Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Treatment

INTRODUCTION — 

More than 95 percent of cases of classic congenital adrenal hyperplasia (CAH) are caused by severe deficiency of 21-hydroxylase due to pathogenic variants (or deletions) in both copies of the CYP21A2 gene. Deficiency of 21-hydroxylase interferes with the 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 as well as overproduction of adrenal androgens (figure 1) [1,2]. (See "Adrenal steroid biosynthesis".)

Classic CAH due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) encompasses a spectrum of phenotypes. 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 21-OHD CAH in infants and children is reviewed here. Other aspects of this disorder are discussed in related topics:

●(See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

●(See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)

●(See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●(See "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents".)

●(See "Management of the infant with atypical genital appearance (difference of sex development)".)

GOALS OF TREATMENT — 

The goals for treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) are to prevent adrenal crisis and optimize growth, sexual maturation, and reproductive function [2].

After first ensuring patients are clinically stable, these goals are accomplished in the following ways:

●Treatment with exogenous glucocorticoids to prevent adrenal crisis and suppress androgen production [4]. Hyperandrogenism causes virilization and accelerated linear growth; in females, it can also cause hirsutism, acne, and male-pattern balding as well as infertility [3]. These goals must be balanced with the potential sequelae of glucocorticoid excess (eg, Cushing syndrome and growth suppression). (See 'Glucocorticoid (all patients)' below.)

●Treatment with exogenous mineralocorticoids (and, in some cases, oral sodium chloride) to maintain normal serum electrolyte concentrations and extracellular fluid volume. Mineralocorticoid replacement also allows for lower-dose glucocorticoid therapy as mineralocorticoid deficiency is a stimulant to adrenocorticotropic hormone (ACTH) production. (See 'Mineralocorticoid (all patients)' below and 'Sodium chloride supplements (all infants and some children)' below.)

MANAGEMENT IN NEONATES ≤1 MONTH

Urgent evaluation in all — Newborn infants with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) may be identified in several ways (eg, prenatal testing, newborn screening, or due to clinical findings). Clinical findings may include signs of adrenal crisis such as lethargy, emesis, hypoglycemia, hypotension, or shock; failure to thrive; or virilized genitalia in 46,XX infants.

For any newborn in whom classic 21-OHD CAH is suspected, the first step in management is to exclude adrenal crisis (also known as salt-wasting crisis). This is done by urgently performing an in-person physical examination and laboratory testing (serum electrolytes, blood urea nitrogen [BUN], creatinine, glucose) with guidance from a pediatric endocrinologist. If possible, the clinician should perform hormonal testing to confirm the classic 21-OHD CAH diagnosis with (at minimum) a 17-hydroxyprogesterone (17-OHP) level prior to administering glucocorticoid. However, the laboratory evaluation may be deferred in patients who are clinically unstable. The laboratory evaluation and differential diagnosis are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Adrenal crisis' and "Uncommon congenital adrenal hyperplasias", section on 'Clinical presentation'.)

For patients in adrenal crisis, emergency stabilization in an inpatient setting is needed. These patients are treated with high-dose glucocorticoids known as "stress-dose" glucocorticoids (see 'Patients in adrenal crisis' below). For patients not in adrenal crisis, standard therapy to replace glucocorticoids and mineralocorticoids is initiated. (See 'Patients not in adrenal crisis' below.)

Subsequent laboratory testing may be required in select patient groups (eg, infants with atypical genitalia and premature infants, in whom 17-OHP levels may be higher than in full-term infants). (See 'Special considerations in patients with atypical genitalia' below and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Interpretation of results'.)

Special considerations in patients with atypical genitalia — The initial evaluation for these infants is focused on clinical stabilization and establishing the CAH diagnosis, as in other patients with suspected classic 21-OHD CAH. Additional evaluation may include testing for less common forms of CAH (table 1) and karyotype or fluorescence in situ hybridization (FISH) for sex chromosome material (SRY probe, if not available from prenatal testing). Infants with atypical genital structures in whom testes cannot be palpated on examination should be presumed to have virilization due to classic 21-OHD CAH. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Atypical genitalia' and "Uncommon congenital adrenal hyperplasias", section on 'Clinical presentation'.)

Support for the parents/caregivers of the infant should be offered beginning at birth, ideally with the involvement of experienced mental health clinicians. It is important to address parent/caregiver concerns related to both the acute illness and to atypical genital structures. However, clinicians should emphasize that urgent evaluation is used to identify and treat conditions associated with adrenal insufficiency and risk of adrenal crisis and that atypical genital structures do not represent a medical emergency. Other aspects of management (eg, decisions about genital surgery) may be deferred until the diagnostic evaluation is complete, the infant is clinically stable, and the family has adjusted to the diagnosis. Family support and approach to infants with atypical genital structures 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'.)

Stabilization and initial medication dosing

Patients in adrenal crisis — Infants with classic 21-OHD CAH may present with adrenal crisis at days 7 to 21 of life, even in countries where newborn screening for this disorder is routinely performed [4]. Urgent medical therapy is necessary because adrenal crisis will result in hypovolemic shock and death if untreated. Management involves treatment of hypotension and dehydration, reversal of electrolyte and glucose abnormalities, and correction of cortisol deficiency, as follows:

●Dehydration is managed with a 10 to 20 mL/kg intravenous (IV) bolus of normal (0.9 percent) saline solution or 5 percent dextrose in normal saline. Hypotonic saline should not be used because it can worsen hyponatremia; the same is true of 5 percent dextrose without the addition of normal saline.

●In patients with hypoglycemia (blood glucose <60mg/dL), we give an IV bolus of 5 to 10 mL/kg of 10 percent dextrose (0.5 to 1 g/kg) [5]. (See "Approach to hypoglycemia in infants and children", section on 'Treatment'.)

●Once serum 17-OHP for confirmatory testing is obtained, administer:

•Give one bolus dose (50 to 100 mg/m²) of hydrocortisone intramuscularly (IM), IV, or enterally. Body surface area (BSA) can be calculated here (calculator 1). In most full-term infants, the BSA will be approximately 0.25mg/m², and the initial hydrocortisone bolus dose will be 25 mg.

•Subsequently, administer IM, IV, or enteral hydrocortisone at a dose of 50 to 100 mg/m² per day divided every six hours until the patient is clinically stable. In a full-term infant with a BSA of 0.25 mg/m², the hydrocortisone dose will be 25 mg divided every six hours or 6 mg every six hours. This is "stress-dosing" of hydrocortisone. Once the patient is stable, transition to standard-dose oral/enteral glucocorticoid and mineralocorticoid therapy and oral sodium chloride. (See 'Patients not in adrenal crisis' below.)

•During treatment with stress-dose hydrocortisone, mineralocorticoid replacement is unnecessary due to the potent mineralocorticoid action of high-dose hydrocortisone.

•Hyperkalemia typically improves promptly after hydrocortisone 50 to 100 mg/m² is administered. On the rare occasions when severe and symptomatic hyperkalemia occurs, administration of glucose and insulin is needed to manage the hyperkalemia. (See "Fluid and electrolyte therapy in newborns", section on 'Hyperkalemia' and 'Mineralocorticoid (all patients)' below.)

Patients not in adrenal crisis — In clinically stable infants in whom classic 21-OHD CAH is suspected, standard doses of glucocorticoid and mineralocorticoid as well as oral sodium chloride supplementation should be initiated after the confirmatory laboratory tests have been obtained. Treatment is continued while awaiting laboratory test results. If the diagnosis of CAH is confirmed, continue treatment; if excluded, discontinue treatment.

If the clinician cannot initiate treatment while awaiting the results of confirmatory steroid hormone measurements, the patient should be closely monitored, with serum electrolytes measured every 24 to 48 hours. Management should be guided by a pediatric endocrinologist. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Diagnosis'.)

●Standard therapy (glucocorticoid, mineralocorticoid, and sodium chloride) – A typical starting regimen for a neonate with classic 21-OHD CAH who is not in adrenal crisis should include all of the following:

•Glucocorticoid replacement – The preferred agent for glucocorticoid replacement is hydrocortisone. Hydrocortisone is dosed based on BSA (calculator 1). The initial dose is 20 to 30 mg/m²/day divided three times daily (eg, 2.5 mg three times per day). However, up to 50 mg/m²/day may be used to treat patients in whom 17-OHP is markedly elevated. The glucocorticoid dose is then rapidly reduced when target hormone levels are achieved, as doses of hydrocortisone that exceed 20 mg/m²/day in infancy have been associated with growth suppression and shorter adult height [2]. (See 'Assessing response to therapy' below.)

We use either the tablet formulation of hydrocortisone (administered by crushing the tablet and mixing with a small amount of water or breast milk/formula) or an immediate-release granule formulation of hydrocortisone (administered by pouring the contents of the sprinkle capsule directly on the tongue) [6].

Liquid hydrocortisone should generally be avoided, as the concentration of hydrocortisone in compounded preparations has been shown to vary significantly between pharmacies [7,8].

•Mineralocorticoid replacement – The preferred agent is fludrocortisone at a dose of 100 mcg (0.1 mg) once daily. Some patients may require a higher dose (eg, 100 mcg twice daily) due to the relative insensitivity of the neonatal kidney to mineralocorticoids.

•Sodium chloride – Oral sodium chloride is given as a solution or as tablets at a dose of 1 to 2 g or 17 to 34 mEq/day (2 to 4 mEq/kg/day), divided in several feedings.

Close monitoring and frequent dose adjustment may be required over time due to growth and changes in response to glucocorticoid and mineralocorticoid treatment. (See 'Dose adjustment' below.)

Dose adjustment — Follow-up laboratory tests (serum 17-OHP, androstenedione, plasma renin activity [PRA], and electrolytes) should be performed within 10 to 14 days of starting treatment. The results should be used to guide dose adjustment 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 'Assessing response to therapy' 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 (see 'Ongoing monitoring' below). Sodium chloride supplements are typically needed in the first year but can usually be discontinued as the child starts to eat table food, which is higher in sodium. (See 'Sodium chloride supplements (all infants and some children)' below.)

STANDARD THERAPY IN CHILDREN >1 MONTH — 

Most patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) are identified in infancy, and medical therapy will be instituted at presentation. As a result, management in older infants, children, and adolescents involves continuation of glucocorticoid, mineralocorticoid, and sodium chloride therapy started during infancy, titration of doses based on clinical findings, and counseling to prevent adrenal crisis. However, a subset of individuals with classic 21-OHD CAH and less severe aldosterone deficiency will present later in infancy or childhood with androgen excess (eg, early pubic hair, growth acceleration, enlargement of genital structures). In such patients, treatment is started only after the diagnosis is confirmed by measuring 17-hydroxyprogesterone (17-OHP). (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Confirmatory serum testing'.)

Glucocorticoid (all patients) — Glucocorticoid replacement is necessary in all children who have classic 21-OHD CAH [1,4].

●Hydrocortisone (preferred) – Hydrocortisone is the preferred agent for glucocorticoid therapy due to its short half-life, which minimizes side effects related to glucocorticoid excess.

•Dosing – Dosing to suppress androgens usually 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 5 to 8 mg/m²/day in children and adolescents [9-11]. Our suggested dosing exceeds endogenous cortisol production to account for incomplete absorption. This is in keeping with clinical practice guidelines on the management of classic 21-OHD CAH [2]:

-Infants >1 month and children who have not completed linear growth – 10 to 15 mg/m²/day divided three times per day.

-Adolescents and young adults who have completed growth are usually treated using regimens comparable to those used for adults. These regimens are discussed in detail elsewhere. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Transition to adult dosing'.)

•Formulation – Low-dose hydrocortisone granules or crushed hydrocortisone tablets may be used for glucocorticoid therapy in infants and children with classic 21-OHD CAH. Low-dose hydrocortisone granules are available in Europe and the United States [6,12,13]. Alternatively, tablets can be cut, crushed, and mixed with a small volume of liquid (eg, breast milk or formula), but accurate dosing for infants remains a concern. We do not use compounded liquid medication due to inconsistent dosing.

A modified-release hydrocortisone capsule formulation designed to mimic physiologic circadian cortisol rhythm when given twice daily is available in the United Kingdom and Europe for patients with CAH who are 12 years and older [14-16]. The lowest dose capsule is 5 mg.

●Other glucocorticoids

•Difficulty with adherence to frequent dosing – For patients with difficulty adhering to three-times daily hydrocortisone dosing, synthetic long-acting glucocorticoids such as dexamethasone, prednisone, or prednisolone may be used due to the convenience of less frequent dosing compared with hydrocortisone [17-19]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Selection of regimen'.)

However, concerns have been raised about their use in children because the longer duration of action and greater potency may increase the risk of overtreatment and growth suppression, and therapy results are frequently suboptimal in terms of adult height [20,21] (see 'Growth and skeletal maturation' below). Limited data from small case series suggest that this may not always be the case if low doses are used [22,23].

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 [22]. Similarly, nine children with adrenal insufficiency had normal short-term (six months) height velocity when receiving prednisolone [23]. 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].

A longer-acting glucocorticoid may be used for adolescents who have reached adult height and have fused epiphyses. When used in adolescents, dexamethasone can be 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 patients who may become pregnant, a glucocorticoid that is inactivated by the placenta (eg, hydrocortisone, prednisone, or prednisolone) is preferred to prevent potential fetal exposure to high levels of glucocorticoids.

•New glucocorticoid preparations and delivery methods – New treatment approaches are being developed and may achieve improved adrenal androgen control with less daily glucocorticoid exposure. As examples:

-A subcutaneous hydrocortisone infusion was designed to mimic physiologic diurnal cortisol secretion [24]. 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 [25].

-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 [26]. In a phase 3 study of 122 adults with classic CAH, patients receiving the modified-release hydrocortisone had improved 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 [14]. This modified-release form of hydrocortisone is available in the United Kingdom and Europe for patients with CAH ages 12 years and older and may be used as an alternative to standard hydrocortisone therapy [16,27]. This medication is not available in the United States. A long-term safety extension study and an additional phase 3 study are underway in patients 16 ages years and older. However, studies are needed in children younger than 12 years old.

Mineralocorticoid (all patients) — Mineralocorticoid replacement (using fludrocortisone) is necessary in patients with all forms of classic 21-OHD CAH, a category that includes both salt-wasting and simple-virilizing 21-OHD CAH [28,29]. Although only the salt-wasting form is typically associated with clinically apparent mineralocorticoid deficiency, aldosterone secretion has been shown to be impaired in the simple-virilizing form [30,31]. In addition, mineralocorticoid treatment appears to improve the height outcome in patients with all forms of classic CAH [32,33]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Dosing − Mineralocorticoid dosing is as follows:

•Infants >1 month – Infants continue with the neonatal dosing of fludrocortisone (0.1 mg once or twice daily), but the dose can be reduced by approximately 50 percent around 6 to 12 months of age. This is 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 21-OHD CAH diagnosed by newborn screening, over one-half developed hypertension in the first 18 months of life [34].

•Older children and adolescents – The usual pediatric dose of fludrocortisone is 100 mcg (0.1 mg) once daily (range 50 to 200 mcg per day [0.05 to 0.20 mg per day]) [2]. Dose adjustments should be guided by the measurement of plasma renin activity (PRA) and blood pressure. (See 'Assessing response to therapy' below.)

Some patients may benefit from an increase in fludrocortisone during hot days.

Sodium chloride supplements (all infants and some children) — Sodium chloride supplementation is also required for infants. Salt tablets/solution can be discontinued as the child begins to eat table food, as salt can be given more easily through a diverse diet (around 8 to 12 months of age).

●Dosing – Sodium chloride dosing is as follows:

•Neonates, infants >1 month, and young children – The sodium chloride dose is 1 to 2 g/day (approximately 17 to 34 mEq/day or 4 mEq/kg/day) distributed in several feedings [4].

•Older children – Older children usually do not require daily sodium chloride supplementation but need additional salt intake during hot weather or with intense exercise due to excess salt loss in these settings. Increased salt intake in the diet (ie, consumption of salty foods) usually suffices during warm weather or with routine sports activities. However, children involved in competitive sports sometimes benefit from taking a 1 g salt tablet prior to events.

MEASURES TO PREVENT ADRENAL CRISIS IN ALL — 

In children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH), adrenal crisis may be triggered by medication omission, routine infectious illnesses (especially gastrointestinal illnesses), physical trauma, or prolonged fasting unless high-dose glucocorticoids are administered. Appropriate teaching of parents/caregivers (and patients when developmentally appropriate) on the use of "stress-dose" glucocorticoids and recognition of adrenal crisis are essential for preventing severe sequelae of classic 21-OHD CAH, such as hypovolemic shock [35].

An overview of the recognition and treatment of an adrenal crisis is shown in the accompanying table (table 2).

Management during illnesses — The increased metabolic demands associated with febrile illnesses, vomiting, marked diarrhea, or significant trauma require increased glucocorticoid production from the adrenal gland to prevent hypoglycemia in patients with adrenal insufficiency.

Stress-dose glucocorticoids — Because patients with adrenal insufficiency are unable to increase endogenous glucocorticoid production, they must be treated with high-dose glucocorticoids (known as "stress-dose" steroids or "stress-dose" glucocorticoids) in such circumstances.

Indications — Stress-dose glucocorticoids are given to patients with classic 21-OHD CAH experiencing acute illnesses such as fever >38°C, vomiting, general anesthesia, or trauma (eg, fracture). Stress-dose glucocorticoids are not required for mild illnesses without fever, emotional stress (eg, school examinations), or before routine physical exercise. For unusual activities beyond normal routines, such as exhaustive physical exercise associated with competitive sports, additional doses of glucocorticoids may be given but are not always required. Decision to use stress-dose steroids will be based on the type and severity of symptoms and is discussed in greater detail elsewhere. (See "Treatment of adrenal insufficiency in children", section on 'Stress conditions'.)

Administration — The severity of the patient's symptoms (eg, vomiting, altered mental status) will usually guide the choice of oral or intramuscular (IM)/intravenous (IV) hydrocortisone formulations for stress dosing.

●Oral glucocorticoids when tolerating intake by mouth – If the child can tolerate oral medication and fluids, stress-dose glucocorticoids may be given by mouth. The appropriate stress dose for an individual patient can be determined in one of several ways. Some providers recommend using three times the normal daily replacement dose. Others recommend a specific dose based on body surface area (BSA; eg, 50 milligrams/m² per day divided every six hours). BSA can be determined using this calculator (calculator 1). If a child is on low-dose glucocorticoid therapy (ie, hydrocortisone 8 mg/m²/day), it is prudent to provide stress dosing based on BSA.

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) [36], although the efficacy of this approach in the prevention of hypoglycemia has not been established (see 'Hypoglycemia' below). Stress dosing of glucocorticoids is discussed in greater detail elsewhere. (See "Treatment of adrenal insufficiency in adults", section on 'Emergency precautions' and "Treatment of adrenal insufficiency in children", section on 'Stress conditions'.)

●IM glucocorticoids when unable to tolerate intake by mouth – Patients with nausea and vomiting who are unable to take oral medications should receive IM hydrocortisone [2,5]. A two-chamber vial system containing hydrocortisone powder for reconstitution and sterile diluent is available and preferred for caregiver administration due to ease of dose preparation and its long shelf-life before reconstitution [37].

Parents/caregivers should be instructed in the techniques for IM administration of glucocorticoids. The optimal IM dose depends on the patient's size and the severity of the intercurrent illness. Typical dosing for this situation is 50 to 100 mg/m² per dose, with a maximum dose of 100 mg per dose. After an IM dose of glucocorticoids is given, parents/caregivers should seek emergency care for the patient [2]. Caregivers' knowledge of indications for and techniques of emergency treatment should be assessed at each clinic visit. (See 'Caregiver teaching' below.)

●IV glucocorticoids for severe illness and trauma – Patients who are hospitalized for severe illness, dehydration, or trauma should receive IV glucocorticoids. An initial IV bolus is followed by additional IV doses. Two dosing strategies are available [2,5]:

•Strategy 1: Age-based dosing

-≤3 years – Give one 50 to 100 mg/m² or 25 mg IV dose of hydrocortisone followed by 25 mg/day hydrocortisone, either divided every six hours or as a continuous infusion

->3 years and <12 years – Give one 50 to 100 mg/m² IV dose of hydrocortisone followed by 50 to 100 mg/m²/day or 50 mg/day hydrocortisone, either divided every six hours or as a continuous infusion

-≥12 years of age – Give one 100 mg IV dose of hydrocortisone followed by 100 mg/m²/day (maximum of 50 mg every six hours) hydrocortisone, either divided every six hours or as a continuous infusion

•Strategy 2: Dosing based on BSA – Give one 50 to 100 mg/m² dose of hydrocortisone (IV, IM, or oral) followed by 50 to 100 mg/m²/day divided every six hours (IV, IM, or oral) or as a continuous infusion. BSA may be determined using this calculator (calculator 1).

●When to resume standard glucocorticoid dosing – Stress doses of hydrocortisone should be reduced rapidly without a taper in response to clinical improvement. This is generally done 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. (See "Glucocorticoid withdrawal".)

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'.)

Hypoglycemia — Patients with classic 21-OHD CAH are at risk for hypoglycemia during illness—especially young children and those in whom oral intake is impaired (eg, patients with gastroenteritis) [2,36]. Unexpected hypoglycemic events that seem unrelated to infection have also been reported, especially in the first four years of life [38].

In addition to receiving stress-dose glucocorticoids every six hours, increased fluid intake and frequent ingestion of simple and complex carbohydrates are 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.

Caregiver teaching — All caregivers of patients with 21-OHD should receive instruction regarding the indications for the use of high-dose glucocorticoids (stress-dose steroids) during periods of physiologic stress to prevent adrenal crisis. Instruction should also include information on the recognition of adrenal crisis. When possible, caregivers should be taught how to administer IM hydrocortisone for patients who cannot tolerate medication by mouth. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Main features' and 'Management during illnesses' above.)

In addition, patients with classic 21-OHD CAH should wear a medical identification (MedicAlert) bracelet or necklace and carry an emergency medical information card [2,4]. These should clearly state that the patient has a diagnosis of "adrenal insufficiency" (rather than CAH) and note the clinician to call in the event of an emergency. Patients can enroll in MedicAlert by calling 1-800-432-5378 or visiting www.medicalert.org (United States) and www.medicalert.ca (Canada).

ONGOING MONITORING — 

Patients with classic congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency (21-OHD; classic 21-OHD CAH) require lifelong outpatient monitoring, which is typically overseen by endocrinologists. Clinical visits involve routine laboratory assessment, physical examination (eg, blood pressure; signs of hyperandrogenism; evaluations of weight, growth, pubertal development; and signs of hypercortisolism) and use of "stress-dose" glucocorticoids. This assessment provides information on the efficacy of hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment, is used to guide adjustments in medication doses, and provides anticipatory guidance regarding management of illness episodes [2,4]. In addition, clinicians should evaluate risks for adverse cardiovascular, metabolic, reproductive, bone health, and quality of life outcomes. Later in childhood, ongoing assessment should include readiness for the transition from pediatric to adult care. (See 'Screening for complications' below.)

Assessing response to therapy — The response to standard medical therapy is assessed with laboratory tests and clinical visits.

Frequency — We see patients for clinical visits (including laboratory assessment) approximately monthly through age six months, every 3 months until age 12 months, then approximately every three to six months in childhood. However, we will perform laboratory tests and clinical assessments more frequently if patients show signs of insufficient medication doses (eg, androgen excess, adrenal crisis) and if medication doses are adjusted between visits.

Laboratory assessment — Routine monitoring of adrenal metabolites is an important component of assessing medication efficacy and adherence. To accurately reflect an individual patient's medication regimen, samples should be obtained at a consistent time in relation to glucocorticoid dosing, ideally in the morning (approximately 8 AM) to reflect peak serum/plasma concentrations. 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 pubertal maturation should be used in the interpretation of all laboratory tests and may vary depending on the laboratory.

The efficacy of glucocorticoid replacement therapy is monitored by measuring serum 17-OHP, androstenedione, and (in some patients) testosterone.

●17-OHP – The appropriate target range for early morning serum 17-OHP concentration is 400 to 1200 ng/dL (12 to 36 nmol/L), which is above the normal range for individuals without CAH [1]. In general, the goal is the upper limit of normal or mild elevation of 17-OHP. Normal levels typically indicate excessive dosing of glucocorticoids and are associated with the risk of iatrogenic Cushing syndrome.

●Androstenedione – The target serum androstenedione concentration is the normal range for the patient's age and sex at the reference laboratory; suppression below the normal range suggests excessive glucocorticoid dosing [1].

●Testosterone – Some experts measure testosterone as part of routine monitoring or when there are concerns about hyperandrogenism based on history or physical examination [35]. 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. (See 'Androgen excess' below.)

The efficacy of mineralocorticoid replacement is monitored by measuring plasma renin activity (PRA) and electrolytes.

●PRA or direct renin (with serum electrolytes) – Plasma renin should be monitored and kept in the normal range for age. A low PRA (which may be accompanied by hypokalemia) reflects excessive mineralocorticoid dosing and increases the risk for hypertension [34,39].

An elevated PRA (which may be accompanied by hyperkalemia and hyponatremia) is indicative of inadequate mineralocorticoid dosing. Once adherence to mineralocorticoid therapy is established, we adjust the fludrocortisone and/or the exogenous salt dose to decrease renin. Of note, markedly elevated levels of 17-OHP have an antimineralocorticoid effect, which may lead to excessive mineralocorticoid dosing in patients treated with inadequate glucocorticoid doses [40]. Therefore, close monitoring for hypertension and other signs of excess mineralocorticoid dosing should be performed in patients undergoing medication adjustments.

Physical examination — A focused physical examination should be performed at each clinical visit. The examination findings discussed below provide information on the efficacy of medical therapy.

Blood pressure and fluid status — Blood pressure should be assessed at every clinical visit using appropriate techniques in all patients with deficiency (classic 21-OHD CAH). (See "Ambulatory blood pressure monitoring in children".)

Patients should be assessed for signs of dehydration (eg, dry mucous membranes, weight loss) and excessive fluid retention (elevated blood pressure, edema). (See "Clinical assessment of hypovolemia (dehydration) in children".)

Growth and skeletal maturation — The most established approach to optimizing linear growth in patients with classic 21-OHD CAH is judicious glucocorticoid and mineralocorticoid dosing as well as close monitoring of growth and skeletal maturation [32,41].

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 should be assessed 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 these findings occur [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 with classic 21-OHD CAH, 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. However, at the lower dose, there was often incomplete suppression of androgen secretion. Several studies have suggested that treatment during the first two years of life and during puberty are the most important factors influencing height outcome [41-44].

The adult height achieved in treated patients is usually less than that in reference groups, although heights close to midparental target height have been reported in patients treated with three-times-daily doses of glucocorticoid replacement and monitoring every three months [2,45,46]. 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 [47]. 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 [32].

Androgen excess — Providers should assess for signs of androgen excess in younger children by noting growth acceleration and the development of axillary and pubic hair, apocrine odor, and growth of genital structures. Such findings reflect ineffective androgen suppression by glucocorticoid therapy but must be interpreted in combination with laboratory measurements of androgen levels and bone age assessment [35]. (See 'Laboratory assessment' above.)

Glucocorticoid excess — Patients may exhibit signs of glucocorticoid excess when higher doses of glucocorticoid are required to suppress hyperandrogenism. In patients who are still growing, growth suppression with persistent weight gain may be the primary sign of excessive glucocorticoid doses. Other symptoms (eg, round face, violaceous striae, mood lability) are outlined in this table (table 3). Adolescent patients treated with longer-acting glucocorticoid formulations (eg, prednisone, dexamethasone) are at particular risk of glucocorticoid excess. This is discussed in detail elsewhere. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Comorbidities due to glucocorticoid therapy'.)

Puberty — Children with CAH should be routinely monitored for signs of pubertal onset throughout childhood. Patients with CAH are at risk for early onset of central puberty (also known as gonadotropin-dependent precocious puberty), which is most likely to develop when the diagnosis of CAH is delayed or when adrenal androgen secretion is poorly controlled.

In general, puberty is considered precocious if the onset of secondary sexual characteristics occurs before the age of eight years in females and nine years in males. If central precocious puberty is suspected, measurement of serum luteinizing hormone (LH) using a sensitive assay is useful. Patients with CAH and central precocious puberty may benefit from treatment with a gonadotropin-releasing hormone (GnRH) analog [48]. (See "Definition, etiology, and evaluation of precocious puberty".)

Routine assessment of pubertal progression is recommended in patients with CAH who have started puberty. Despite earlier onset of puberty in females with CAH, the mean age of menarche is similar to that of the general population or delayed in patients with poor treatment adherence [49].

Screening for complications — Routine monitoring for other complications associated with classic 21-OHD CAH should be performed during follow-up visits.

Urogenital and menstrual complications — In patients with classic 21-OHD CAH who have a uterus but have not undergone urogenital surgery, evaluation for possible obstruction of menstrual flow should be performed before onset of menarche. Patients who have undergone urogenital surgery (typically in infancy) may be at risk of urinary incontinence and vaginal stenosis [50]. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Clinical approach to 46,XX congenital adrenal hyperplasia'.)

We ask about satisfaction with genital appearance, sexual function, and menstrual regularity in 46,XX adolescents and young adults with classic 21-OHD CAH. Patients may express concerns about cosmesis and anatomical considerations (eg, vaginal stenosis) that impact sexual function [51-53]. In addition, irregular menstruation is common among adolescents and young adults with CAH due to a combination of progesterone and adrenal androgen hypersecretion [3,54]. Counseling about these concerns and the need for counseling about pregnancy prevention and fertility are discussed in detail elsewhere. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Achieve functional anatomy' and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Fertility and reproductive health'.)

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 males with classic 21-OHD CAH ages 2 to 18 years ranges from 18 to 24 percent [55,56] and increases with age, especially during puberty [57]. Screening with testicular ultrasound should begin in adolescence. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Screening for testicular adrenal rest tumors'.)

Bone density — Because children with CAH who are treated with appropriate treatment doses of glucocorticoids appear to have a low risk for reduced bone mineral density during childhood, routine evaluation of bone mineral density is not recommended until the transition to adult care or in young adulthood [2,58]. However, age-appropriate calcium and vitamin D intake, along with weight-bearing exercise, is recommended as an important preventative measure [59]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

A longitudinal study from childhood to adulthood found a downward trend in bone density scores from attainment of adult height to early adulthood, suggesting that bone mineral density monitoring should begin during adolescence or upon transition to an adult health care provider [60]. (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 — Children with classic 21-OHD CAH are at risk for obesity and should be monitored for excessive weight gain and metabolic risk factors [61,62]. Lifestyle interventions should be recommended, with referral to a weight management program if appropriate. Obesity and increased visceral fat are complications in glucocorticoid-treated patients with 21-OHD [63,64] and may be associated with higher glucocorticoid dose and parental obesity. Age of adiposity rebound (the time when body mass index [BMI] begins to increase after its nadir at approximately five to seven years of age) is younger in patients with CAH [65]; early adiposity rebound is considered a predictive marker of obesity and related metabolic disease. In addition, carotid intima-media thickness, a marker of cardiovascular disease, is greater in obese patients with CAH compared with nonobese patients with CAH [66].

Obesity in CAH is often attributed to supraphysiologic doses of glucocorticoid or use of long-acting glucocorticoids, which are not recommended in children. In a retrospective study of 53 prepubertal children, overtreatment with glucocorticoid (defined as complete suppression of androstenedione) was associated with a BMI standard deviation score (SDS) above 0 and showed an increasing trend with time, although hydrocortisone doses were within the recommended range [67].

In a review of 89 children from Germany with 21-OHD (ages 0.2 to 17.9 years), 17 percent of patients had a BMI that was >2 SD from the mean for age [63]. The risk was increased for children with a parent who had obesity. There was no difference in the incidence of obesity based on sex or the clinical form of 21-OHD (simple-virilizing versus salt-wasting forms). All patients received glucocorticoid therapy, and there was a positive correlation between dose of medication prescribed and BMI.

In a longitudinal study of 57 patients with classic CAH including data spanning both childhood and adulthood, obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein cholesterol were more prevalent in children with CAH compared with the general population. In adulthood, obesity, hypertension, and insulin resistance were more prevalent in the CAH group compared with the general population [68]. In a meta-analysis including 300 children/adolescents and 137 adults, patients with CAH had higher homeostatic model assessment for insulin resistance (HOMA-IR) values, a marker of insulin resistance, although no differences were observed for fasting insulin and fasting glucose [69]. Interventions aimed at preventing cardiometabolic complications should begin in childhood.

Metabolic and cardiovascular outcomes in adults with classic 21-OHD CAH 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 [70]. 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'.)

MANAGEMENT WHEN STANDARD THERAPY FAILS — 

Patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) may be ineffectively managed on standard therapy. This may be because they experience sequelae of glucocorticoid excess (eg, Cushing syndrome and growth suppression) at treatment doses required to suppress hyperandrogenism or because of challenges with adherence to standard medical therapy, which results in undertreatment and androgen excess. Depending on the clinical concerns, additional therapies may be considered in addition to standard medical treatment.

Adjunctive treatment when glucocorticoid doses are excessive

Corticotropin-releasing factor (CRF) type 1 receptor antagonist (crinecerfont) — Crinecerfont, a selective oral antagonist of the CRF type 1 receptor, has been approved by the US Food and Drug Administration as an adjunctive therapy to glucocorticoids for patients age ≥4 years with classic 21-OHD CAH [71]. Crinecerfont reduces CRF-stimulated adrenocorticotropic hormone (ACTH) release and resultant ACTH-stimulated adrenal androgen production. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Corticotropin-releasing factor (CRF) type 1 receptor antagonist (crinecerfont)'.)

●Indications and dosing – For patients age ≥4 years with classic 21-OHD CAH in whom androgen production is inadequately suppressed on doses of glucocorticoid >10 to 12 mg/m²/day and/or in whom glucocorticoid doses required for androgen suppression have caused impaired linear growth or adverse effects of glucocorticoid excess (eg, hyperglycemia, excessive weight gain, mood changes, decreased bone density), we suggest the addition of crinecerfont to standard therapy (glucocorticoid and mineralocorticoid replacement).

Dosing of crinecerfont is based on weight:

•10 to <20 kg – 25 mg twice daily

•20 kg to <55 kg – 50 mg twice daily

•≥55 kg – 100 mg twice daily

Dosing may need to be adjusted in patients taking medications affecting the cytochrome P450 3A4 enzyme (table 4).

●Adjustment of glucocorticoid dose – When treatment has begun, glucocorticoid doses may be reduced using a closely supervised stepwise approach. In most cases, the dose of fludrocortisone or other mineralocorticoid required for aldosterone replacement will not change during therapy.

More data are needed to determine the optimal approach to adjusting glucocorticoid doses once crinecerfont is initiated.

One approach is as follows [72]:

•Obtain baseline laboratory evaluation for CAH disease control (eg, 17-hydroxyprogesterone [17-OHP], androstenedione, plasma renin activity [PRA], with or without testosterone).

•Start crinecerfont at the recommended weight-based dose.

•Monitor for side effects. At four to six weeks, repeat laboratory evaluation.

•If 17-OHP, androstenedione, testosterone, and PRA are not elevated, reduce glucocorticoid dose by 10 to 20 percent.

•If there are no symptoms of glucocorticoid withdrawal (eg, headache, fatigue, nausea), continue to repeat laboratory evaluation followed by reduction in glucocorticoid dose by 10 to 20 percent every four to six weeks as long as adrenal biomarkers are not elevated. The glucocorticoid dose should not be reduced more frequently than every four weeks, and the time between glucocorticoid dose reductions can be extended as needed. The hydrocortisone dose should not be reduced below the physiologic dose for cortisol replacement (a minimum of 8 mg/m²/day).

●Additional precautions while reducing glucocorticoid dose – Patients treated with crinecerfont still require "stress-dose" glucocorticoids for illnesses, injury, and surgery as these agents do not alleviate adrenal insufficiency. Stress-dose glucocorticoids should be given based on body surface area (BSA) and be administered every six hours. (See 'Dose adjustment' above and 'Management during illnesses' above.)

●Efficacy – Crinecerfont has been shown to reduce glucocorticoid requirements for androgen suppression in pediatric patients with classic 21-OHD CAH [72-74]. In a 28-week trial of 103 children (ages 2 to 17 years, mean 12.1 years) with classic 21-OHD CAH previously managed with supraphysiologic glucocorticoid doses (mean baseline glucocorticoid dose 16.4 mg/m²/day), participants randomly assigned to crinecerfont had a reduction in androstenedione compared with those treated with placebo (mean difference -268 ng/dL [-9.3 nmol/L]) at week 4 of the study [72]. By week 28, participants taking crinecerfont achieved a reduction in glucocorticoid dose (-18 percent versus +5.6 percent in the placebo group) while maintaining control of androstenedione levels. However, androstenedione levels slowly increased over the course of the study. Additional studies are needed to determine the long-term efficacy of crinecerfont.

●Adverse effects – In the trial described above, the most common side effects compared with placebo were headache, abdominal pain, and upper respiratory infection [72].

In a phase 2 study of an alternative CRF type 1 receptor antagonist (tildacerfont), 12 weeks of therapy resulted in reduction of ACTH, 17-OHP, and androstenedione in adults with poorly controlled CAH at baseline [75]. Further studies mostly evaluating once-daily tildacerfont are on hold because preliminary data showed that higher doses and twice-daily dosing may be needed for efficacy.

Surgical adrenalectomy (rarely used) — Bilateral adrenalectomy should rarely be considered and only performed in selected patients with CAH who have failed medical therapy, such as those with intractable hyperandrogenism or iatrogenic Cushing syndrome who cannot be managed with standard medical therapy (including CRF receptor antagonists) [2,76]. The benefit of surgical adrenalectomy is that it lowers circulating adrenal androgen levels, thereby allowing lower doses of glucocorticoids. However, it heightens the dependency on glucocorticoid and mineralocorticoid replacement therapy and therefore increases the risk of adrenal crisis, especially in patients who do not adhere to therapy.

A long-term (average five years) follow-up study of 18 patients with classic 21-OHD CAH who underwent bilateral adrenalectomy revealed improved signs and symptoms of hyperandrogenism and less obesity after surgery [77]. A minimum hydrocortisone dose of 11 mg/m²/day was necessary in most patients to prevent hyperpigmentation and the activation of ectopic adrenal tissue in the testes or ovaries. Fludrocortisone therapy was 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 [76].

EXPERIMENTAL MEDICAL THERAPY

Prenatal glucocorticoid therapy — Prenatal therapy with glucocorticoids is an experimental approach aimed at minimizing genital virilization in affected 46,XX fetuses. It does not prevent adrenal insufficiency in affected patients or alleviate the need for lifelong hormonal therapy. This intervention is only considered as part of a research protocol when a fetus is known to be at risk for classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH) because of an affected sibling or birth parents who are heterozygous for pathogenic CYP21A2 gene variants causative of classic 21-OHD CAH [78-80].

Although prenatal glucocorticoid therapy has been shown to be effective at reducing genital virilization if initiated before the ninth postmenarchal week [4], it is not routinely used in clinical practice. This is because of concerns about adverse effects of prenatal glucocorticoid exposure in patients without CAH [81]. In patients without CAH, adverse effects from prenatal glucocorticoid therapy include abnormalities in cognitive function [80,82,83], brain structure [84], and lipid and glucose metabolism [85,86] as well as concerns about an increased risk of cleft lip and palate [87,88]. Maternal adverse effects of prenatal glucocorticoid therapy may also occur, including increased appetite, early and excessive weight gain, edema, striae, and signs and symptoms of Cushing syndrome [81,89]. In addition, treatment often must be initiated before confirmation of the CAH diagnosis, meaning that some unaffected fetuses will be exposed to prenatal glucocorticoid.

Treatment with prenatal glucocorticoid therapy in 46,XX fetuses at risk of virilization should therefore only be conducted by a highly experienced team in a research setting using treatment protocols approved by an institutional review board. Such protocols should involve a detailed discussion about potential benefits and adverse effects [2,4,90,91]. Alternative options for couples who are known carriers of classic CAH include in vitro fertilization with or without preimplantation genetic testing [92]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'Other uses' and "Preimplantation genetic testing".)

Other experimental therapies

●Combination therapy with antiandrogen and aromatase inhibitors – Antiandrogen (flutamide) and aromatase inhibitor medications have been used together to minimize the effects of excess androgens, including premature cessation of growth. Such therapies (with or without growth hormone therapy) have been used in patients with CAH with a predicted adult height below what is expected. These medications should only be considered in patients in whom management of hyperandrogenism is challenging despite standard therapy and adjunctive treatment with CRF antagonists.

Several studies have evaluated these regimens in children with classic 21-OHD CAH, although they remain infrequently used in clinical practice [93-95]. As an example, in a long-term randomized trial following prepubertal children with classic CAH to adult height, those who received a four-drug regimen in the prepubertal period (flutamide, aromatase inhibitor [testolactone or letrozole], reduced-dose hydrocortisone, and fludrocortisone) had greater predicted adult height at pubertal onset compared with those treated with standard therapy (hydrocortisone, fludrocortisone) [94]. However, no difference in adult height was found between the two groups, reflecting the important contribution of the pubertal growth spurt in determining adult height; furthermore, all groups achieved adult heights greater than the initial predicted heights. Antiandrogen treatment during puberty in females allowed for lower-dose glucocorticoid treatment and achievement of adult heights approximating their genetic potential.

●Growth hormone therapy – Because short stature commonly occurs despite 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 [96-98]:

•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 [96]. Growth hormone-treated patients had increased growth rate and predicted height as well as a decreased height deficit for bone age compared with the historical controls [96].

•Similar results were seen in a study of 14 children with 21-OHD who received combined therapy with growth hormone and a GnRHa for four years [97]. Treated patients had improved final height standard deviation (SD) scores compared with historical controls, who only received glucocorticoid therapy (-0.4 SD versus -1.4 SD).

•Among 34 growth hormone-treated patients with CAH (of which 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 [98]. 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 – An adrenocorticotropic hormone (ACTH) receptor antagonist that acts selectively at the melanocortin type 2 receptor (MC2R) on the adrenal glands is being studied in classic 21-OHD CAH [99].

COUNSELING IN OLDER CHILDREN AND ADOLESCENTS — 

Children should be informed of their condition by both their clinicians and parents/caregivers; 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 [17,100]. According to the Endocrine Society Clinical Practice Guideline, genetic counseling should be offered to adolescents [2]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Transition from pediatric to adult care'.)

Genetic counseling is also indicated for family planning in adult patients with CAH and is discussed in a separate topic review. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Fertility and reproductive health'.)

Patients and family members may find helpful information at patient support group websites such as the CARES Foundation (caresfoundation.org) and the Magic Foundation (magicfoundation.org).

Additional resources for patients are provided below. (See 'Information for patients' below.)

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 5^th to 6^th 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 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 10^th to 12^th 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 treatment – Most cases of classic congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency (21-OHD; classic 21-OHD CAH). 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 (PRA) as well as allow for lower glucocorticoid dosing. (See 'Goals of treatment' above.)

●Urgent evaluation in neonates – Neonates may be suspected of classic 21-OHD CAH based on newborn screening, prenatal testing, or atypical genitalia. In addition, newborns with classic 21-OHD CAH may present with adrenal crisis, which is characterized by hypotension or shock and electrolyte abnormalities (hyponatremia, hyperkalemia, metabolic acidosis, and hypoglycemia) occurring between the first and third week of life (table 2).

All patients with suspected classic 21-OHD CAH should undergo a thorough physical examination, assessing for signs of adrenal crisis, with measurement of blood pressure, assessment of volume status and electrolytes (eg, sodium, potassium, glucose, bicarbonate). If possible, a 17-hydroxyprogesterone (17-OHP) level should be obtained. (See 'Urgent evaluation in all' above.)

While awaiting laboratory results, presumptive medical therapy for CAH should be considered, especially in infants with male-appearing genitalia and nonpalpable gonads, to minimize the risk of adrenal crisis. (See 'Stabilization and initial medication dosing' above.)

●Stabilization and initial medication dosing − The initial medical management depends on the patient's clinical status, specifically whether the patient is experiencing adrenal crisis.

•Adrenal crisis – Infants with suspected adrenal crisis should be urgently treated with fluid replacement. High-dose glucocorticoids ("stress-dose" steroids or "stress-dose" glucocorticoids) should be given as soon as possible and, if possible, after a serum sample is obtained to measure a confirmatory 17-OHP level. Glucocorticoids should be given as hydrocortisone, typically at a dose of 50 to 100 mg/m²/day (approximately 25 mg in full-term infants). This is given once as a bolus, and then the same dose is divided every six hours. Mineralocorticoid replacement is not needed while patients are treated with stress-dose steroids. When patients are clinically stable, they may be transitioned to a standard dosing regimen of glucocorticoid, mineralocorticoid, and sodium chloride therapy. (See 'Patients in adrenal crisis' above.)

•Not in adrenal crisis – In patients who are clinically stable, a blood sample should be obtained for confirmatory 17-OHP.

After the confirmatory blood sample is obtained, standard dosing of glucocorticoids, mineralocorticoids, and oral sodium chloride supplementation should be initiated in all infants in whom CAH is suspected as follows:

-Hydrocortisone (glucocorticoid replacement) 20 to 30 mg/m²/day calculated based on body surface area (BSA) (calculator 1) divided three times per day.

-Fludrocortisone (mineralocorticoid replacement) at 100 mcg (0.1 mg) given once or twice daily.

-Oral sodium chloride, given as a solution or tablets at 1 to 2 g or 17 to 34 mEq/day (2 to 4 mEq/kg/day) divided in several feedings. (See 'Stabilization and initial medication dosing' above.)

Medications can be discontinued if CAH is definitively excluded.

•Additional considerations in infants with atypical genital appearance – Newborns with atypical genital appearance require urgent medical attention to evaluate for classic 21-OHD, which is the most common cause of virilization in 46,XX infants. In addition to physical examination and measurement of 17-OHP and electrolytes, evaluation for rarer types of CAH may be indicated. (See 'Special considerations in patients with atypical genitalia' above.)

●Medications in older infants, children, and adolescents – All children with classic 21-OHD CAH require both glucocorticoid and mineralocorticoid treatment. This is true for patients with both salt-wasting and simple-virilizing forms of classic 21-OHD CAH:

•Glucocorticoids – In infants and older children, glucocorticoid replacement is usually administered as hydrocortisone in a dose of 10 to 15 mg/m² BSA per day. In the early phase of treatment, children may require 20 mg/m²/day of hydrocortisone, but stress doses of up to 50 mg/m²/day may be temporarily needed to reduce markedly elevated 17-OHP. Where available, modified-release hydrocortisone may be used as an alternative. Longer-acting glucocorticoid preparations increase the risk of growth failure but may be used in some adolescents and adults. (See 'Glucocorticoid (all patients)' above.)

•Mineralocorticoids – Mineralocorticoid replacement (usually with fludrocortisone) is recommended in all patients with classic 21-OHD CAH. The dose can often be reduced after four to six months of age but is continued at the lower dose thereafter. 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 PRA and blood pressure. (See 'Mineralocorticoid (all patients)' above.)

•Adrenal crisis – Children with classic 21-OHD CAH are at risk for developing adrenal crisis. To prevent adrenal crisis, stress-dose glucocorticoids should be administered when patients with classic 21-OHD CAH become ill with fever or gastroenteritis, undergo surgery with general anesthesia, or experience significant physical trauma. Fasting should be avoided, especially in young children and infants. Parents/caregivers should receive teaching in the use of stress-dose glucocorticoids and recognition of adrenal crisis. (See 'Measures to prevent adrenal crisis in all' above.)

•Ongoing monitoring for efficacy of therapy – Efficacy of glucocorticoid replacement therapy is monitored by measuring serum 17-OHP and androstenedione. Mineralocorticoid replacement is monitored by measuring blood pressure, PRA, and electrolytes. Clinicians should also monitor height velocity, the onset and progression of puberty, and the rate of skeletal maturation.

Laboratory and clinical monitoring should be performed monthly in the first three months of life and every three to six months thereafter. Bone age should be measured every 6 to 12 months after two years until skeletal maturity. Additional monitoring for obesity and cardiovascular disease risk, bone health, menstrual irregularity, and testicular rest tumors should be performed in older children and adolescents. (See 'Assessing response to therapy' above and 'Screening for complications' above.)

•Adjunctive therapy – For children with classic 21-OHD CAH age ≥4 years in whom androgen production is inadequately suppressed on doses of glucocorticoid >10 to 12 mg/m²/day or in whom glucocorticoid doses required for androgen suppression have led to impaired linear growth or signs/symptoms of glucocorticoid excess, we suggest the addition of a corticotropin-releasing factor (CRF) type 1 receptor antagonist such as crinecerfont (where available) to standard therapy (glucocorticoid and mineralocorticoid replacement) (Grade 2C). Patients treated with CRF antagonists continue to have adrenal insufficiency and remain at risk of adrenal crisis; they require ongoing glucocorticoid and mineralocorticoid therapy and stress-dose glucocorticoids during illness. (See 'Corticotropin-releasing factor (CRF) type 1 receptor antagonist (crinecerfont)' above.)