Version May 2024
INTRODUCTION — More than 95 percent of cases of congenital adrenal hyperplasia (CAH) are caused by autosomal recessive deficiency of 21-hydroxylase, due to mutations of the CYP21A2 gene. Deficiency of 21-hydroxylase interferes with conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and conversion of progesterone to deoxycorticosterone, resulting in diminished or absent production of cortisol and aldosterone and overproduction of adrenal androgens (figure 1) [1,2] (see "Adrenal steroid biosynthesis"). Clinical manifestations depend on the severity of the deficiency and adequacy of treatment but most commonly include risk for adrenal crisis, virilization including atypical genitalia (in 46,XX infants), abnormal growth during childhood, early puberty, adult short stature, menstrual dysfunction, and infertility [3].
The treatment of classic CAH due to 21-hydroxylase deficiency in infants and children is reviewed here. Management of atypical genitalia is discussed separately. (See "Management of the infant with atypical genital appearance (difference of sex development)".)
Other aspects of this disorder are discussed in related topics:
●(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
OVERVIEW — The goals for treatment of classic 21-hydroxylase deficiency are to prevent adrenal crisis and optimize growth, sexual maturation, and reproductive function. This is accomplished by replacing glucocorticoid and mineralocorticoid in sufficient doses to reduce the associated excessive corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion and hyperandrogenemia. Mineralocorticoid replacement is especially important in patients with the salt-losing form of the disorder to maintain normal serum electrolyte concentrations and extracellular fluid volume but also may be beneficial for patients with classic non-salt-losing (simple virilizing) CAH. These goals can be difficult to achieve without overtreatment and its attendant risk of growth retardation and other clinical manifestations of Cushing syndrome [3]. (See "Epidemiology and clinical manifestations of Cushing syndrome".)
MANAGEMENT IN NEONATES — Newborn infants with CAH may be identified through targeted prenatal diagnosis in affected families or by neonatal screening programs. Others may present with atypical genitalia in affected females or with adrenal crisis, which typically presents at approximately 10 to 20 days of life. Because of the risk of adrenal crisis, every newborn with atypical genitalia or a suspected diagnosis of CAH should be urgently evaluated by a pediatric endocrinologist.
Approach by clinical presentation
Positive newborn screen — Newborn screening for classic CAH is routinely performed in all 50 of the United States and at least 40 other countries [2]. A positive newborn screening test for CAH must be confirmed by a second serum/plasma sample. The urgent medical issue is identification of infants with the salt-losing form before they develop an adrenal crisis. Symptoms of salt losing, including vomiting, poor feeding with failure to thrive, lethargy, hypovolemia, dehydration, hyponatremia with reciprocal hyperkalemia, hypoglycemia, and cardiovascular collapse, can occur within the first few weeks of life if CAH is not treated [4]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
As soon as CAH is suspected on the basis of a positive newborn screen, a sample of blood should be obtained for confirmatory steroid hormone measurements (most importantly, 17-hydroxyprogesterone [17-OHP]) and serum electrolytes should be measured. The 17-OHP should be measured in a major national laboratory that offers the assay with rapid turnaround time. To distinguish 21-hydroxylase deficiency from other rarer causes of CAH, serum concentrations of 11-deoxycortisol, 17-hydroxypregnenolone, androstenedione, dehydroepiandrosterone (DHEA), and cortisol should also be measured, and these can be consolidated as multitest panels in major commercial laboratories. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Additional testing for infants with equivocal results'.)
After the confirmatory blood sample is obtained, treatment doses of glucocorticoid and mineralocorticoid should be initiated in all infants in whom CAH is a consideration (see 'Medications and dosing' below) to prevent the potentially life-threatening manifestations of an adrenal crisis. If the clinician chooses not to initiate treatment while awaiting the results of confirmatory steroid hormone measurements, serum electrolytes should be measured every 24 to 48 hours to monitor for adrenal insufficiency. These patients should be managed by a pediatric endocrinologist.
Prenatal diagnosis — A few infants with CAH will be identified by prenatal diagnosis if they are born to a family with a history of CAH in a parent or sibling. For these infants, treatment should be initiated after birth and after a confirmatory blood sample is obtained, as described below. (See 'Medications and dosing' below.)
Atypical genitalia — Infants with atypical genitalia require urgent medical attention. The initial evaluation should include history, physical examination, rapid and reliable measurement of 17-OHP and serum electrolytes, karyotype or fluorescence in situ hybridization (FISH) for sex chromosome material (SRY probe; if not available from prenatal testing), and pelvic ultrasonography to evaluate internal genitalia (presence or absence of uterus and location of gonads). This evaluation is discussed in detail separately. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
Infants with genital atypia and nonpalpable gonads should be presumed to have 46,XX CAH and empirically treated for CAH until the diagnosis is confirmed or excluded. After the blood sample for 17-OHP is obtained, treatment doses of glucocorticoid and mineralocorticoid as well as sodium chloride supplementation should be initiated in all such infants to prevent the potentially life-threatening manifestations of an adrenal crisis. While awaiting laboratory results, therapy should be initiated, as outlined below. (See 'Medications and dosing' below.)
An appropriate therapeutic plan can be developed only with the full participation of the parents/caregivers and after a careful and complete evaluation by an experienced interdisciplinary team of endocrinologists, surgeons, and mental health professionals with expertise in managing the psychosocial aspects of disorders of sex development. The team should provide sensitive and expert psychosocial support to the parents and family who may need some time to adjust to the diagnosis before they are capable of making decisions regarding surgical management. The family should be informed about surgical options including avoiding or delaying surgery. Surgery should be performed by a surgeon with special expertise in treating this population. Family support and management of the infant are discussed in detail separately. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Is it a boy or a girl? Family coping'.)
Adrenal crisis — Urgent medical therapy is necessary for infants who present in an adrenal crisis. A rapid overview guiding the recognition and treatment of an adrenal crisis is shown in the accompanying table (table 1). Infants with CAH occasionally present with adrenal crisis, even in countries where newborn screening for CAH (secondary to 21-hydroxylase deficiency) is routinely performed, such as the United States.
The initial goals are treatment of hypotension and dehydration, reversal of electrolyte and glucose abnormalities, and correction of cortisol deficiency.
●Give an intravenous (IV) bolus of 10 to 20 mL/kg of normal (0.9%) saline solution or 5% dextrose in normal saline. Hypotonic saline should not be used, because it can worsen the hyponatremia; the same is true of 5% dextrose without the addition of normal saline.
●If there is significant hypoglycemia, give an IV bolus of 5 to 10 mL/kg of 10% dextrose (0.5 to 1 g/kg) or, alternatively, 2 to 4 mL/kg of 25% dextrose infused slowly at a rate of 2 to 3 mL/min (maximum single dose 25 g dextrose) [5].
●Hyperkalemia typically improves promptly, simply as a result of the potent mineralocorticoid action of high-dose hydrocortisone. On rare occasion, for severe and symptomatic hyperkalemia, administration of glucose and insulin is needed to manage the hyperkalemia. (See "Fluid and electrolyte therapy in newborns", section on 'Hyperkalemia' and 'Mineralocorticoid and sodium chloride' below.)
●Obtain a blood sample for steroid hormone measurements (most importantly, 17-OHP to evaluate for 21-hydroxylase deficiency), then administer stress doses of hydrocortisone. Give an initial dose of hydrocortisone of 50 to 100 mg/m2 as an IV bolus (typical neonatal dose is 25 mg), followed by hydrocortisone at a dose of 50 to 100 mg/m2 IV per day divided every six hours. Continue to administer these stress doses of hydrocortisone until the patient is stable and feeding normally.
During treatment with stress doses of hydrocortisone, mineralocorticoid replacement is unnecessary. If the diagnosis of classic 21-hydroxylase deficiency is confirmed, infants should receive glucocorticoid and mineralocorticoid therapy as well as salt supplementation (see 'Management in older infants and children' below). If the diagnosis of 21-hydroxylase deficiency is not confirmed, further evaluation will be needed to determine the cause of the adrenal insufficiency, which may include uncommon causes of CAH or other rare causes of congenital adrenal insufficiency [5]. (See "Causes of differences of sex development" and "Causes of primary adrenal insufficiency in children".)
Medications and dosing — Glucocorticoid therapy should be initiated in newborns with:
●Confirmed CAH – Initiate treatment with hydrocortisone at standard starting doses and continued indefinitely, with dose adjustment based on regular monitoring. In addition, treat with mineralocorticoids and sodium chloride supplements.
●Suspected CAH (eg, in an infant presenting with a positive newborn screen or atypical genitalia) – After obtaining a blood sample to confirm the diagnosis, initiate treatment with hydrocortisone, fludrocortisone, and sodium chloride supplements at standard starting doses. Continue this treatment until the diagnosis of CAH is either confirmed or excluded.
●Adrenal crisis – Administer glucocorticoids at stress doses. (See 'Adrenal crisis' above.)
Initial dosing for newborns — In the absence of adrenal crisis, a typical starting regimen for an infant includes:
●Hydrocortisone at 20 to 30 mg/m2/day, divided three times daily (ie, 2.5 mg three times a day), with rapid dose reduction when target hormone levels are reached. Use either the tablet formulation of hydrocortisone (administered by crushing the tablets and mixing with a small amount of water) or an immediate-release granule formulation of hydrocortisone (Alkindi Sprinkle). Liquid hydrocortisone should not be used.
and
●Fludrocortisone 100 mcg (0.1 mg) once or twice daily.
and
●Sodium chloride, 1 to 2 g or 17 to 34 mEq/day (2 to 4 mEq/kg/day), divided in several feedings.
Higher doses of hydrocortisone (ie, 50 mg/m2/day) may be used for initial reduction of markedly elevated adrenal hormones, but it is important to very rapidly reduce the dose when target hormone levels are achieved. Doses of hydrocortisone that exceed 20 mg/m2/day in infancy have been associated with growth suppression and shorter adult height [2] and thus should be avoided.
Monitoring and dose adjustment — Follow-up laboratory tests (serum 17-OHP, androstenedione, plasma renin activity, and electrolytes) should be performed no more than 10 to 14 days after starting treatment. The results should be used to guide adjustment of the doses of glucocorticoids and mineralocorticoids. Sufficient glucocorticoid doses are needed to ensure suppression of adrenal androgens, but excessive dosing can impair growth. Sufficient mineralocorticoid doses are needed to maintain normal fluids and electrolytes, but excessive dosing can induce hypertension or hypokalemia and possibly contribute to growth impairment. (See 'Medications and dosing' below.)
The doses of these medications are further adjusted based on serial blood sampling and blood pressure monitoring at least monthly during the first three months of life, every three months during infancy, and every three to six months thereafter during childhood. Sodium chloride supplements are typically needed in the first year but can usually be discontinued as the child starts to eat table food.
MANAGEMENT IN OLDER INFANTS AND CHILDREN
Medications and dosing
Glucocorticoid — Glucocorticoid replacement is necessary in children who have classic 21-hydroxylase deficiency and in symptomatic children with nonclassic 21-hydroxylase deficiency [1,4]. The goal of therapy is to replace deficient steroids while minimizing adrenal sex hormone and iatrogenic glucocorticoid excess [4]. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Glucocorticoid in infants and children is usually administered as hydrocortisone (cortisol) in a dose of 10 to 15 mg/m2/day [1,2,4], divided into three doses, although higher doses are sometimes needed and treatment should be individualized. This dose range exceeds the daily cortisol secretory rate of normal infants and children, which is estimated to be 7 to 9 mg/m2/day in neonates and 6 to 7 mg/m2/day in children and adolescents [6-8]. It is important to use the lowest effective glucocorticoid dose because excessive dosing reduces linear growth.
Low-dose hydrocortisone granules for the treatment of infants with CAH are now available in Europe and the United States (Alkindi Sprinkle) [9,10]. Accurate dosing of infants in other parts of the world remains a concern because pediatric dose formulations are not available. This new formulation eliminates concerns about the inaccuracies of compounding of hydrocortisone tablets. A modified-release hydrocortisone capsule formulation (Efmody), designed to mimic physiologic circadian cortisol rhythm when given twice daily, is now available in the United Kingdom and Europe for patients with CAH who are 12 years and older [11,12].
Concerns have been raised about the use in children of long-acting glucocorticoids such as dexamethasone, prednisolone, and prednisone because the longer duration of action and greater potency may increase the risk of overtreatment and results of therapy are frequently suboptimal in terms of adult height [13,14] (see 'Growth' below). However, limited data from small case series suggest that treatment with these drugs does not necessarily limit growth. As an example, one study of 26 children treated with dexamethasone (average dose 0.27 mg/m2 every morning) for an average of seven years demonstrated normal growth and control of androgen secretion with normal sexual maturation [15]. Similarly, nine children with adrenal insufficiency had normal short-term (six months) height velocity when receiving prednisolone at a dose of 5:1 relative potency to hydrocortisone [16]. It is possible that the doses used in these studies were sufficiently low to avoid the growth-suppressing effects. However, because of ongoing concerns about growth, hydrocortisone remains the glucocorticoid of choice and the standard of care during childhood [1,2,4].
For older adolescents who have completed their growth, long-acting glucocorticoids such as dexamethasone or prednisone are often used for treatment [17] due to the convenience of less frequent dosing compared with hydrocortisone. Dexamethasone is usually given once daily at an oral dose of 0.25 to 0.50 mg, preferably at bedtime, but a twice-daily regimen may be needed in some patients. Alternatively, oral prednisone or prednisolone can be given at a daily dose of 5 to 7.5 mg, divided into two doses. Higher doses are sometimes needed, and treatment should be individualized. For sexually active females, a glucocorticoid that is inactivated by the placenta (eg, hydrocortisone, prednisone, or prednisolone) is preferred.
Mineralocorticoid and sodium chloride — Mineralocorticoid replacement is recommended in all patients who have classic CAH due to 21-hydroxylase deficiency, whether or not it is the salt-losing form. Although only the salt-losing form is associated with clinically apparent mineralocorticoid deficiency, aldosterone secretion has been shown to be impaired in the simple virilizing form [18,19] and mineralocorticoid treatment appears to improve the height outcome in patients with all forms of classic CAH [20,21]. The mineralocorticoid dose should be periodically reassessed in each patient since sensitivity to mineralocorticoids may vary over time [2]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genotype versus phenotype'.)
Fludrocortisone is used for mineralocorticoid replacement, given in a dose sufficient to restore normal serum sodium and potassium concentrations and to maintain plasma renin activity within the normal range. The usual pediatric dose of fludrocortisone is 100 mcg (0.1 mg) per day (range 50 to 200 mcg per day [0.05 to 0.20 mg per day]) [2]. Dose adjustments should be guided by measurement of plasma renin activity and blood pressure. (See 'Monitoring and dose adjustment' below.)
Signs of excessive dosing include suppressed plasma renin activity, hypertension, hypokalemia, and, possibly, impaired growth [22]. Paradoxically, underdosing also can lead to poor growth with failure to thrive. This may be in part because inadequate mineralocorticoid replacement increases the glucocorticoid replacement requirement, which, in turn, impairs growth [22,23]. In addition, inadequate mineralocorticoid replacement may lead to increased adrenal androgen production. This is because patients may be chronically volume depleted, which is clinically inapparent but results in persistent overproduction of renin and angiotensin II. Angiotensin II stimulates vasopressin and adrenocorticotropic hormone (ACTH), leading to higher adrenal androgen synthesis [24,25]. For all of these reasons, mineralocorticoid therapy appears to benefit patients with either the classic salt-losing form or the classic non-salt-losing (simple virilizing) form of 21-hydroxylase deficiency.
Newborn infants often require higher doses of fludrocortisone (0.1 mg twice daily). For most infants, the dose should be reduced around 6 to 12 months of age because sensitivity to mineralocorticoid increases as the kidneys mature in the first year of life, which may cause hypertension if the dose is not reduced. This needs to be closely monitored. In a study of 33 patients with classic CAH diagnosed by newborn screening, over one-half developed hypertension in the first 18 months of life [26].
Sodium chloride supplementation is also required for infants at 1 to 2 g/day (approximately 17 to 34 mEq/day or 4 mEq/kg/day) distributed in several feedings [4]. Salt tablets/solution can be discontinued as the child begins to eat table food and the taste for salty food increases (around 8 to 12 months of age). Older children may need additional salt intake during hot weather or with intense exercise due to excess salt loss in these settings. Increased salt intake during the summer months when outside activities are planned or during the days of sports activities usually suffices. However, children involved in competitive sports sometimes benefit from taking a 1 g salt tablet prior to events.
Monitoring and dose adjustment — The response to therapy should be evaluated monthly in the first three to six months of life, every three months in older infants, and every three to six months thereafter [2,4]. More frequent monitoring is sometimes clinically indicated. Adjustments in the dose of hydrocortisone and fludrocortisone are based on the results of the serum tests listed below, which serve as markers of the adequacy of treatment and of patient adherence to it, along with measurements of growth and skeletal maturation.
●Serum tests – Blood samples should be obtained at a consistent time in relation to glucocorticoid dosing, optimally in the morning to reflect peak serum/plasma concentrations at approximately 8:00 AM. The morning glucocorticoid dose is best delayed until after the blood sample is obtained. Alternatively, blood samples may be obtained one to two hours after the morning hydrocortisone dose is administered [1,4], as long as the clinician is consistent in his or her approach and the timing of the medication in relation to the blood draw is considered when interpreting the hormonal data. Normative laboratory data for age and sexual maturation should be used in the interpretation of all laboratory tests and may vary depending on the laboratory.
•17-hydroxyprogesterone (17-OHP) – Appropriate target ranges are a serum 17-OHP concentration of 400 to 1200 ng/dL (12 to 36 nmol/L), which are above the normal range for individuals without CAH [1]. Normal levels of 17-OHP generally indicate excessive dosing of glucocorticoids and are associated with the risk of iatrogenic Cushing syndrome. Moreover, excessive dosing of glucocorticoids does not necessarily prevent androgen excess, since this may persist because of avid adrenal conversion of 17-OHP to androgens [27].
•Androstenedione – Androstenedione should be measured routinely to ensure that the glucocorticoid dose is adequate. Target serum androstenedione concentrations are the normal range for the patient's age and sex at the reference laboratory; suppression below the normal range suggests excessive glucocorticoid dosing [1].
Patients with mild elevations of androstenedione can be managed by upward titration of the glucocorticoid dose. Patients with more marked elevations of androstenedione or testosterone levels due to poor compliance may respond more rapidly to a brief (7- to 10-day) course of dexamethasone administered in supraphysiologic doses, followed by the standard replacement doses. It is essential that the high-dose course be brief to avoid compromising growth and increasing weight.
•Testosterone – Testosterone should be measured when disease is not well controlled to evaluate the extent of the hyperandrogenism. For example, it may be useful to measure testosterone in an adolescent female with menstrual irregularity or in children with advanced bone age and signs of androgen excess.
•Plasma renin activity or direct renin – Plasma renin should be monitored and kept in the normal range for age. A suppressed plasma renin activity reflects excessive mineralocorticoid dosing and increases the risk for hypertension [26,28]. In patients with elevated plasma renin activity, indicating ongoing salt loss, the first step is to adjust the fludrocortisone and/or the exogenous salt doses to decrease renin before increasing the glucocorticoid dose. However, markedly elevated levels of 17-OHP have an anti-mineralocorticoid effect [29]. Therefore, the interrelationship between glucocorticoid and mineralocorticoid actions should be accounted for in the management.
●Growth and skeletal maturation – Measurements of growth rate and bone age reflect long-term control.
•Growth rate – Linear growth should be measured at every follow-up visit and analyzed by plotting on a standard growth chart and calculating height velocity. Interpretation of serial growth measurements, including calculation of Z-scores for height, is discussed separately. (See "Diagnostic approach to children and adolescents with short stature", section on 'Is the child's height velocity impaired?'.)
•Bone age – Bone age should be determined every 6 to 12 months after two years of age [2]. If bone age becomes advanced for chronologic age, repeat measurements should be performed more frequently (eg, every six months). (See "Diagnostic approach to children and adolescents with short stature", section on 'Bone age determination'.)
In general, increased growth rate and advanced bone age suggest excessive androgen exposure, whereas reduced growth rate and delayed bone age suggest excessive glucocorticoid dosing. Ideally, treatment should be modified well before there is evidence of altered growth rate or bone maturation [2]. In practice, however, it may be difficult to find a glucocorticoid dose that is high enough to suppress androgen secretion while also permitting optimal growth. As an example, in a randomized trial in 26 children, hydrocortisone at a dose of 25 mg/m2/day caused significant slowing of growth over the course of one year, compared with a dose of 15 mg/m2/day [27]. However, at the lower dose, there was often incomplete suppression of androgen secretion. Another study focused on glucocorticoid dosing in patients with CAH who are pubertal and concluded that hydrocortisone doses above 17 mg/m2/day are associated with reduced growth velocity in both males and females, leading to adult height at the lower limit of genetic potential [30]. Thus, the patient's symptoms and signs of androgen excess and measurements of serum steroid hormone levels, growth velocity, physical development, and rate of bone age maturation all need to be considered when adjusting glucocorticoid doses.
●Pubertal maturation – Children with CAH should also be monitored for signs of pubertal onset. They are more likely to have early central puberty compared with healthy children, especially when the diagnosis of CAH is delayed or when adrenal androgen secretion is poorly controlled. If central precocious puberty is suspected, measurement of serum luteinizing hormone (LH) using a sensitive immunochemiluminescence assay is useful. (See 'Puberty' below.)
Prevention and management of adrenal crisis — In children with classic CAH, adrenal crisis may be triggered by routine illnesses unless the glucocorticoid regimen is appropriately increased. A rapid overview guiding the recognition and treatment of an adrenal crisis is shown in the accompanying table (table 1).
Every patient should wear a medical identification (MedicAlert) bracelet or necklace and carry an Emergency Medical Information Card [2,4]. These should indicate the diagnosis "adrenal insufficiency" (not CAH) and the clinician to call in the event of an emergency. Patients can enroll in MedicAlert by calling 1-800-432-5378 or online at www.medicalert.org (United States) and www.medicalert.ca (Canada).
Management during illnesses — Stress doses of glucocorticoids are warranted for illnesses associated with fever, vomiting, and/or marked diarrhea and significant trauma. Increased doses of glucocorticoids are not required for mild illnesses without fever, emotional stress (eg, school examinations), or before physical exercise. Treatment depends on the type and severity of symptoms:
●If the child can tolerate oral medication and fluids, the usual oral dose of glucocorticoids should be doubled or tripled for the duration of illness; changes in fludrocortisone dose are not required [2].
●If a patient is unable to tolerate oral medication, hydrocortisone should be given intramuscularly (IM) and medical advice should be sought promptly.
●If there are significant fluid losses (diarrhea or vomiting and impaired oral intake), with or without fever, the child should receive an IM injection of hydrocortisone and be urgently assessed by a medical team. This injection can be administered either by trained caregivers in the home or, in states that allow it, by emergency medical services personnel using either injectable hydrocortisone that is carried on emergency rigs or using patient-held medication. Administration of parenteral glucocorticoids, saline, and glucose may be needed until the child can resume adequate oral intake.
●Patients with CAH and febrile illnesses are at risk for hypoglycemia, especially in young children and if oral intake is impaired [2,31]. Unexpected hypoglycemic events that seem unrelated to infection have also been reported, especially in the first four years of life [32]. Because of the risk of hypoglycemia, it is best to increase the frequency of hydrocortisone dosing during illnesses to four times daily with a maximum span of six to seven hours between doses (rather than three times daily) [31], although the efficacy of this approach in the prevention of hypoglycemia has not been established. Increased fluid intake and frequent ingestion of simple and complex carbohydrates is also recommended. If the child becomes lethargic, they should be given 15 g of simple carbohydrates (one-half cup of juice, regular soda, or applesauce) and evaluated by emergency services.
Intramuscular administration of glucocorticoids — Parents/caregivers should be instructed in the techniques for IM administration of glucocorticoids and not rely solely on rapid access to an emergency center. Patients with nausea and vomiting who are unable to take oral medications should receive IM hydrocortisone sodium succinate (Solu-Cortef) [2,5]. In the preferred two-chamber Act-o-Vial formulation, this medication has a shelf-life of five years unopened. The optimal IM dose and frequency depends on the patient's size and the severity of the intercurrent illness. Typical dosing for this situation is 50 to 100 mg/m2/dose, with a maximum dose of 100 mg [2]. The caregivers' knowledge of indications for and techniques of emergency treatment should be assessed at each clinic visit.
Stress dosing of glucocorticoids — Patients who have severe illness or trauma should receive intravenous (IV) glucocorticoids, as indicated below. An initial IV bolus is followed by additional IV doses, as outlined in the following age-related protocol [2,5]:
●≤3 years – Give one dose of hydrocortisone (Solu-Cortef), 25 mg IV, followed by 25 mg/day either divided every six hours or as a continuous infusion
●>3 years and <12 years – Give one dose of hydrocortisone, 50 mg IV, followed by 50 mg/day either divided every six hours or as a continuous infusion
●≥12 years of age – Give one dose of hydrocortisone, 100 mg IV, followed by 100 mg/day either divided every six hours or as a continuous infusion
Alternatively, dosing can be based on body surface area rather than age: Give one dose of hydrocortisone, 50 to 100 mg/m2, followed by 50 to 100 mg/m2/day, divided every six hours or as a continuous infusion.
Stress doses of hydrocortisone should be tapered rapidly according to the clinical improvement, generally by reducing the dose to the patient's usual glucocorticoid daily dose when the illness is resolved and the patient is tolerating a normal diet.
For patients undergoing surgery, glucocorticoid dosing depends on the length of surgery, as detailed in a separate topic review. (See "Treatment of adrenal insufficiency in children", section on 'Surgical procedures'.)
COUNSELING — Parents should be offered counseling as soon as the diagnosis of CAH is established. If the infant presents with atypical genitalia, immediate and ongoing counseling by an expert team is particularly important. Details about counseling and management of patients with atypical genital appearance, including decisions about genital surgery, are discussed in a separate topic review. (See "Management of the infant with atypical genital appearance (difference of sex development)".)
Children should be informed of their condition by both their clinicians and parents; the information should be provided in a manner that is appropriate to the age and developmental status of the child and should be repeated at regular intervals beginning at a young age. Adolescents should receive reassurance and independent counseling if warranted [17,33]. According to the Endocrine Society Clinical Practice Guideline, genetic counseling should be provided to adolescents [2]. Genetic counseling is also indicated for family planning for the adult patient with CAH and is discussed in a separate topic review of adults. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
Patients and family members may find helpful information at the following websites [4]:
●The Hospital for Sick Children (choose "conditions" and then "CAH")
OUTCOMES OF INTEREST — The outcome of therapy for 21-hydroxylase deficiency can be measured by evaluating growth and development, gonadal function and fertility, bone density, and quality of life. In addition, children with 21-hydroxylase deficiency are at risk for obesity, possibly in part due to therapy.
Growth — The adult height achieved in treated patients is usually less than that in reference groups. A meta-analysis of studies of patients treated for CAH reported a mean adult height score of -1.4 standard deviations (SD) or 10 cm below the population mean [34]. The mean weighted adult height SD score was closer to normal for patients who began treatment during infancy compared with those who began treatment after one year of age (adult height -1.1 SD versus -1.6 SD). A subsequent meta-analysis reported a mean adult height of -1.03 SD and found that mineralocorticoid users had a better height outcome compared with nonusers [20].
Impaired growth in children with CAH involves both hypercortisolism and hyperandrogenism, as shown in retrospective studies in which adult height of patients with CAH was independent of the degree of control of adrenal androgen concentrations [35-37]. Several studies have suggested that treatment during the first two years of life and during puberty are the most important factors influencing height outcome [30,37-39]. Adequate mineralocorticoid doses are also needed to optimize growth [20].
The best established approach to optimizing linear growth is judicious glucocorticoid and mineralocorticoid dosing and close monitoring; heights approximating target height have been reported in patients treated with thrice-daily doses of medication and monitoring every three months [2,40,41]. Experimental therapies to improve linear growth in patients with CAH include sex steroid blockade, growth hormone, and/or gonadotropin-releasing hormone agonists (GnRHa). These treatments can be considered for patients with CAH and growth failure (predicted adult height -2.25 SD) in the setting of a controlled research trial [2]. (See 'Experimental medical therapy' below.)
Reproductive function
Puberty — Patients with CAH are at risk for early onset of central puberty (also known as gonadotropin-dependent precocious puberty). In general, puberty is considered precocious if the onset of secondary sexual characteristics is before the age of eight years in girls and nine years in boys. Central precocious puberty is most likely to develop when the diagnosis of CAH is delayed or when adrenal androgen secretion is poorly controlled; such patients may benefit from treatment with a GnRH analog [42]. In boys with CAH, the onset of central puberty has been closely linked to a bone age between 12 years and 12 years 6 months [43], but no clear association has been identified in girls. If central precocious puberty is suspected, measurement of serum luteinizing hormone (LH) using a sensitive immunochemiluminescence assay is useful. (See "Definition, etiology, and evaluation of precocious puberty".)
Menstrual function — Menstrual dysfunction is common among women with CAH. One study reported that, despite earlier onset of puberty in females with CAH, the mean age of menarche is comparable with the general population; however, patients with poor adrenal control have delayed onset of menarche [44]. Low fertility rates and irregular menses have been attributed to progesterone hypersecretion, although adrenal androgens, secondary polycystic ovaries, and anatomical differences can also impair fertility [3,45]. In a female patient with classic CAH who has not undergone genital surgery, evaluation for possible obstruction of menstrual flow should be performed at the onset of puberty. Other surgical concerns that may arise during adolescence include urinary incontinence, vaginal stenosis, and cosmesis [17].
Testicular function — Ectopic adrenal tissue located in the testes (testicular adrenal rest) is commonly found in males with CAH and can interfere with testicular function, causing infertility. The prevalence of testicular adrenal rest in boys with classic CAH ages 2 to 18 years ranges from 18 to 24 percent [46,47] and increases with age, especially during puberty [48]. Temporary increases in glucocorticoid dose may decrease testicular adrenal rest and reverse infertility but may also lead to side effects consistent with Cushing syndrome. Dexamethasone 0.75 mg daily and dexamethasone 0.5 mg given twice daily have been reported to restore fertility in a few cases [49,50]. Successful induction of fertility has also been described in a case report with low-dose dexamethasone followed by twice-daily prednisone [51]. Testis-sparing surgery is rarely indicated but may be considered in patients when medical therapy fails. However, in one study of eight adult men with CAH, testicular adrenal rest, and infertility, testis-sparing surgery successfully removed the tumors but did not restore fertility [52]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Males'.)
Bone density — The effect on bone mineral density depends on the age of the patient studied. As an example, in one study of younger patients (mean age 17.5 years), those treated with glucocorticoid therapy for a mean of 15 years did not have decreased bone mineral density compared with normal subjects matched for age, sex, and weight [53]. However, another report of older adults who had been treated since childhood found significantly lower bone density compared with a reference population, most likely because of overtreatment with glucocorticoids [54]. Decreased bone mineral density in CAH patients may in part be explained by decreased height [55].
Because children with CAH who are treated with appropriate treatment doses of glucocorticoids appear to have a low risk for reduced bone mineral density, routine evaluation of bone mineral density is not recommended [2]. However, adults with CAH tend to have low bone mineral density and should be monitored. Age-appropriate calcium and vitamin D intake, along with weightbearing exercise, is recommended. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Monitoring for long-term complications'.)
Metabolic and cardiovascular risk — Obesity is a complication in glucocorticoid-treated patients with 21-hydroxylase deficiency [56-59] and may be associated with higher glucocorticoid dose and parental obesity. In addition, carotid intima-media thickness, a marker of cardiovascular disease, is greater in obese CAH patients compared with nonobese CAH patients [60]. Thus, affected children and their families should be monitored for excessive weight gain and obesity and referred to a weight management program, if appropriate.
In one study, 37 children with CAH (26 classic, 11 nonclassic) were compared with healthy controls [61]. Children with classic CAH had more fat mass than controls, whereas children with nonclassic CAH had more lean mass but higher insulin levels, suggesting that glucocorticoid therapy plays a role in the development of obesity in CAH. In the largest review of 89 children from Germany with 21-hydroxylase deficiency (ages between 0.2 and 17.9 years), 17 percent of patients were obese, as defined by a body mass index (BMI) that was >2 SD from the mean BMI for age [56]. The risk was increased for children with a parent who had obesity. There was no difference in incidence of obesity based on sex or clinical form of 21-hydroxylase deficiency (simple-virilizing and salt-losing forms). All patients received glucocorticoid therapy, and there was a positive correlation between dose of medication prescribed and BMI. The BMI of normally growing children with CAH has been found to increase throughout childhood more than the expected age-related increase [62]. In another study, increased BMI was associated with elevated blood pressure [58]. In a longitudinal study of 57 patients with classic CAH, with data spanning both childhood and adulthood, higher prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein cholesterol was found during childhood and higher prevalence of obesity, hypertension, and insulin resistance was found during adulthood when compared with the general United States population [63].
Metabolic and cardiovascular outcomes in adults are discussed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Monitoring for long-term complications'.)
Mortality — Mortality is increased threefold in patients aged one to four years, often because of an adrenal crisis after an infection; improved parent education about CAH and its treatment, especially during episodes of acute illness (eg, infection), may reduce mortality [64]. In adults, mortality rates are elevated compared with a healthy population; the main causes of death are adrenal crisis and cardiovascular disease. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Patient safety and counseling'.)
EXPERIMENTAL MEDICAL THERAPY
Prenatal therapy — Prenatal therapy with glucocorticoids is an experimental approach aimed at reducing the virilization of an affected 46,XX fetus. This intervention does not change the need for lifelong hormonal therapy. This intervention could be considered when a fetus is known to be at risk because of an affected sibling or when both parents are known to be heterozygous for one of the severe mutations of the CYP21A2 gene. However, because adverse effects of prenatal therapy (on the fetus and mother) have been described and long-term risks are unknown, several groups have concluded that prenatal therapy should be regarded as experimental and undertaken only by a highly experienced team in a research setting and after a detailed discussion with the pregnant couple about potential benefits and adverse effects, using treatment protocols approved by an institutional review board, while awaiting follow-up data [2,4,65,66]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal diagnosis'.)
●Rationale – The rationale for prenatal therapy is that exogenous glucocorticoids can suppress production of fetal corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion, thereby reducing hyperandrogenemia and preventing or reducing virilization of the external genitalia of affected females. This is accomplished by maternal administration of dexamethasone, which is not degraded by the placenta and crosses into the fetal circulation. Because virilization of affected female fetuses begins as early as four to nine weeks gestation, therapy is only effective if it can be initiated in very early pregnancy. Unfortunately, because molecular diagnosis of CAH by chorionic villous sampling is not possible until 8 to 10 weeks of gestation, therapy must be initiated before the diagnosis can be confirmed. Since the risk of having an affected female fetus is only one in eight when both parents are known carriers, seven in eight fetuses will receive treatment who in retrospect are not affected females.
●Technique – Maternal administration of dexamethasone is started as soon as the pregnancy is recognized and continued to term if subsequent testing demonstrates that the fetus is 46,XX and has CAH [67,68]. If treatment cannot be begun by the ninth postmenarchal week, it should not be given at all [69].
If treatment is initiated, fetal sex and genotype should be determined as soon as possible, and treatment should be discontinued if testing reveals either a 46,XY fetus or a 46,XX fetus who does not have CAH, as determined by molecular diagnosis. Fetal sex can be determined as early as five weeks gestation by testing circulating cell-free fetal DNA in the maternal circulation (SRY test) [2,70]. There are now commercially available prenatal cell-free DNA screening tests that are routinely utilized to screen for trisomies and that also identify the fetal karyotype. Testing can be done at 10 weeks gestation, and turnaround time is several days. If this type of test is performed promptly at 10 weeks gestation, the karyotype results will be available before it can be determined by either chorionic villous sampling or amniocentesis and dexamethasone treatment can be discontinued in fetuses with a 46,XY karyotype. (See "Prenatal screening for common aneuploidies using cell-free DNA".)
●Efficacy – If prenatal treatment is initiated sufficiently early (before the ninth postmenarchal week), approximately 85 percent of affected 46,XX infants are born with normal genitalia and the remainder are only slightly virilized [4]. Treatment failures have been attributed to early cessation of therapy, late start of therapy, nonadherence, suboptimal dosing, or differences in dexamethasone metabolism.
●Adverse effects – Early prenatal dexamethasone exposure in children not affected by CAH was shown to have an adverse effect on future cognitive function, especially poor visual-spatial working memory and especially in girls [71,72]. Follow-up with repeat neuropsychological testing in a subgroup of the cohort as adults showed less pronounced effects, indicating a possibility for improvement over time [73]. Metabolic ramifications, such as adverse effects on lipid and glucose metabolism, have been reported in young adults who received prenatal dexamethasone therapy [74,75]. A study in 19 adults at risk for but without CAH who had early prenatal exposure to dexamethasone reported alterations in brain structure, including altered white matter microstructure, compared with an unexposed control group [76]. Separate studies suggest that exposure to corticosteroids early in pregnancy modestly increases the risk for cleft lip and palate, but the indications for and doses of glucocorticoids were not reported [77]. A case of an orofacial cleft in a girl born with CAH who received prenatal dexamethasone has been reported [78].
Adverse effects for the mother include increased appetite, early and excessive weight gain, edema, striae, and signs and symptoms of Cushing syndrome [69,79]. (See "Epidemiology and clinical manifestations of Cushing syndrome".)
Other experimental therapies
●New glucocorticoid preparations and delivery methods – New treatment approaches are being developed and might achieve improved adrenal androgen control with less daily glucocorticoid exposure. As examples:
•Infusion of hydrocortisone in a circadian fashion to patients with poorly controlled CAH successfully reduced adrenal hormone levels [80,81].
•A subcutaneous hydrocortisone infusion was designed to mimic physiologic diurnal cortisol secretion. In a phase 2 study of eight patients with CAH and multiple comorbidities, a six-month course of this treatment resulted in significant improvements in adrenal androgen production, quality-of-life measurements, and fatigue [82].
•A modified-release oral form of hydrocortisone was designed to mimic physiologic cortisol secretion. In a phase 2 study of 16 patients with CAH, this preparation achieved improved control of adrenal androgen production compared with conventional glucocorticoid therapy [83]. In a phase 3 study of 122 adults with classic CAH, patients receiving the modified-release hydrocortisone had improved 17-hydroxyprogesterone (17-OHP) and androstenedione levels in the morning and early afternoon, with decreased hormonal fluctuations throughout the day, compared with those receiving standard glucocorticoid therapy [11]. This modified-release form of hydrocortisone (Efmody) is now available in the United Kingdom and Europe for patients with CAH 12 years and older. In the United States and Japan, a long-term safety extension study and an additional phase 3 study are underway in patients 16 years and older (NCT05299554, NCT05063994)
●Combination therapy with antiandrogens – As an alternative to standard therapy, an antiandrogen (flutamide) and aromatase inhibitor (testolactone) have been used together to minimize the effects of excess androgens, permitting reduction of the glucocorticoid dose. This was evaluated in a randomized trial of 28 children with classic 21-hydroxylase deficiency who were treated with a four-drug regimen of flutamide, testolactone, reduced-dose hydrocortisone (average 8.3 mg/m2/day), and standard doses of fludrocortisone. This experimental regimen was compared with a control regimen of hydrocortisone (average dose 13.3 mg/m2/day) and fludrocortisone [84]. Although serum androgen concentrations remained high in the experimental group because of the lower glucocorticoid dose, these children had a normal rate of linear growth and bone maturation after two years of therapy.
●Growth hormone therapy – Because short stature commonly occurs in spite of good adrenal hormonal control during childhood and puberty, exogenous growth hormone therapy has been given to improve linear growth and adult height in patients with CAH. In some cases, gonadotropin-releasing hormone agonist (GnRHa) therapy has been added to block excess androgen activity that promotes premature epiphyseal fusion. This is illustrated by the following studies [85-87]:
•In one study, 20 children who received growth hormone therapy for two years (eight of whom also received GnRHa therapy for precocious puberty) were compared with historical control children receiving glucocorticoid replacement only [85]. Growth hormone-treated patients had increased growth rate and predicted height and decreased height deficit for bone age as compared with the historical controls [85].
•Similar results were seen in a study of 14 children with 21-hydroxylase deficiency who received combined therapy with growth hormone and a GnRHa for four years [86]. Treated patients had improved final height standard deviation (SD) score compared with historical controls who only received glucocorticoid therapy (-0.4 SD versus -1.4 SD).
•Among 34 growth hormone-treated patients with CAH (27 were also treated with a GnRHa), 29 (85 percent) reached a minimum adult height within 1 SD of their midparental target height, compared with 55.3 percent of historical controls not treated with growth hormone or GnRHa [87]. In the group treated with growth hormone (with or without the GnRHa), adult height was significantly higher than the initial pretreatment predicted adult height.
●Other – Several experimental drugs are being evaluated as possible adjunctive treatments to reduce glucocorticoid exposure in CAH:
•An experimental approach under study is to use a corticotropin-releasing factor-1 (CRF-1) receptor antagonist to reduce ACTH production. A study in eight women with classic CAH showed a decrease in ACTH by over 40 percent following a single dose of a CRF-1 receptor antagonist [88]. Two similar CRF-1 receptor antagonists are under investigation. Two weeks of therapy in 18 adults with classic CAH showed dose-dependent reductions in ACTH, 17-OHP, and androstenedione [89]. In a phase 2 study of a similar CRF-1 receptor antagonist, 12 weeks of therapy resulted in reduction of ACTH, 17-OHP, and androstenedione in patients with poorly controlled disease at baseline [90]. Phase 2 and 3 studies of testing these CRF-1 receptor antagonists (crinecerfont and tildacerfont) are underway in both adults and children (NCT 04045145, NCT05128942, NCT 04457336, NCT04490915, NCT04457336, NCT04544410, NCT04806451).
•Preliminary studies have evaluated the use of abiraterone acetate, a 17-hydroxylase inhibitor, to inhibit steroid production. In a phase 1 study of six women with classic CAH and elevated androstenedione, this agent effectively normalized androstenedione after seven days of treatment [91]. A study of abiraterone acetate in prepubertal children with classic CAH is in progress (NCT 02574910).
•Novel cell-based therapies are being studied in preclinical stages of development [3,92]. The safety and efficacy of an adeno-associated virus vector-based gene therapy are now being tested in adults with classic CAH (NCT04783181).
SURGICAL ADRENALECTOMY — Bilateral adrenalectomy should be considered only in selected patients with CAH who have failed medical therapy, such as intractable hyperandrogenism or iatrogenic Cushing syndrome [2,93]. In children, hyperandrogenism causes virilization and accelerated linear growth; in females, it can also cause hirsutism, acne, and male-pattern balding, as well as infertility. The benefit of surgical adrenalectomy is that it lowers circulating adrenal androgen and progesterone and 17-hydroxyprogesterone (17-OHP) levels, thereby allowing lower doses of glucocorticoids. However, it also heightens the dependency on glucocorticoid and mineralocorticoid replacement therapy and may increase the risk of adrenal crisis, especially for patients who do not adhere to therapy.
Reported long-term (average five years) follow-up of 18 patients with CAH who underwent bilateral adrenalectomy revealed improved signs and symptoms of hyperandrogenism and less obesity after surgery [94]. A minimum dose of hydrocortisone of 11 mg/m2/day was necessary in most patients to prevent hyperpigmentation and the activation of ectopic adrenal tissue. Fludrocortisone therapy is also required. In a meta-analysis that included 48 patients who underwent bilateral adrenalectomy for CAH, the majority (71 percent) reported symptomatic improvement postoperatively, but eight patients (17 percent) had an adrenal crisis after surgery [93].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Congenital adrenal hyperplasia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – Most cases of classic congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency. Affected individuals require glucocorticoid replacement to normalize growth, sexual maturation, and, later, reproductive function. Mineralocorticoid replacement is given to maintain normal serum electrolyte concentrations, extracellular fluid volume, and plasma renin activity and to allow for lower glucocorticoid dosing. (See 'Overview' above.)
●Initial management in neonates – Initial management depends on the reason that CAH is suspected (see 'Management in neonates' above):
•Positive newborn screen – For newborn infants with a positive newborn screen suggesting CAH, a sample of blood should be obtained for confirmatory steroid hormone measurements (most importantly, urgent measurement of serum electrolytes and 17-OHP). After the confirmatory blood sample is obtained, treatment doses of glucocorticoid and mineralocorticoid as well as sodium chloride supplementation should be initiated in all such infants until the diagnosis of CAH can be definitively confirmed or excluded. (See 'Positive newborn screen' above and 'Medications and dosing' above.)
•Atypical genital appearance – Newborn infants with atypical genital appearance require urgent medical attention to evaluate for CAH, which is the most common cause of virilization in 46,XX infants and can be complicated by adrenal crisis. The evaluation includes steroid hormone measurements (most importantly, 17-OHP), a karyotype, and a pelvic ultrasound to evaluate for müllerian structures. Evaluation for other rarer types of CAH may be indicated. (See 'Atypical genitalia' above and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
While awaiting laboratory results, presumptive medical therapy for CAH should be initiated to minimize the risk for adrenal crisis. (See 'Medications and dosing' above.)
•Adrenal crisis – Some newborns with classic CAH present with adrenal crisis, which is characterized by hypotension or shock, and electrolyte abnormalities (hyponatremia, hyperkalemia, metabolic acidosis, and hypoglycemia), typically during the second week of life (table 1). Infants with a suspected adrenal crisis should be urgently treated with fluid replacement. Stress doses of glucocorticoids (the typical dose for neonates is 25 mg) should be given after a blood sample is obtained for serum steroid hormone measurements (most importantly, 17-OHP) to confirm the diagnosis of CAH. (See 'Adrenal crisis' above.)
●Subsequent medical management – All infants and children with classic CAH due to 21-hydroxylase deficiency require both glucocorticoid and mineralocorticoid treatment:
•Glucocorticoids – In infants and children, glucocorticoid replacement is usually administered as hydrocortisone (cortisol) in a dose of 10 to 15 mg/m2 body surface area per day. In the early phase of treatment, infants may require 20 mg/m2/day of hydrocortisone, but stress doses of up to 50 mg/m2/day may be needed temporarily to reduce markedly elevated adrenal hormones. Longer-acting glucocorticoid preparations increase the risk for growth failure but may be used in some adolescents and adults. (See 'Glucocorticoid' above.)
•Mineralocorticoids – Mineralocorticoid replacement can often be tapered after four to six months of age but should be continued at lower doses thereafter to optimize growth velocity. Caution should be used to avoid excessive dosing, especially in the first 18 months of life, to avoid inducing hypertension as the neonatal kidney matures and becomes more sensitive to mineralocorticoids. Dosing should be guided by measurement of plasma renin activity and blood pressure. (See 'Mineralocorticoid and sodium chloride' above.)
•Monitoring response – Response to therapy is monitored by measuring serum 17-OHP, androstenedione, and plasma renin activity or direct renin, as well as growth velocity (measured by serial measurements of height), blood pressure, and the rate of skeletal maturation. Laboratory and clinical monitoring should be performed every month in the neonate and infant and every three to six months thereafter. Bone age should be measured every 6 to 12 months after two years of age until skeletal maturity. (See 'Monitoring and dose adjustment' above.)
●Prevention of adrenal crisis – Infants and children with classic CAH are at risk for developing an adrenal crisis, which is characterized by hypotension or shock, and electrolyte abnormalities (hyponatremia, hyperkalemia, metabolic acidosis, and hypoglycemia) (table 1). To avoid an adrenal crisis, patients with CAH should be treated with stress doses of glucocorticoids when they become ill with fever or gastroenteritis, undergo surgery with general anesthesia, or have significant trauma. Fasting should be avoided, especially in the young child. (See 'Prevention and management of adrenal crisis' above.)
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