Continuing Education Activity

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive conditions caused by genetic mutations that disrupt enzymes responsible for producing glucocorticoids, mineralocorticoids, and sex steroids from cholesterol in the adrenal glands. These mutations impair cortisol synthesis, prompting a compensatory increase in adrenocorticotropic hormone, which leads to adrenal cortex hyperplasia—hence the name "CAH." The condition manifests in infants, children, or adults with symptoms of corticosteroid deficiency, often accompanied by either a deficiency or an excess of mineralocorticoids and sex steroids, depending on the specific enzyme defect. The most common form, 21-hydroxylase (21-OH) deficiency, accounts for approximately 95% of cases. Clinical presentations vary by enzyme defect, ranging from ambiguous genitalia in genotypic females to potentially life-threatening adrenal insufficiency in males.

Newborn screening programs measuring 17-hydroxyprogesterone levels have significantly improved early detection and outcomes by identifying nearly all infants with classic (severe) CAH due to 21-OH deficiency, along with some milder variants. Standard treatment involves glucocorticoid replacement, supplemented with mineralocorticoid therapy as needed. Advances in therapeutic approaches aim to achieve more physiologic glucocorticoid replacement while reducing the adverse effects associated with prolonged steroid use, with ongoing research focused on improving long-term hormonal balance and patient outcomes. This activity provides an overview of the evaluation, diagnosis, and management of congenital adrenal hyperplasia, emphasizing the importance of timely detection and treatment. This activity also underscores the critical role of interprofessional collaboration among healthcare providers, including endocrinologists, pediatricians, genetic counselors, and nurses, in optimizing patient outcomes.

Objectives:

• Identify the genetic and enzymatic defects underlying congenital adrenal hyperplasia and their impact on glucocorticoid, mineralocorticoid, and sex steroid synthesis.
• Implement evidence-based glucocorticoid and mineralocorticoid replacement therapies tailored to age, growth status, and clinical needs.
• Apply strategies to minimize the adverse effects of prolonged glucocorticoid use, including monitoring growth, bone age, and metabolic health.
• Collaborate with a multidisciplinary healthcare team, including endocrinologists, genetic counselors, pediatricians, and nurses, to ensure congenital adrenal hyperplasia management.

Introduction

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive conditions caused by mutations in genes encoding enzymes involved in the production of glucocorticoids, and sometimes mineralocorticoids and sex steroids, from cholesterol in the adrenal glands. These mutations impair cortisol synthesis, triggering a compensatory increase in adrenocorticotropic hormone (ACTH), which leads to adrenal cortex hyperplasia—hence the term "CAH." The condition can manifest in infants, children, or adults with symptoms of corticosteroid deficiency, often accompanied by either a deficiency or excess of mineralocorticoids and sex steroids, depending on the specific enzymatic defect.[1][2]

21-Hydroxylase (21-OH) deficiency is the most common form of CAH. In affected males, this deficiency is often undiagnosed until they develop severe adrenal insufficiency, which can be life-threatening if not treated promptly. Newborn screening programs in the United States and many other countries measure 17-hydroxyprogesterone (17-OHP) levels, enabling the detection of nearly all infants with classic (severe) CAH and some with milder variants. These screening programs have significantly reduced the morbidity and mortality associated with CAH.[1]

Etiology

Gene mutations that cause defects in steroidogenesis are classified as CAH and involve the following enzymes and proteins:

• 21-Hydroxylase (21-OH)
• 11β-Hydroxylase (11β-OH)
• 3β-Hydroxysteroid dehydrogenase type-2 (3β-HSD-2)
• 17α-Hydroxylase/17,20-lyase (17α-OH)
• P450 oxidoreductase (POR)
• Steroidogenic acute regulatory protein (StAR)
• Cholesterol side-chain cleavage enzyme (SCC) [2]

Defects in the CYP21A2 gene, which causes 21-OH deficiency, account for approximately 95% of cases.[1] CYP21A2 gene is located within the class III region of the human major histocompatibility complex on chromosome 6 (6p21.3). Loss or impairment of CYP21A2 results in reduced production of the enzyme cytochrome P450c21 (21-OH). As a result, 21-OH deficiency hinders the conversion of 17-OHP to 11-deoxycortisol, the penultimate step in cortisol synthesis, and the conversion of progesterone to deoxycorticosterone (DOC) in aldosterone synthesis. Disease severity and phenotypic presentation vary depending on the location and extent of gene mutations or deletions, resulting in complex allelic variations.[3] For example, nearly 200 different CYP21A2 mutations have been identified, making genotyping of affected individuals challenging.[4]

CAH can be divided into 2 types—classic and nonclassic—depending on the severity of the variant and the degree of enzyme function loss. Classic (severe) CAH may present as simple virilizing CAH or salt-wasting CAH, typically diagnosed in infancy. In contrast, patients with nonclassic CAH, which presents with milder symptoms, may be asymptomatic, show mild virilization postnatally, or lead to features of polycystic ovary syndrome (PCOS) and infertility in adolescents and adult females.

Defects in StAR (also known as STARD1/8p11.23) impair the synthesis of all steroids due to its role at the proximal site in steroidogenesis (see Fig. 1). Similarly, mutations in SCC (CYP11A1/15q23-q24) are indistinguishable from StAR defects because they occur near the site of StAR's action. Defects in 3β-HSD-2 (HSD3B2/1p13.1) impair the conversion of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) to progesterone, 17-OHP, and androstenedione, respectively, leading to defective synthesis of cortisol, aldosterone, and androgens. Additionally, deficiencies in 11β-OH (CYP11B1/6p21.1) and 17α-OH (CYP17A1/10q24.3) result in the accumulation of mineralocorticoid precursors, causing hypertension and cortisol deficiency in affected individuals.

Cytochrome P450 oxidoreductase (POR/7q11.2) defects lead to variable clinical presentations, as cytochrome P450 has a role in 21-hydroxylation, 17-hydroxylation, and the aromatization of androgens to estrogens. POR also participates in the final steps of aldosterone synthesis and the SCC of cholesterol molecules.

Epidemiology

CAH is more prevalent among Native Americans and Yupik people in the United States.[5] Among Whites, the incidence is approximately 1 in 15,000 individuals. The global incidence of classic 21-OH–deficient CAH is estimated to be 1 in 15,000 to 20,000 births in Western countries. Approximately 75% of the affected infants present with the salt-wasting form, whereas 25% have the simple virilizing form.[1][6][7] The nonclassic form of CAH has a prevalence of approximately 1 in 1000 in the general population but may occur as frequently as 1 in 100 to 200 in certain ethnic groups.

The prevalence of rare CAH types varies by ethnicity and region, influenced by the founder effect and consanguinity rates. As all forms of CAH follow an autosomal recessive inheritance pattern, both sexes are equally affected. Over 250 cases of lipoid CAH, resulting from more than 120 identified StAR mutations, have been reported. This type of CAH is most prevalent in Japan and Korea, followed by the Middle East. In Japan and Korea, over 70% of affected alleles carry the Q258X variant, likely due to the founder effect. A nationwide report from Japan estimated the prevalence to be approximately 2 per million.[2][8] 

Fewer than 100 cases of SCC deficiency have been documented, with the most common variant being R451W, primarily reported in Turkey.[2][9] In contrast, 3β-HSD-2 defects have been identified globally, with an estimated incidence of less than 1 in 1,000,000 live births.[10] 

The incidence of 11β-OH deficiency is estimated to range from 1 in 100,000 to 200,000 live births. To date, more than 200 mutations have been identified. Certain regions in North Africa and the Middle East have reported notably high prevalence rates.[2] The incidence of 17α-OH deficiency is approximately 1 in 50,000 live births,[11] with a higher prevalence in Brazil, likely due to founder mutations.[2] The prevalence and incidence of POR deficiency remain unknown, with slightly over 100 cases reported in the literature.[5]

Pathophysiology

The adrenal cortex is the site for steroidogenesis and produces 3 significant hormone classes, as mentioned below.

• Glucocorticoids: Glucocorticoids, primarily cortisol, regulate the body's metabolism and immune response.
• Mineralocorticoids: Mineralocorticoids, mainly aldosterone, help regulate electrolytes, blood pressure, and vascular volume.
• Adrenal androgens: Adrenal androgens are the sex hormones that control secondary sex characteristics.

Cholesterol, obtained from endogenous synthesis or dietary sources, serves as the precursor for steroid synthesis. The pathway for steroid synthesis is mediated by multiple enzymatic steps, beginning with StAR, which regulates the entry of cholesterol from the outer to the inner mitochondrial membrane. SCC catalyzes the first step of steroid synthesis, converting cholesterol to pregnenolone (desmolase or SCC; Figure 1), while 11β-OH catalyzes the final step, converting 11-deoxycortisol to cortisol. These enzymes are essential for the synthesis of cortisol and aldosterone in the zona fasciculata and zona glomerulosa of the adrenal cortex.

Both cortisol and aldosterone are deficient in the most severe salt-wasting form of the disease. However, in CAH with excess mineralocorticoid activity, such as 11β-OH (CYP11B1) or 17α-OH (CYP17A1) deficiency, the excessive accumulation of aldosterone precursors with mineralocorticoid activity results in hypertension, hypokalemia, and metabolic alkalosis. Although the classification of classic and nonclassic CAH helps in understanding the severity of the disease, this distinction is becoming less clear as more experience is gained. The condition represents a continuous spectrum of manifestations rather than distinct categories defined by the classification.[12]

Cortisol deficiency triggers feedback stimulation of ACTH release from the pituitary gland. Elevated ACTH levels can cause adrenal cortex hyperplasia, accumulation of cortisol precursors, and diversion of steroidogenic pathways, resulting in excess production of androgens or mineralocorticoid precursors. Inadequate sex steroid production may occur depending on the extent of the enzyme defect in steroidogenesis (eg, 17α-OH, POR, StAR, and SCC). This disruption can lead to clinical manifestations in infants, including hyperpigmentation from elevated ACTH, failure to thrive, electrolyte imbalances, acidosis or alkalosis, and shock due to adrenal insufficiency. Additional features include virilization in 46,XX infants from excessive androgen levels or undervirilization in 46,XY individuals.

Steroidogenic Acute Regulatory Protein

A defect in StAR (STARD1) impairs the transport of cholesterol to the inner mitochondrial membrane, disrupting the production of all steroid hormones. Severe StAR defects result in classic lipoid congenital adrenal hyperplasia (LCAH), which is characterized by lipid accumulation in steroidogenic cells of the adrenal glands and gonads. This condition presents with adrenal insufficiency during the neonatal period or early infancy and female or near-female genitalia, regardless of chromosomal sex. Affected individuals exhibit primary adrenal and gonadal insufficiency, reflected by elevated ACTH levels, increased plasma renin activity, high gonadotropin levels, and low or undetectable levels of cortisol, aldosterone, and sex steroids. The adrenal glands and gonads do not respond to ACTH or human chorionic gonadotropin (hCG) stimulation, and the adrenal glands become enlarged due to the accumulation of cholesterol and cholesterol esters. Milder StAR defects with partially retained function result in a less severe (nonclassic) form of the disease, characterized by cortisol deficiency while preserving the production of mineralocorticoids and sex steroids.[9]

A notable phenomenon is the "2-hit hypothesis," which explains spontaneous puberty in some females. The "first hit" involves the absence of StAR at the outer mitochondrial membrane, impairing the major pathway (approximately 85%) of steroid production, leading to elevated ACTH and gonadotropins. The "second hit" occurs with the accumulation of cholesterol and cholesterol esters in the adrenal glands and gonads, ultimately damaging the entire steroid synthesis machinery. In 46,XX individuals, the ovaries are not receptive to gonadotropins before puberty. After puberty, one follicle develops at a time under the influence of gonadotropins during hormonal cycles. If diagnosed early and provided appropriate treatment to protect the ovaries from further damage, these females can reach adolescence and produce sufficient estrogens through StAR-independent mechanisms (typically around 15% of total estrogen), resulting in spontaneous feminization.[12]

A milder form, known as nonclassic LCAH, occurs when approximately 20% to 30% of enzyme activity is preserved. This form presents with insidious onset adrenal insufficiency, mild or no mineralocorticoid inadequacy, mild hypergonadotropic hypogonadism, and minimal to no genital ambiguity. Criteria proposed in a recent study to differentiate the classic from the nonclassic form include:

• Good masculinization of the external genitalia in 46,XY individuals.
• Preserved mineralocorticoid secretion.
• Onset of primary adrenal insufficiency in individuals aged 1 or older.[8][9]

Side-Chain Cleavage Enzyme

SCC catalyzes the cleavage of the side chain of cholesterol, marking the initial step in hormone synthesis. Severe SCC defects lead to phenotypes clinically indistinguishable from StAR defects; however, unlike StAR defects, patients with SCC defects do not exhibit massive adrenal hyperplasia. The onset of adrenal insufficiency and genital appearance (in 46,XY individuals) varies depending on the severity of the mutation. This condition can also present as a milder nonclassic variant.[2][9][12][13]

3β-Hydroxysteroid Dehydrogenase Type-2

Defects in 3β-HSD-2 (HSD3B2) impair the conversion of pregnenolone, 17-hydroxypregnenolone, and DHEA to progesterone, 17-OHP, and androstenedione, respectively. This leads to defective synthesis of cortisol, aldosterone, and androgens. Accumulated DHEA sulfate (DHEAS) is a weak androgen and insufficiently potent to virilize a 46,XY infant. Less commonly, the DHEAS and androgens produced by peripheral 3β-HSD-1 can cause virilization of 46,XX individuals, resulting in genital ambiguity in both genotypes. A nonclassic (less severe) variant of this condition may also occur.[2][10]

The enzyme 11β-OH (CYP11B1) is essential for converting 11-deoxycortisol to cortisol and DOC to corticosterone. A defect in this enzyme leads to cortisol deficiency, redirecting the steroid production pathway toward mineralocorticoid and androgen excess. This results in the accumulation of DOC, causing hypertension, hypokalemia, alkalosis with suppressed plasma renin activity, and early virilization in both sexes, including premature pubarche. Affected infants may initially experience transient salt-wasting before eventually developing hypertension.[2] A milder, nonclassic form of the condition exists, which does not involve genital ambiguity in females and presents with hypertension in both sexes. Heterogeneity in presentation and the absence of salt-wasting can delay diagnosis.[14][15]

CYP17A1 catalyzes 17-hydroxylation and subsequent 17,20 lyase activity. A defect in this enzyme disrupts both of these reactions. In rare cases, isolated 17,20 lyase defects have been identified, where only androgen synthesis is impaired while cortisol production remains normal. Therefore, this condition is not classified as part of CAH but rather as an isolated androgen synthetic defect. CYP17A1 metabolizes pregnenolone and progesterone to their 17-hydroxy derivatives early in the steroidogenic pathway. Severe defects in this enzyme prevent the synthesis of cortisol and sex steroids, leading to the accumulation of mineralocorticoids, such as DOC (see Figure 1).

DOC binds to mineralocorticoid receptors, resulting in manifestations of hyperaldosteronism. Unlike other forms of CAH, this type rarely exhibits features of cortisol deficiency due to the accumulation of steroid precursors with cortisol-like activity, such as corticosterone.[16][17] Severe defects result in a female phenotype in both sexes. The absence of pubertal progression and the presence of hypertension often prompt diagnostic evaluation during adolescence. A less severe, nonclassic form of this condition also exists, presenting with varied biochemical and clinical features.

POR defects result in variable clinical and biochemical presentations due to the involvement of 21-OH, 17α-OH, and aromatase enzymes. The phenotype depends on the extent and specific enzyme impairment caused by the mutation. Clinical manifestations can range from genital ambiguity in both 46,XX and 46,XY individuals with adrenal insufficiency to milder forms presenting as PCOS in 46,XX individuals or hypogonadism and late-onset infertility in 46,XY individuals. Certain variants are associated with a syndromic presentation, such as Antley–Bixler syndrome, which involves skeletal abnormalities in both sexes. These features may include craniosynostosis, brachycephaly, midface hypoplasia, proptosis, choanal stenosis, radiohumeral or radioulnar synostosis, bowed femora, and arachnodactyly, appearing in various combinations. Antenatal maternal virilization is another potential manifestation.[2][5][18][12]

Table

Table. Emerging Therapies for Congenital Adrenal Hyperplasia.

Abbreviations: 21-OH, 21-hydroxylase; 17-OHP, 17-hydroxyprogesterone; 17α-OH, 17α-hydroxylase/17,20-lyase; 11β-OH, 11β-hydroxylase; 3β-HSD-2, 3β-hydroxysteroid dehydrogenase type-2; ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; G, glucocorticoids; hCG, human chorionic gonadotropin hormone; M, Mineralocorticoids; POR, P450 oxidoreductase; PRA, plasma renin activity; S, Sex hormones; SCC, cholesterol side-chain cleavage enzyme; StAR, steroidogenic acute regulatory protein.

Histopathology

The histological features of CAH include:

• Adrenal cortex hyperplasia.
• Disorganized architecture of the adrenal medulla and cortex without distinct zones.
• Lipoid deposits representing cholesterol and cholesterol esters that fail to enter mitochondria for steroid synthesis (observed in lipoid CAH cases).
• Hypertrophy of the juxtaglomerular apparatus in cases of salt-wasting.[19]

History and Physical

The symptoms of CAH are mentioned below. 

• Cortisol inadequacy: Failure to thrive, hyperpigmentation, vomiting, or even adrenal crisis, which may present as shock or sudden infant death.

• Mineralocorticoid inadequacy: Salt-wasting, leading to dehydration, hypovolemia, shock, and potentially death in salt-wasting types of CAH, such as classic 21-OH, StAR, P450 side-chain cleavage (PSCC), 3β-HSD-2, and possibly POR deficiencies.

• Mineralocorticoid excess: Hypertension, hypertensive crisis, cardiac failure, recurrent hypokalemia, metabolic alkalosis, and related symptoms.

• Sex steroid (androgen) excess: Sex steroid (androgen) excess in CAH leads to a range of clinical manifestations, including early puberty, virilization, and reproductive challenges in both males and females.

  • Early pubic hair development and rapid growth during childhood in both genders.
  • Significant virilization in 46,XX individuals, including ambiguous genitalia at birth, enlarged clitoris, heterosexual precocious puberty, menstrual irregularity, infertility due to anovulation, shallow vagina, and excessive facial hair.
  • In 46,XY individuals, a functional, average-sized penis with extreme virilization but no sperm in virilizing CAH (eg, 21-OH and 11β-OH), and variable virilization in 3β-HSD-2 and POR defects.

• Sex steroid inadequacy: Defects in StAR, PSCC, and 17α-OH cause undervirilization and sexual infantilism in 46,XY and 46,XX individuals, respectively. Deficiencies in 3β-HSD-2 and possibly POR may cause under-virilization in 46,XY individuals and modest virilization in 46,XX individuals. The external genitalia may appear fully male (Prader 5) in 46,XX individuals or fully female in 46,XY individuals, depending on the type and severity of the enzyme defect.

The examination of external genitalia should include descriptions of the phallus size, number of openings, location of the urethral opening, and the position of the gonads if palpable. Prader staging and the External Masculinization Score (EMS) or External Genitalia Score (EGS) should be used to standardize findings and minimize interobserver variability.[20][21][22] Additionally, the examiner may document a pictorial representation of the genitalia to reduce the need for repeated examinations and minimize trauma to the individual.

Evaluation

CAH due to 21-OH deficiency is a common cause of ambiguous genitalia in genotypic female infants (46,XX). Females with less severe forms may present with early pubarche. In young women, the condition may manifest as oligomenorrhea, PCOS, or hirsutism.[23][24]

Most males show no signs of CAH at birth. However, some may present with hyperpigmentation and penile enlargement, while those with salt-wasting disease often present early with hyponatremia and hypovolemia. Males with non–salt-wasting disease typically present later with signs of virilization. In certain forms of CAH, such as 3β-HSD-2, 17α-OH, POR, StAR, and PSCC deficiencies, males may exhibit varying degrees of undervirilization, ranging from mild hypospadias to completely female genitalia, depending on the gene affected and the severity of the variant. CAH caused by 21-OH deficiency and most other forms occur in both classic and nonclassic forms. Nonclassic forms are characterized by late-onset adrenal insufficiency and mild or absent genital ambiguity in affected individuals. 

Diagnosis

Newborn screening: In the United States and many developed countries, newborns are screened for 21-OH deficiency CAH between 2 to 4 days after birth. Neonatal screening programs use reference ranges adjusted for weight and gestational age, as elevated levels of 17-OHP can also occur in sick, stressed, or premature infants without CAH. Early detection of elevated 17-OHP levels allows timely treatment and also leads to improved outcomes and relatively normal life.

A 2-tier diagnostic approach is recommended for CAH. The initial screening involves measuring 17-OHP levels to identify 21-OH deficiency. If the result is positive, a repeat 17-OHP test should be conducted along with a serum electrolyte panel. Classic 21-OH deficiency typically results in 17-OHP levels exceeding 10,000 ng/dL, whereas nonclassic and rarer forms usually exhibit levels between 1000 and 10,000 ng/dL. For cases with mild elevation of 17-OHP, either second-tier liquid chromatography–tandem mass spectrometry (LC-MS/MS) testing or cosyntropin stimulation testing should be performed before initiating steroid treatment.

If 17-OHP levels are ambiguous (200-1000 ng/dL) or other enzyme defects, such as 11β-OH, 3β-HSD-2, 17α-OH, or POR are suspected, cosyntropin stimulation testing should be performed. A complete adrenal profile following cosyntropin stimulation should be drawn, including measurements for 17-OHP, progesterone, cortisol, DOC, 11-deoxycortisol, pregnenolone, 17-hydroxypregnenolone, DHEA, and androstenedione. Samples are collected immediately before and 60 minutes after administering 0.25 mg of cosyntropin—a synthetic ACTH. Cosyntropin provides a pharmacologic stimulus to the adrenal glands, enhancing hormone secretion. A stimulation test is generally unnecessary for diagnosing typical 21-OH deficiency CAH with a consistent clinical profile and unambiguously high 17-OHP levels.

In addition to 17-OHP, 21-deoxycortisol can be used as a screening marker for 21-OH deficiency CAH. This hormone is formed through the action of 11β-OH on accumulated 17-OHP. Compared to 17-OHP, 21-deoxycortisol is considered a more reliable screening marker due to its concentrations being less influenced by gestational age and the timing of sample collection. Furthermore, it is a more specific marker for diagnosing 21-OH deficiency CAH.[25]

Other Laboratory Studies

All forms of CAH exhibit glucocorticoid insufficiency, leading to elevated ACTH and low cortisol levels across all classic CAH types. In salt-wasting varieties, laboratory findings include hyponatremia, hyperkalemia, acidosis, low aldosterone, and elevated plasma renin activity. In contrast, 11β-OH and 17α-OH deficiencies may present with hypokalemia, alkalosis, and the accumulation of mineralocorticoid precursors (such as DOC and corticosterone), accompanied by suppressed plasma renin activity. Additionally, the accumulation of specific precursors and abnormal precursor-to-product ratios aids in diagnosing specific CAH variants. Please refer to the Etiology and Pathophysiology sections for more details.[2]

Patients with 3β-HSD-2 deficiency exhibit significantly elevated levels of Δ5 steroids, including pregnenolone, 17-hydroxypregnenolone, DHEA, and DHEAS, along with an increased Δ5 to Δ4 steroid ratio (eg, progesterone, 17-OHP, and Δ4-androstenedione) compared to controls. A recent study demonstrated that a high baseline 17-hydroxypregnenolone-to-cortisol ratio combined with low 11-oxy-androgen concentrations, measured via LC-MS/MS, can accurately identify individuals with 3β-HSD-2 deficiency.[10]

The accumulation of 11-deoxycortisol and DOC, along with elevated androgen levels, is diagnostic of 11β-OH deficiency. Increased urinary tetrahydro-11-deoxycortisol and low cortisol metabolites can also help diagnose this condition. Furthermore, the 11-deoxycortisol-to-cortisol ratio and 11-DOC-to-cortisol ratio can be used to differentiate between classic and nonclassic forms of the disorder.[15] The accumulation of DOC and corticosterone, along with a high progesterone-to-17-OHP ratio and low sex steroids in the appropriate clinical context, is diagnostic of 17α-OH deficiency.[10][16][17] 

Androgen excess (seen in 21-OH, 11β-OH, and possibly POR defects) and androgen deficiency (seen in 17α-OH, StAR, and SCC defects) can both occur, depending on the type of CAH. Classic StAR and SCC defects result in complete adrenal and sex steroid deficiency. These defects prevent the formation of any steroid biosynthesis precursors, as they involve the proximal sites of steroidogenesis. Hypertension and hypokalemia distinguish 11β-OH defects from 21-OH deficiency and 3β-HSD-2 deficiencies, while androgen excess differentiates 11β-OH from 17α-OH deficiencies.

The diagnosis of POR deficiency is based on the impaired activity of both CYP21A2 and CYP17A1. This results in a biochemical and clinical presentation that combines features of both defects, such as mild elevation of pregnenolone, progesterone, 17-hydroxypregnenolone, 17-OHP, and DOC.[2][12] This condition may be suspected and diagnosed based on antenatal maternal virilization and fetal skeletal malformations observed during prenatal scans.[18] Due to its rarity and varied presentation, genetic studies are typically required to confirm the diagnosis.

Imaging Studies

Imaging studies are generally not required for evaluating patients with CAH unless adrenal hemorrhage is suspected. However, in cases of LCAH, massively enlarged adrenal glands due to lipid deposition may provide a clue to the diagnosis. For patients with ambiguous genitalia, a pelvic ultrasound may be performed to assess for other anomalies and to define the anatomy of the urogenital tract.

Genetic Testing

Genetic testing is typically performed in infants with ambiguous genitalia to establish the genotypic sex. For 21-OH deficiency, molecular genetic analysis may be helpful but is generally not required if classic clinical and laboratory findings are present, except in certain situations. These include initiating steroid treatment before a firm diagnosis is established, providing genetic counseling for future pregnancies, and addressing diagnostic dilemmas.[1] Genetic analyses are particularly important in cases of diagnostic uncertainty and play a crucial role in confirming CAH caused by other enzyme deficiencies, as their clinical presentations can be highly variable and laboratory diagnostic criteria may not always be definitive.

Treatment / Management

The goal of medical treatment for CAH varies depending on the patient's age. CAH is inherited in an autosomal recessive manner, meaning both parents must be carriers of the recessive gene. Couples with a history of recessive CAH genes for CAH may prevent the condition through preimplantation genetic diagnosis.[1][26][27] Prenatal treatment is not recommended and is currently considered experimental.[1]

Medical Therapy

Acute adrenal crisis: Despite the significant reduction in infant mortality due to widespread newborn screening for CAH, the adrenal crisis remains the leading cause of death in individuals with the condition. Therefore, clinicians managing CAH must understand the critical need for administering stress doses of steroids during illness or physical stress.[1]

• Adrenal crisis: An acute adrenal crisis is a medical emergency requiring immediate intervention. 

• Initial management: This should involve stress doses of intravenous (IV) or intramuscular (IM) hydrocortisone, administered at 50 to 100 mg/m² or a neonatal dose of 25 mg, followed by 100 mg/m²/d divided every 6 hours. Steroids should be administered as early as possible, concomitant with IV fluid treatment.

• Fluid resuscitation: An IV bolus of isotonic sodium chloride solution (20 mL/kg) should be promptly administered, with repeated boluses as needed. If the patient is hypoglycemic, dextrose should be given, and rehydration with dextrose-containing fluids is required after the bolus to prevent further hypoglycemia.

• Management of hyperkalemia: Life-threatening hyperkalemia may require additional treatments such as potassium-lowering resins, IV calcium, insulin, and bicarbonate.

Positive Newborn Screen

Newborn screening for CAH is routinely performed in all 50 states of the United States and at least 40 other countries.[1][28] This screening is primarily aimed at detecting common 21-OH deficiency CAH, which can lead to salt-wasting and potentially life-threatening adrenal crises. These screening programs are based on 17-OHP levels, but they may not detect other rare forms of CAH.

A positive newborn screening result for CAH requires confirmation with a second plasma sample to measure 17-OHP levels, along with serum electrolyte testing. Following the confirmatory blood sample, glucocorticoid treatment—and mineralocorticoid treatment if necessary—should be promptly initiated in all infants suspected of having CAH to prevent life-threatening adrenal crises. If treatment is withheld while awaiting confirmatory steroid hormone measurements, serum electrolytes should be monitored daily. A pediatric endocrinologist should manage patient care.

Long-Term Management

The goals of therapy are as follows:

• Treatment aims to provide adequate glucocorticoid replacement during infancy and childhood to prevent adrenal crises, limit early virilization, support normal growth, and ensure sufficient mineralocorticoid levels (and salt, if needed) to prevent electrolyte imbalances and dehydration. In adolescents and adults, the focus of the treatment shifts to achieving normal reproductive function and fertility while avoiding chronic complications of medication insufficiency or excess, including Cushing syndrome. To minimize exposure to glucocorticoids in adulthood and reduce the adverse outcomes associated with supraphysiological steroid doses, control of adrenal-derived androgens is typically relaxed after adult height is reached.[29] 

• CAH with deficient mineralocorticoid activity and virilization should not be treated with spironolactone. However, CAH with excessive mineralocorticoid activity requires antihypertensive therapy. Additionally, CAH with insufficient sex steroid production needs appropriate supplementation during puberty and reproductive years. Further treatment may be required to optimize growth, including delaying puberty or bone maturation when necessary.

• Educating parents, caregivers, and older patients with CAH about the signs, symptoms, prevention, and emergency treatment of adrenal crises is a crucial aspect of CAH management. All patients with CAH should be advised to wear medical identification and keep a glucocorticoid emergency injection kit readily available for use during adrenal crises.

Glucocorticoid replacement: Glucocorticoid replacement in CAH is essential for managing adrenal insufficiency, controlling androgen excess, and promoting normal growth and development. Treatment is tailored to the specific variant and age of the patient.

• Cortisol replacement: Hydrocortisone is the preferred treatment due to its short half-life and minimal impact on growth suppression. Oral hydrocortisone is administered in 3 equally divided doses of 10 to 20 mg/m²/d, as patients with classic 21-OH deficiency (virilizing CAH) require supraphysiological doses of long-term glucocorticoid treatment to inhibit excessive secretion of CRH and ACTH, as well as to reduce the abnormally high serum concentrations of adrenal androgens. In under-virilizing CAH, physiological doses of hydrocortisone are usually sufficient.

• Treatment efficacy: This is best assessed by monitoring growth, blood pressure, and the development of age- and gender-appropriate secondary sexual characteristics in all varieties of CAH. Additionally, morning measurements of ACTH, 17-OHP, DHEA sulfate, and androstenedione are routinely monitored in the most common variety, 21-OH deficiency. Although 17-OHP levels remain elevated, a target range of 500 to 1000 ng/dL is aimed to avoid the adverse effects of overtreatment. After implementing the initial management plan with close monitoring, the frequency of follow-up should be every 3 months until 18 months of age, then every 4 months from 18 months until growth completion. Children should also undergo an annual bone age radiograph and careful monitoring of linear growth.

• In other rare variants, monitoring may include other relevant metabolites, including:

  • With excessive mineralocorticoid activity, DOC levels should be measured. 
  • With an 11β-OH deficiency, 11-deoxycortisol levels should be measured.
  • With 3β-HSD-2 defects, pregnenolone, 17-hydroxypregnenolone, and DHEA levels should be measured. 

• Once growth is complete in older children and adolescents, treatment may involve prednisone (5-7.5 mg daily in 2 equally divided doses) or once-daily dexamethasone (0.25-0.5 mg).

• In adults, in addition to the aforementioned hormonal and clinical monitoring, annual assessments should include blood pressure, body mass index (BMI), and evaluation for Cushingoid features.

Mineralocorticoid replacement: Mineralocorticoid replacement is a cornerstone of managing salt-wasting CAH to address sodium loss, prevent adrenal crises, and optimize growth and development.

• Infants with salt-wasting forms of CAH typically require mineralocorticoid replacement with fludrocortisone at doses of 0.05 to 0.2 mg daily, although some may need up to 0.4 mg/d. Fludrocortisone doses are generally reduced in the latter half of infancy due to increased mineralocorticoid sensitivity.

• The sodium content in human milk and most infant formulas is around 8 mEq/L, which is insufficient to replace sodium lost in these infants. As a result, salt supplementation (1-2 g of sodium chloride) is an essential part of the treatment during infancy.

• Plasma renin activity levels are useful for monitoring the effectiveness of mineralocorticoid and sodium replacement. Hypotension, hyperkalemia, and elevated renin levels indicate the need for a dose increase, while hypertension, tachycardia, suppressed plasma renin activity, and hypokalemia suggest overtreatment. Adequate fludrocortisone replacement reduces steroid doses by lowering ACTH drive caused by hypovolemia and arginine vasopressin release. However, excessive fludrocortisone dosing may impair growth.

Mineralocorticoid excess: In CAH with excessive mineralocorticoid activity, along with adequate cortisol replacement, antihypertensive measures may be necessary. Aldosterone blockade, such as spironolactone in 11β-OH defects, can help manage both hypertension and excessive androgen levels.

Sex steroid replacement: In CAH variants with insufficient sex steroid production, such as StAR, PSCC, 17α-OH, 3β-HSD-2, and possibly POR, sex steroid supplementation may be required at appropriate ages to support normal pubertal development.

Nonclassic congenital adrenal hyperplasia treatment: Steroid treatment is often necessary for children with early pubarche, rapid pubertal progression, and bone age advancement, as well as for adolescents with overt virilization. In adult women, indications for treatment include hirsutism and infertility. Hydrocortisone (15–20 mg) in 3 equally divided doses is administered before conception and continued throughout gestation to reduce miscarriage risk. Once fertility goals are achieved, hirsutism and acne may be managed with oral contraceptives, with or without spironolactone. For previously treated patients, hydrocortisone therapy is maintained until growth completion, after which treatment may be discontinued.[1][4]

Stress dosing: Families should be educated on stress dosing to prevent adrenal crises during illnesses such as fever over 38.5 °C, gastroenteritis with dehydration, major surgery requiring anesthesia, or trauma. Typically, a 2- to 3-fold increase in the daily glucocorticoid dose is sufficient. Increased fluid intake and regular consumption of simple and complex carbohydrates are recommended to prevent dehydration and hypoglycemia. If oral intake is not possible, an IM injection of hydrocortisone (50–100 mg/m²) should be administered. Patients should wear medical identification tags. In nonclassic CAH, stress dosing is needed only when cosyntropin-stimulated cortisol is below 14 to 18 µg/dL.[1][4]

Treatment during pregnancy: Successful conception is typically achievable with adequate disease control. As dexamethasone crosses the placenta, hydrocortisone or prednisolone should be used during pregnancy. As with other cases of primary adrenal insufficiency, a 20% to 40% increase in steroid dose is necessary during the second and third trimesters. Stress dosing should be administered during labor and delivery.[1]

Newer Treatment Options

Current research is focused on developing more physiological glucocorticoid replacements, as standard therapies often fail to control excess androgen production and pose the risk of supraphysiological steroid exposure. This highlights an unmet need for new treatments that can prevent excessive androgen production without requiring higher doses of steroids.

• Modified-release hydrocortisone was evaluated in a recent phase-3 trial in adults.[30] Although the study did not achieve its primary end point of improved control of 24-hour 17-OHP levels at 24 weeks, it demonstrated potential for dose reduction during an 18-month extension, as well as patient-reported benefits, including restoration of menses and a higher pregnancy rate.

• Continuous subcutaneous hydrocortisone infusion (CSHI) was evaluated in a phase-2 trial involving difficult-to-treat adults.[31] After 6 months of CSHI, there was a reduction in morning and 24-hour levels of 17-OHP, androstenedione, ACTH, and progesterone compared to baseline. Additionally, improvements were observed in bone turnover markers and quality of life scores.

• Nevanimibe, a potent inhibitor of sterol O-acyltransferase-1, blocks cholesterol esterification and steroid synthesis in the adrenal cortex. A phase-2, single-blind dose titration study successfully reduced 17-OHP levels, but further development was halted due to insufficient efficacy.[32]

• Abiraterone, a CYP17A1 inhibitor, reduced androgen production from elevated precursors in a phase-1 dose-escalation study in adult females, suggesting its potential as an adjunct to current therapy.[33] A phase-1/2 study in children is underway with the same goals.

• Crinecerfont, an oral corticotropin-releasing factor type-1 receptor antagonist, was studied in recent phase-3 randomized placebo-controlled trials in adults and children.[34][35][36] This drug was safe and effective in reducing steroid doses and improving control of androstenedione in both studies. Crinecerfont was approved by the US Food and Drug Administration (FDA) on December 13, 2024, for use in children aged 4 and older for the same purpose.

• Atumelnant, an oral melanocortin type-2 receptor (ACTH receptor) antagonist, is currently being studied in a dose-finding open-label phase-2 trial. Initial findings indicate a significant and sustained reduction in morning levels of androstenedione and 17-OHP in participants.[37]

• Lu AG13909, an ACTH monoclonal antibody in IV formulation, is being evaluated in a phase-1 open-label study to assess its impact on morning 17-OHP, androstenedione, and ACTH levels. The first patient worldwide to receive this investigational drug in a phase-1 trial was treated at NIHR UCLHs.

• BBP-631, a gene-based therapy in early-stage development, aims to treat congenital adrenal hyperplasia (CAH) by promoting endogenous cortisol production in the adrenal glands (BridgeBio Pharma).

Differential Diagnosis

Features of adrenal insufficiency in infancy, with or without genital atypia, should prompt a thorough evaluation for CAH. However, other conditions that may mimic CAH at various stages of life should also be considered.

• Primary adrenal insufficiency: Adrenal hypoplasia congenita (DAX1), autoimmune adrenal insufficiency, bilateral adrenal hemorrhage, and familial glucocorticoid deficiency.
• Other causes of hyperkalemia or hyponatremia: Hypoaldosteronism and pseudohypoaldosteronism, which may arise from genetic or acquired renal causes,
• Genital atypia: Disorders of sex development may also result from placental aromatase deficiency, defects in androgen synthesis or action, or maternal androgen-producing tumors.
• Oligomenorrhea or amenorrhoea with hyperandrogenism or infertility: Polycystic ovary syndrome.
• Hypertension with hypokalemia, alkalosis, and suppressed plasma renin: Liddle syndrome, apparent mineralocorticoid excess, or a DOC-producing tumor.
• Other overlapping disorders: 3'-Phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2; apparent DHEA sulfotransferase deficiency) and hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency) are distinct disorders that are not classified as CAH. However, they may present with overlapping features. These conditions should be considered when evaluating rare forms of CAH.[38][39]

Surgical Oncology

Surgical Therapy

Most available data on surgical interventions and long-term outcomes pertain to 21-OH deficiency CAH, with limited information on other types of CAH, which may be extrapolated from these findings. Infants with ambiguous genitalia may require a surgical consultation if caregivers opt for this approach. A multidisciplinary team—including a pediatric endocrinologist, urologist, surgeon, and anesthesiologist—should thoroughly discuss the risks and benefits of early versus delayed surgery with the caregivers to ensure informed decision-making. Surgical procedures should be performed exclusively at centers specializing in genitoplasty.

In 46,XX children with classic CAH raised as girls, surgical intervention is often necessary to reduce clitoromegaly and correct posterior fusion to facilitate penovaginal intercourse. A retrospective analysis from Turkey reported similar anatomical and cosmetic outcomes for surgeries performed before versus after 2 years of age. However, the early surgery group experienced a higher rate of repeated interventions and lower parental satisfaction.[40]

Sexual function is a significant concern for females undergoing genitoplasty. A systematic review of approximately 1200 patients revealed that while most achieved satisfactory surgical outcomes, only about half of individuals reported comfortable intercourse, and a considerable proportion of patients had impaired sexual function scores.[41] A European registry-based study of girls who underwent surgery in early childhood found that about three-fourths preferred feminizing surgery during infancy or early childhood. Approximately 60% described the surgery as having a positive impact, whereas about 10% expressed negative opinions. Additionally, one-third of patients reported dissatisfaction with their sexual life.[42] Another Swedish study involving women with CAH found that approximately 40% preferred early surgery, another 40% had no preference regarding timing, and about 20% preferred delayed surgery.[43] 

In conclusion, the timing of surgery (early versus late) remains an active area of research. Many experts and human rights organizations now advocate for delayed surgery due to the risk of repeated interventions, potential gender identity concerns, and legal issues arising from the child's exclusion in decision-making. However, the rights of parents and caregivers to make decisions about their child's care must also be respected. Until more definitive data become available, healthcare providers should present all relevant information and discuss the controversies surrounding early and delayed surgery to support informed decision-making.[44]

Prognosis

Most long-term studies and trials focus on 21-OH deficiency CAH, with isolated case reports or small case series available for other rare variants. Patients with CAH have higher mortality rates compared to controls, with mortality rates ranging from 1.5 to 5 times greater than that of the general population. The adrenal crisis remains the most common cause of mortality.[45] Providing written education on stress-dose steroid administration and emphasizing its timely use is crucial and cannot be overstated.

Children with CAH who experience suboptimal control often exhibit tall stature in early childhood but ultimately achieve shorter adult heights. Recent data indicate that individuals with CAH are, on average, about 10 cm below their parentally predicted height targets. Contributing factors include advanced bone age and central precocious puberty from androgen excess, leading to early epiphyseal fusion. Additionally, glucocorticoid therapy may suppress growth and reduce final height. Experimental treatments using growth hormone and luteinizing hormone-releasing hormone analogs to delay puberty have demonstrated an average height gain of 7.3 cm.[46][47] Despite normal bone mineral density, individuals with CAH have an increased fracture risk, emphasizing the importance of closely monitoring bone health.[48]

Fertility in males may be compromised due to primary gonadal failure caused by testicular adrenal rest tumors (TARTs) and secondary gonadal failure from elevated adrenal androgens. In females, secondary PCOS or suboptimal sexual function can also impair fertility.

Individuals with CAH face an increased risk of impaired quality of life due to several factors, including chronic health issues, short stature, progressive virilization, the necessity for repeated surgeries, undesirable surgical cosmetic outcomes, and challenges with sexual function and fertility. Additionally, the psychological impact of 21-OH deficiency warrants careful consideration.[49]

The prevalence of metabolic abnormalities, including obesity, insulin resistance, dyslipidemia, and PCOS, has been reported to be high, either as a result of the disease itself or due to glucocorticoid treatment. This disease, along with its treatment complications and long-term consequences, presents significant challenges for both patients and practitioners. While newer therapies show promise, their long-term effectiveness and safety have yet to be fully established. Please refer to the Treatment/Management section for more information.

Complications

Among the various genetic defects causing CAH, 21-OH deficiency has been the most extensively studied. Complications are common and arise from the challenge of balancing inadequate steroid replacement, which leads to adrenal insufficiency and uncontrolled androgen production driven by ACTH, with supraphysiological steroid replacement that causes glucocorticoid-related toxicity. These imbalances can result in short stature, progressive virilization in females, suboptimal fertility, and other complications.

Although current studies have shown conflicting results, there are growing concerns about decreased bone mineral density and an increased risk of fractures in individuals with CAH due to supraphysiological steroid exposure. Therefore, taking all necessary precautions to maintain steroid doses as low as possible while ensuring adequate disease control is crucial.[48][49][50] Although data are limited, these complications are less prevalent in CAH variants with underproduction of sex steroids, as these variants typically require nearly physiological doses of corticosteroid replacement. This helps limit short stature and complications related to steroid toxicity.[8]

Patients with CAH are at an increased risk of cardiometabolic diseases, including hypertension, obesity, dyslipidemia, insulin resistance, impaired glucose homeostasis, increased carotid intima-media thickness, and cardiovascular events. However, most data available are based on surrogate markers rather than definitive outcomes.[51][52] Practitioners should remain cautious, promote a healthy lifestyle, and continue analyzing longer-term data to assess hard outcomes.

Aldosterone deficiency can lead to salt-wasting, resulting in failure to thrive, hypovolemia, and shock. On the other hand, complications from excessive mineralocorticoid administration or inadequate control of mineralocorticoid activity in CAH with hypertension can include persistent hypertension, hypokalemia, and an increased risk of cardiometabolic issues.

Due to suboptimal management with available treatments, another complication affecting the quality of life in males with CAH is TART, which can lead to obstructive infertility. This complication typically manifests during the second decade of life but may also arise earlier if disease management is inadequate. Yearly testicular ultrasound screenings should begin at puberty. Early TART lesions often improve with tighter ACTH control through optimized steroid treatment.

Poor outcomes related to genital surgery or surgical complications contribute to morbidity in female patients with CAH. Additionally, patients with CAH have a higher prevalence of adrenal masses, most commonly myelolipomas, compared to the general population. Uncontrolled ACTH stimulation of the adrenal cortex is the likely cause of these masses. In addition to these complications, patients with all varieties of CAH often experience a suboptimal quality of life, including challenges in psychosocial well-being and sexual function, influenced by multiple factors.[49]

Consultations

An interprofessional approach is crucial for managing CAH. Pediatric endocrinologists oversee hormonal imbalances and glucocorticoid therapy, whereas pediatric surgeons and urologists may address ambiguous genitalia. Gynecologists and fertility specialists manage reproductive health and infertility, and urologists handle genital surgeries and TART-related issues. Adult endocrinologists ensure continuity of care, while radiologists assist with diagnostics and medical geneticists provide genetic counseling. Psychologists support patients with emotional and psychological challenges. Collaborative consultation with these specialists ensures a comprehensive, patient-centered approach to managing CAH.

Deterrence and Patient Education

• Genetic counseling should be offered to children transitioning to adult care, patients diagnosed with nonclassic CAH, and those planning a pregnancy to discuss inheritance patterns and the risk of recurrence in future generations.

• Molecular genetic testing of the fetus (chorionic villous sampling around the 10th week of gestation) and prenatal treatment of mothers with dexamethasone in specific settings are possible interventions.
• Antenatal dexamethasone treatment for a fetus is 46,XX fetus can prevent virilization, but it remains experimental as of now and should only be administered under protocols approved by Institutional Review Boards.[1]

• Newborn screening is crucial for early diagnosis and intervention, preventing life-threatening episodes and improving long-term outcomes.

• Patient and family education on proper treatment, particularly adherence to medical therapy, is critical for individuals with CAH. Both over- and under-treatment with glucocorticoids can significantly impact growth and overall health. As patients get older, it is important for both caregivers and patients to receive counseling on appropriate treatment and when to seek medical care.

• Patients should be advised on how to prevent life-threatening events, such as adrenal crises, which is a crucial approach. They should be made aware that during illness or stress, their need for glucocorticoids increases. Additionally, they must be educated on the technique of IM injections in case oral intake is not possible.

Enhancing Healthcare Team Outcomes

CAH is a relatively rare autosomal recessive disorder that can lead to significant mental and physical morbidity and mortality. Newborn screening is essential for detecting infants with the most common form of CAH, significantly reducing mortality and morbidity associated with delayed diagnosis. Early referral to specialists and centers offering both medical and surgical treatment improves overall outcomes and enhances the quality of life for affected individuals. In addition to medical management by pediatric endocrinologists and surgical care by pediatric urologists, psychologists and social workers have crucial roles in addressing the psychosocial aspects of care. Transition clinics, which include both pediatric and adult specialists, can foster trust and ensure a smooth transition from pediatric to adult care. 

Ethical considerations must be considered when determining treatment options while respecting patient autonomy in decision-making. Caregivers of children diagnosed with CAH should receive comprehensive education on treatment options and potential complications of the condition. Responsibilities within the interprofessional healthcare team must be clearly defined, with each member contributing their specialized knowledge and skills to optimize patient care. Effective communication within the healthcare team fosters a collaborative environment—where information is shared, questions are welcomed, and concerns are addressed promptly.

Lastly, care coordination is essential for ensuring seamless and efficient patient care. Clinicians, advanced practitioners, pharmacists, and other healthcare providers must collaborate to streamline the patient's journey—from diagnosis to treatment and follow-up. This collaboration minimizes errors, reduces delays, and enhances patient safety, ultimately improving outcomes and providing patient-centered care that prioritizes the well-being and satisfaction of individuals affected by CAH.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Nov 01;103(11):4043-4088. [PMC free article: PMC6456929] [PubMed: 30272171]

2.

Gurpinar Tosun B, Guran T. Rare forms of congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2024 Oct;101(4):371-385. [PubMed: 38126084]

3.

Neocleous V, Fanis P, Phylactou LA, Skordis N. Genotype Is Associated to the Degree of Virilization in Patients With Classic Congenital Adrenal Hyperplasia. Front Endocrinol (Lausanne). 2018;9:733. [PMC free article: PMC6286958] [PubMed: 30559721]

4.

Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med. 2020 Sep 24;383(13):1248-1261. [PubMed: 32966723]

5.

Gusmano C, Cannarella R, Crafa A, Barbagallo F, La Vignera S, Condorelli RA, Calogero AE. Congenital adrenal hyperplasia, disorders of sex development, and infertility in patients with POR gene pathogenic variants: a systematic review of the literature. J Endocrinol Invest. 2023 Jan;46(1):1-14. [PMC free article: PMC9829634] [PubMed: 35842891]

6.

Daae E, Feragen KB, Nermoen I, Falhammar H. Psychological adjustment, quality of life, and self-perceptions of reproductive health in males with congenital adrenal hyperplasia: a systematic review. Endocrine. 2018 Oct;62(1):3-13. [PMC free article: PMC6153586] [PubMed: 30128958]

7.

Rama Chandran S, Loh LM. The importance and implications of preconception genetic testing for accurate fetal risk estimation in 21-hydroxylase congenital adrenal hyperplasia (CAH). Gynecol Endocrinol. 2019 Jan;35(1):28-31. [PubMed: 30044156]

8.

Ishii T, Tajima T, Kashimada K, Mukai T, Tanahashi Y, Katsumata N, Kanno J, Hamajima T, Miyako K, Ida S, Hasegawa T. Clinical Features of 57 Patients with Lipoid Congenital Adrenal Hyperplasia: Criteria for Nonclassic Form Revisited. J Clin Endocrinol Metab. 2020 Nov 01;105(11) [PubMed: 32835366]

9.

Miller WL. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):18-37. [PubMed: 26960203]

10.

Guran T, Kara C, Yildiz M, Bitkin EC, Haklar G, Lin JC, Keskin M, Barnard L, Anik A, Catli G, Guven A, Kirel B, Tutunculer F, Onal H, Turan S, Akcay T, Atay Z, Yilmaz GC, Mamadova J, Akbarzade A, Sirikci O, Storbeck KH, Baris T, Chung BC, Bereket A. Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases. J Clin Endocrinol Metab. 2020 Mar 01;105(3) [PubMed: 31950145]

11.

Turcu AF, Auchus RJ. The next 150 years of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2015 Sep;153:63-71. [PMC free article: PMC4568140] [PubMed: 26047556]

12.

Miller WL. MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis. Eur J Endocrinol. 2018 Sep;179(3):R125-R141. [PubMed: 29880708]

13.

Guran T, Buonocore F, Saka N, Ozbek MN, Aycan Z, Bereket A, Bas F, Darcan S, Bideci A, Guven A, Demir K, Akinci A, Buyukinan M, Aydin BK, Turan S, Agladioglu SY, Atay Z, Abali ZY, Tarim O, Catli G, Yuksel B, Akcay T, Yildiz M, Ozen S, Doger E, Demirbilek H, Ucar A, Isik E, Ozhan B, Bolu S, Ozgen IT, Suntharalingham JP, Achermann JC. Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort. J Clin Endocrinol Metab. 2016 Jan;101(1):284-92. [PMC free article: PMC4701852] [PubMed: 26523528]

14.

Zhou Q, Wang D, Wang C, Zheng B, Liu Q, Zhu Z, Jia Z, Gu W. Clinical and Molecular Analysis of Four Patients With 11β-Hydroxylase Deficiency. Front Pediatr. 2020;8:410. [PMC free article: PMC7396487] [PubMed: 32850530]

15.

Yildiz M, Isik E, Abali ZY, Keskin M, Ozbek MN, Bas F, Ucakturk SA, Buyukinan M, Onal H, Kara C, Storbeck KH, Darendeliler F, Cayir A, Unal E, Anik A, Demirbilek H, Cetin T, Dursun F, Catli G, Turan S, Falhammar H, Baris T, Yaman A, Haklar G, Bereket A, Guran T. Clinical and Hormonal Profiles Correlate With Molecular Characteristics in Patients With 11β-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3714-e3724. [PubMed: 33830237]

16.

Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):71-78. [PMC free article: PMC4976049] [PubMed: 26862015]

17.

Maheshwari M, Arya S, Lila AR, Sarathi V, Barnabas R, Rai K, Bhandare VV, Memon SS, Karlekar MP, Patil V, Shah NS, Kunwar A, Bandgar T. 17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature. J Endocr Soc. 2022 Mar 01;6(3):bvac011. [PMC free article: PMC8845120] [PubMed: 35178494]

18.

Zhang J, Woo KL, Hai Y, Wang S, Lin Y, Huang Y, Peng X, Wu H, Zhang S, Yan L, Li Y. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. Front Endocrinol (Lausanne). 2022;13:1020880. [PMC free article: PMC9742467] [PubMed: 36518257]

19.

Kolli V, da Cunha IW, Kim S, Iben JR, Mallappa A, Li T, Gaynor A, Coon SL, Quezado MM, Merke DP. Morphologic and Molecular Characterization of Adrenals and Adrenal Rest Affected by Congenital Adrenal Hyperplasia. Front Endocrinol (Lausanne). 2021;12:730947. [PMC free article: PMC8488225] [PubMed: 34616364]

20.

McNamara ER, Swartz JM, Diamond DA. Initial Management of Disorders of Sex Development in Newborns. Urology. 2017 Mar;101:1-8. [PubMed: 27538800]

21.

Ahmed SF, Achermann JC, Arlt W, Balen A, Conway G, Edwards Z, Elford S, Hughes IA, Izatt L, Krone N, Miles H, O'Toole S, Perry L, Sanders C, Simmonds M, Watt A, Willis D. Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015). Clin Endocrinol (Oxf). 2016 May;84(5):771-88. [PMC free article: PMC4855619] [PubMed: 26270788]

22.

van der Straaten S, Springer A, Zecic A, Hebenstreit D, Tonnhofer U, Gawlik A, Baumert M, Szeliga K, Debulpaep S, Desloovere A, Tack L, Smets K, Wasniewska M, Corica D, Calafiore M, Ljubicic ML, Busch AS, Juul A, Nordenström A, Sigurdsson J, Flück CE, Haamberg T, Graf S, Hannema SE, Wolffenbuttel KP, Hiort O, Ahmed SF, Cools M. The External Genitalia Score (EGS): A European Multicenter Validation Study. J Clin Endocrinol Metab. 2020 Mar 01;105(3) [PubMed: 31665438]

23.

Rushworth RL, Torpy DJ, Stratakis CA, Falhammar H. Adrenal Crises in Children: Perspectives and Research Directions. Horm Res Paediatr. 2018;89(5):341-351. [PubMed: 29874655]

24.

Walia R, Singla M, Vaiphei K, Kumar S, Bhansali A. Disorders of sex development: a study of 194 cases. Endocr Connect. 2018 Feb;7(2):364-371. [PMC free article: PMC5825923] [PubMed: 29386228]

25.

Held PK, Bialk ER, Lasarev MR, Allen DB. 21-Deoxycortisol is a Key Screening Marker for 21-Hydroxylase Deficiency. J Pediatr. 2022 Mar;242:213-219.e1. [PubMed: 34780778]

26.

Nour MA, Gill H, Mondal P, Inman M, Urmson K. Perioperative care of congenital adrenal hyperplasia - a disparity of physician practices in Canada. Int J Pediatr Endocrinol. 2018;2018:8. [PMC free article: PMC6131860] [PubMed: 30214458]

27.

El-Maouche D, Hargreaves CJ, Sinaii N, Mallappa A, Veeraraghavan P, Merke DP. Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2018 Jun 01;103(6):2336-2345. [PMC free article: PMC6276663] [PubMed: 29584889]

28.

Yanase T, Tajima T, Katabami T, Iwasaki Y, Tanahashi Y, Sugawara A, Hasegawa T, Mune T, Oki Y, Nakagawa Y, Miyamura N, Shimizu C, Otsuki M, Nomura M, Akehi Y, Tanabe M, Kasayama S. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J. 2016 Sep 30;63(9):765-784. [PubMed: 27350721]

29.

Chen S, Wu L, Ma X, Guo L, Zhang J, Gao H, Zhang T. Current status and prospects of congenital adrenal hyperplasia: A bibliometric and visualization study. Medicine (Baltimore). 2024 Nov 08;103(45):e40297. [PMC free article: PMC11557083] [PubMed: 39533614]

30.

Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Lindén Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2063-e2077. [PMC free article: PMC8063257] [PubMed: 33527139]

31.

Nella AA, Mallappa A, Perritt AF, Gounden V, Kumar P, Sinaii N, Daley LA, Ling A, Liu CY, Soldin SJ, Merke DP. A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2016 Dec;101(12):4690-4698. [PMC free article: PMC5155681] [PubMed: 27680873]

32.

El-Maouche D, Merke DP, Vogiatzi MG, Chang AY, Turcu AF, Joyal EG, Lin VH, Weintraub L, Plaunt MR, Mohideen P, Auchus RJ. A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2020 Aug 01;105(8):2771-8. [PMC free article: PMC7331874] [PubMed: 32589738]

33.

Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Aug;99(8):2763-70. [PMC free article: PMC4121028] [PubMed: 24780050]

34.

Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH., CAHtalyst Adult Trial Investigators. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024 Aug 08;391(6):504-514. [PMC free article: PMC11309900] [PubMed: 38828955]

35.

Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ, Clemente M, Fechner PY, Vogiatzi MG, Speiser PW, Auchus RJ, Rosales GBG, Roberts E, Jeha GS, Farber RH, Chan JL., CAHtalyst Pediatric Trial Investigators. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med. 2024 Aug 08;391(6):493-503. [PubMed: 38828945]

36.

Newfield RS, Sarafoglou K, Fechner PY, Nokoff NJ, Auchus RJ, Vogiatzi MG, Jeha GS, Giri N, Roberts E, Sturgeon J, Chan JL, Farber RH. Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2023 Oct 18;108(11):2871-2878. [PMC free article: PMC10583973] [PubMed: 37216921]

37.

Sarafoglou K, Auchus RJ. Future Directions in the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2025 Jan 21;110(Supplement_1):S74-S87. [PMC free article: PMC11749912] [PubMed: 39836617]

38.

Oostdijk W, Idkowiak J, Mueller JW, House PJ, Taylor AE, O'Reilly MW, Hughes BA, de Vries MC, Kant SG, Santen GW, Verkerk AJ, Uitterlinden AG, Wit JM, Losekoot M, Arlt W. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. J Clin Endocrinol Metab. 2015 Apr;100(4):E672-80. [PMC free article: PMC4399300] [PubMed: 25594860]

39.

Lavery GG, Walker EA, Tiganescu A, Ride JP, Shackleton CH, Tomlinson JW, Connell JM, Ray DW, Biason-Lauber A, Malunowicz EM, Arlt W, Stewart PM. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. J Clin Endocrinol Metab. 2008 Oct;93(10):3827-32. [PMC free article: PMC2579651] [PubMed: 18628520]

40.

Erginel B, Ozdemir B, Karadeniz M, Poyrazoglu S, Keskin E, Soysal FG. Long-term 10-year comparison of girls with congenital adrenal hyperplasia who underwent early and late feminizing genitoplasty. Pediatr Surg Int. 2023 Jun 29;39(1):222. [PubMed: 37386261]

41.

Almasri J, Zaiem F, Rodriguez-Gutierrez R, Tamhane SU, Iqbal AM, Prokop LJ, Speiser PW, Baskin LS, Bancos I, Murad MH. Genital Reconstructive Surgery in Females With Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2018 Nov 01;103(11):4089-4096. [PubMed: 30272250]

42.

Krege S, Falhammar H, Lax H, Roehle R, Claahsen-van der Grinten H, Kortmann B, Duranteau L, Nordenskjöld A., dsd-LIFE group. Long-Term Results of Surgical Treatment and Patient-Reported Outcomes in Congenital Adrenal Hyperplasia-A Multicenter European Registry Study. J Clin Med. 2022 Aug 08;11(15) [PMC free article: PMC9369813] [PubMed: 35956243]

43.

Falhammar H, Holmdahl G, Nyström HF, Nordenström A, Hagenfeldt K, Nordenskjöld A. Women's response regarding timing of genital surgery in congenital adrenal hyperplasia. Endocrine. 2025 Feb;87(2):830-835. [PMC free article: PMC11811264] [PubMed: 39422838]

44.

Lee PA, Fuqua JS, Houk CP, Kogan BA, Mazur T, Caldamone A. Individualized care for patients with intersex (disorders/differences of sex development): part I. J Pediatr Urol. 2020 Apr;16(2):230-237. [PubMed: 32249189]

45.

Pofi R, Ji X, Krone NP, Tomlinson JW. Long-term health consequences of congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2024 Oct;101(4):318-331. [PubMed: 37680029]

46.

Bachelot A, Grouthier V, Courtillot C, Dulon J, Touraine P. MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment. Eur J Endocrinol. 2017 Apr;176(4):R167-R181. [PubMed: 28115464]

47.

King TF, Lee MC, Williamson EE, Conway GS. Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clin Endocrinol (Oxf). 2016 Jun;84(6):830-6. [PubMed: 26666213]

48.

Wiromrat P, Raruenrom Y, Namphaisan P, Wongsurawat N, Panamonta O, Pongchaiyakul C. Prednisolone impairs trabecular bone score changes in adolescents with 21-hydroxylase deficiency. Clin Exp Pediatr. 2024 Nov 13; [PubMed: 39533718]

49.

Lind-Holst M, Hansen D, Main KM, Juul A, Andersen MS, Dunø M, Rasmussen ÅK, Jørgensen N, Gravholt CH, Berglund A. Delineating the psychiatric morbidity spectrum in congenital adrenal hyperplasia: a population-based registry study. J Clin Endocrinol Metab. 2024 Nov 15; [PubMed: 39545512]

50.

Rangaswamaiah S, Gangathimmaiah V, Nordenstrom A, Falhammar H. Bone Mineral Density in Adults With Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2020;11:493. [PMC free article: PMC7438951] [PubMed: 32903805]

51.

Tamhane S, Rodriguez-Gutierrez R, Iqbal AM, Prokop LJ, Bancos I, Speiser PW, Murad MH. Cardiovascular and Metabolic Outcomes in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2018 Nov 01;103(11):4097-4103. [PubMed: 30272185]

52.

Kim JH, Choi S, Lee YA, Lee J, Kim SG. Epidemiology and Long-Term Adverse Outcomes in Korean Patients with Congenital Adrenal Hyperplasia: A Nationwide Study. Endocrinol Metab (Seoul). 2022 Feb;37(1):138-147. [PMC free article: PMC8901972] [PubMed: 35255606]

Disclosure: Lokesh Sharma declares no relevant financial relationships with ineligible companies.

Disclosure: Ifeanyi Momodu declares no relevant financial relationships with ineligible companies.

Disclosure: Gurdeep Singh declares no relevant financial relationships with ineligible companies.