mineralocorticoid therapy may be started.

In patients who are sick and who have signs of adrenal insufficiency, therapy should consist of stress dosages of hydrocortisone (50-100 mg/m² or 1-2 mg/kg IV administered as an initial dose), followed by 50-100 mg/m²/d IV divided every 6 hours. Comparable stress dosages include 10-20 mg/m² of methylprednisolone administered IV or intramuscularly (IM) and 1-2 mg/m² of dexamethasone. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. Therefore, if the patient is hypovolemic, hyponatremic, or hyperkalemic, large dosages of hydrocortisone (double or triple the stress dosages mentioned above) are preferred because of its mineralocorticoid effect.

No parenteral form of mineralocorticoid is currently available in the United States, but, if the patient has good GI function, administer 0.05-0.2 mg of fludrocortisone by mouth (PO).

Long-term medical therapy

The goal of therapy for 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 glands to produce abnormal concentrations of adrenal androgens that result in further virilization. In the growing child with adrenal insufficiency, long-term 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. The dosage must be tailored to each patient, but the general average dosage is 10-25 mg/m²/d of hydrocortisone PO divided in 2-3 doses.

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

Prednisone, prednisolone, or even dexamethasone suspensions may be used. Prednisone is available in a suspension of 1 mg/mL, and prednisolone is available in a solution of 5 or 15 mg/5 mL. The estimated equivalencies are as follows (Barone, 1996):

• One mg of prednisone is equal to 4 mg of hydrocortisone.

• One mg of prednisolone is equal to 5 mg of hydrocortisone.

• One mg of dexamethasone is equal to50 mg of hydrocortisone.

These forms of glucocorticoid have the advantage of half-lives longer than those of hydrocortisone, permitting twice-daily or even once-daily dosing (dexamethasone), which often aids compliance. However, because of their increased potency, 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 NaCl (2-5 g/d) to infants to counteract salt wasting. Older children can usually scavenge adequate salt to provide for their needs and may lose their salt-wasting tendencies as they mature. The dose of glucocorticoid is adjusted by clinically evaluating the patient (for an 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- to 500-ng/dL range and keeping androstenedione in the normal physiologic range is desirable.

Plasma ACTH concentrations are of little help in adjusting doses of glucocorticoid in patients with primary adrenal insufficiency. Monitoring symptoms of salt craving and blood pressure, PRA, and electrolyte levels are helpful in adjusting the dose of fludrocortisone. High blood pressure with suppressed PRA should prompt a reduction in fludrocortisone dose.

Stress or illness

One of the important physiologic responses to stress is an increase in the cortisol production that ACTH mediates. Patients with adrenal insufficiency of any etiology cannot mount this response and must be given stress doses of glucocorticoid. In the patient with a minor illness (temperature of <38°C), the dosage of hydrocortisone should be at least doubled. For patients with relatively severe illness (temperature of >38°C), the dosage of glucocorticoid should be tripled. If the patient is vomiting or listless, administer parenteral glucocorticoid (50-75 mg/m² of hydrocortisone IM or IV or an equivalent dosage of methylprednisolone or dexamethasone). Because hydrocortisone succinate has a short duration of action, the dose must be repeated every 6-8 h at a dosage 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. Glucocorticoid or mineralocorticoid replacement has no contraindications when it is needed, and it has few drug-drug interactions.

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

Drug Name	Hydrocortisone (A-Hydrocort, Cortef, Hydrocort) -- Same as cortisol, which is the primary steroid hormone secreted by adrenal zona fasciculata and reticularis. DOC in children due to short half-life and decreased potential for growth suppression. Mineralocorticoid effect at 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; coadministration with anticoagulants may prolong PT; potassium-depleting diuretics may enhance hypokalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Live-virus immunizations well tolerated in patients taking physiologic replacement doses of glucocorticoids; with large doses, avoid live-virus immunizations; regularly observe patients for potential iatrogenic Cushing syndrome; may suppress growth (closely monitor children for growth); increases risk of severe infections; monitor for signs of adrenal insufficiency when tapering; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, cataracts, and infections are possible complications of glucocorticoid use

Drug Category: Mineralocorticoids -- Replacement of mineralocorticoids is required in 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 renal tubule to promote sodium retention in exchange for potassium or hydrogen ion and thus maintain intravascular and extracellular volume. For patients who require parenteral mineralocorticoid therapy, high-dose hydrocortisone must be used. Available only as tab; 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; hypokalemia
Interactions	Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause sodium retention, hypokalemia, or hypertension; caution in patients with hypertension or patients taking potassium-depleting diuretics or digoxin; gradually taper when discontinuing

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• Closely monitor patients with adrenal hyperplasia for adequacy of dosing of glucocorticoid, mineralocorticoid, or both.


• • Too little glucocorticoid results in symptoms of adrenal insufficiency (eg, anorexia, nausea, vomiting, abdominal pain, asthenia) and 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. Short stature in adulthood is frequently the outcome in virilizing forms of adrenal hyperplasia because of the effect of uncontrolled adrenal androgens on skeletal maturation or the effects of excess glucocorticoid administration on growth (see Image 4).

Deterrence/Prevention:

• Prenatal testing using amniocentesis or chorionic villus sampling has been successful in diagnosing congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency if a sibling had a known mutation or deletion in a previous pregnancy. Because these disorders are consistent with normal development and survivable if treated, the choice to terminate an affected pregnancy is rare. Prenatal diagnosis is usually part of prenatal treatment.



• Prenatal treatment of congenital adrenal hyperplasia appears to be somewhat successful in preventing the virilization due to 21-hydroxylase deficiency in a female fetus. According to the protocol Carlson et al proposed in 1999, the mother is treated with 20 mcg/kg/d of dexamethasone divided into 3 doses as soon as the pregnancy is recognized to suppress fetal ACTH secretion and to prevent the fetal adrenal gland from overproducing adrenal androgens.



• Dexamethasone treatment is discontinued if chorionic villus sampling (done at 8-12 wk) or amniocentesis (done 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 in 7 of 8 fetuses. However, because virilization occurs within the first 12 weeks of gestation, the virilization of an affected female fetus will have already occurred if one waits until the sex and diagnosis of the fetus are known.
  
  
  
  • So far, this strategy has not resulted in an increase in fetal wastage or congenital malformations in treated pregnancies. However, it is associated with considerable maternal adverse effects during the pregnancy.
  
  
  
  • Long-term follow-up studies are ongoing and required to determine whether dexamethasone treatment in early pregnancy results in any long-term adverse effects.
  
  
  
• Methods have been developed to screen neonates for congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency by measuring 17-hydroxyprogesterone from heel blood samples collected on filter paper.


• • At present, 13 countries and 45 of the 50 US states 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 whose condition is unrecognized at birth and resulted in the identification of both completely virilized females who may be mistaken for males with cryptorchidism and patients of both sexes with simple virilizing adrenal hyperplasia, enabling early treatment before undue advancement in skeletal maturation.
  
  
  
  • Whether politicians 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 include hypertension and hypokalemia.



• Short stature is a frequent complication of virilizing forms of congenital adrenal hyperplasia. In general, patients have final heights 1-2 standard deviations below their estimated genetic potential. This difference results from exposure to excessive concentrations of adrenal androgens that cause rapid skeletal maturation or from excessive exposure to glucocorticoids that limit growth. Early central puberty is often observed in children with advanced skeletal maturation and can contribute to the limitation in growth (see Image 4).



• Female patients with virilizing forms of adrenal hyperplasia have a decreased fertility rate. The reasons are believed to be multifactorial and include abnormal genital anatomy, vaginal stenosis, and poor control of adrenal androgen production that results in diminished ovulation. When pregnancy does occur, the baby is generally born by means of caesarian delivery because of vaginal stenosis or an android pelvis.



• Males with uncontrolled congenital adrenal hyperplasia may develop masses in the testes (adrenal rests or adrenal tissue) because the gonads and adrenal glands are derived from the same embryologic 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 and surgical therapy, the prognosis is good. However, problems with psychological adjustment are common and usually stem from the genital abnormality that accompanies some forms of congenital adrenal hyperplasia.



• Short stature and infertility are common.



• The gender identity in females with virilizing adrenal hyperplasia is usually female if female gender assignment is made early in life, if adequate medical and surgical support are provided, and if the family (and eventually the patient herself) are given 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 must also 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.



• Useful Web sites for patients and parents include the National Adrenal Diseases Foundation and the Congenital Adrenal Hyperplasia Research Education and Support (CARES) Foundation.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Education is essential for parents and affected children to understand the pathophysiology of their 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 are often reluctant to provide stress doses when needed and they are particularly reluctant to administer injectable glucocorticoids when the patient is unable to take oral medication or when he or she is severely lethargic. Disastrous consequences can result.
  
  
  
  • Encourage patients to wear medical alert identification tags stating that they are taking 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 no surgery until the child can participate in these momentous decisions. Although this approach certainly would alleviate the parents’ or physician’s responsibility for making these decisions on behalf of the patient, it may leave the patient with an ambiguous gender identity and an ambiguous role through childhood. In addition, it exposes the child to further embarrassment of having ambiguous genitalia.
  
  
  
  • In the author's opinion, this delayed approach increases the risks to the physical and psychological welfare of the patient.
  
  
  

Special Concerns:

• Some patient groups, such as the Intersex Society of North America, have been vocal in criticizing the treatment (particularly the surgical treatment) of patients with congenital virilizing adrenal hyperplasia or 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, the author is concerned that the vocality of such groups (some of which are composed of dissatisfied patients who underwent poor medical management in an era of low sensitivity to the feelings of the child and unsophisticated genital reconstruction techniques) restricts physicians and parents who struggle to arrive at decisions that are in the best interest of children born with this difficult problem.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 2-week-old male neonate presents to the emergency department with a history of recurrent vomiting and dehydration. His weight is less than his birth weight, and he appears dehydrated. His pulse is elevated. His blood pressure is 50 mm Hg on palpation. Serum electrolyte levels are as follows: sodium 115 mEq/L, potassium 8.5 mEq/L, chloride 90 mEq/L, and bicarbonate 12 mEq/L. His BUN level is 30 mg/dL, and his creatinine level is 0.7 mg/dL. Which of the following is the most likely diagnosis?

A: Pyloric stenosis
B: Acute gastroenteritis
C: Congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency
D: Congenital adrenal hyperplasia secondary to 11-hydroxylase deficiency
E: Sepsis

The correct answer is C: A vomiting infant who is dehydrated may have pyloric stenosis, sepsis, renal failure, or adrenal insufficiency. This patient’s electrolyte levels are typical of adrenal insufficiency. The most common cause of adrenal insufficiency is congenital adrenal hyperplasia secondary to 21-hyroxylase deficiency. Approximately 50% of these infants have salt wasting. In female neonates, this condition is usually detected at birth because of their ambiguous genitalia. Male neonates have normal genitalia and escape detection at birth but come to attention with a salt-wasting crisis at 1-4 weeks of life.

CME Question 2: A 4-year-old boy presents with early pubic hair. His height is 2.8 standard deviations above the mean for his age, and his growth curve demonstrates a progressive climb from the 50th percentile in height to more than the 95th percentile. His parents are of average height. His physical findings are normal, except for the teeth, which reveal 6-year molars, and the genitalia, which reveal Tanner stage III pubic hair, a stretched penile length of 8 cm (5 cm is normal for age), and testes of 2 cm³ (prepubertal). Which of the following is the most likely diagnosis?

A: Excess growth hormone secretion
B: Central precocious puberty
C: Cerebral gigantism (Soto syndrome)
D: Simple congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency
E: Benign precocious adrenarche

The correct answer is D: Patients with excess growth hormone secretion and cerebral gigantism (Soto syndrome) are not expected to show early pubic hair and penile enlargement. A male patient with central precocious puberty who has pubic hair and penile enlargement is expected to have enlarged testes due to follicle-stimulating hormone (FSH) stimulation. The best explanation for the excessive growth rate, advanced skeletal development, pubic hair, and penile enlargement without testicular enlargement is adrenal androgen production. The most common cause of excessive adrenal androgen production is congenital virilizing adrenal hyperplasia. An alternative diagnosis is a virilizing adrenal tumor, but this type of tumor is rare. Patients with simple virilizing adrenal hyperplasia do not have salt wasting; therefore, the condition is not detected in infancy.

Pearl Question 1 (T/F): Congenital virilizing adrenal hyperplasia is inherited as an autosomal dominant disorder.

The correct answer is False: All forms of congenital adrenal hyperplasia are inherited as autosomal recessive disorders.

Pearl Question 2 (T/F): A male infant with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency (cytochrome P450 [CYP] 21B) is expected to have ambiguous genitalia.

The correct answer is False: 21-Hydroxylase deficiency in the male neonate does not result in ambiguous genitalia because the testosterone-producing mechanisms are intact. 21-Hydroxylase deficiency does result in ambiguous genitalia in the female neonate because of overproduction of adrenal androgens that virilize the female fetus.

Pearl Question 3 (T/F): If the prevention of virilization is to be successful in a female fetus with 21-hydoxylase deficiency, the mother must be treated with dexamethasone early in the pregnancy.

The correct answer is True: Fusion of the posterior labial folds occurs in the first trimester of pregnancy. Therefore, if fusion of the posterior labial folds is to be prevented, the mother must be treated with dexamethasone as early in the pregnancy as possible. Enlargement of the phallus may occur progressively throughout gestation.

Pearl Question 4 (T/F): In hypertensive forms of adrenal hyperplasia, plasma renin activity is suppressed.

The correct answer is True: The 2 hypertensive forms of adrenal hyperplasia, one due to 17-alpha-hydroxylase deficiency (cytochrome P450 [CYP] 17) and the other due to 11-beta-hydroxlase deficiency (CYP11B1), result in high concentrations of deoxycorticosterone, which serves as a mineralocorticoid that causes sodium retention, volume expansion, and suppression of renin secretion.

PICTURES

Section 11 of 12

Caption: Picture 1. Steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis. A mutation or deletion of any of the genes that code for enzymes involved in cortisol or aldosterone synthesis results in congenital adrenal hyperplasia. The particular phenotype that results depends on the sex of the individual, the location of the block in synthesis, and the severity of the genetic deletion or mutation.
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Caption: Picture 2. A 46 XX female patient with mild virilization due to congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency. Despite the mild clitoromegaly, this patient has fusion of the labial-scrotal folds and salt wasting.
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Caption: Picture 3. Severe virilization in a 46 XX female patient with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. This patient also has salt wasting.
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Caption: Picture 4. Short stature in a male patient with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. His compliance with medical therapy was poor, and early growth and skeletal maturation was advanced, resulting in early puberty and completion of growth. This 12-year-old boy has reached final adult height, which is well below that of his mother.
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BIBLIOGRAPHY

Section 12 of 12

• Barone MA, ed: The Harriet Lane Handbook. St Louis, Mo: Mosby-Year Book; 1996: 681.
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• Purandare A, Godil MA, Prakash D, et al: Spontaneous adrenal hemorrhage associated with transient antiphospholipid antibody in a child. Clin Pediatr (Phila) 2001 Jun; 40(6): 347-50[Medline].
• Skinner CA, Rumsby G, Honour JW: Single strand conformation polymorphism (SSCP) analysis for the detection of mutations in the CYP11B1 gene. J Clin Endocrinol Metab 1996 Jun; 81(6): 2389-93[Medline].
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