Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Clinical manifestations depend on the specific enzyme affected. Notably, CAH is the most common cause of ambiguous genitalia in genotypic female individuals. All forms of CAH cause low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH), and adrenal hyperplasia. Laboratory studies help confirm the diagnosis. Lifelong glucocorticoid replacement is needed, and surgical correction of ambiguous genitalia is often performed.

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Epidemiology and Genetics

Epidemiology

  • Most common cause of 46,XX genotypic female individuals with ambiguous or undetermined genitalia
  • Incidence of classical congenital adrenal hyperplasia (CAH) worldwide: 1 in 15,000 live births
  • Genetic predisposition varies depending on ethnicity and geographic location.
  • Classical CAH predisposition:
    • In the United States, prevalence greater for whites (1 in 15,000 live births) than African Americans (1 in 42,000 live births)
    • Yupik in Alaska: 1 in 280 live births
    • White Europeans: 1 in 5,000–23,0000 live births
  • Non-classical CAH predisposition
    • Whites: 1 in 100–1,000 live births
    • ↑ Prevalence amongst Ashkenazi Jews, Mediterraneans, and Hispanics

Genetics

Congenital adrenal hyperplasia comprises a spectrum of disorders in which different gene mutations cause different enzyme deficiencies affecting steroid biogenesis, which is carried out by the adrenal glands.

  • Inheritance pattern: autosomal recessive for all types
  • 21-hydroxylase deficiency
    • Caused by mutations in the CYP21A2 gene
    • Most common cause of CAH (> 90% of cases)
    • Severity of mutation and resulting 21-hydroxylase function or lack thereof causes 2 different clinical forms of the disorder:
      • Classical CAH (severe)
      • Non-classical CAH (milder, more common)
  • 11β-hydroxylase deficiency
    • Caused by mutations in CYP11B1 gene
    • Causes up to 5% of cases
  • 17α-hydroxylase deficiency: caused by mutations in CYP17A1 gene
  • P450 oxidoreductase deficiency (PORD): caused by mutations in POR gene
  • 3β-hydroxysteroid-dehydrogenase (3BHSD): caused by mutations in HSD3B2 gene
  • Aldosterone synthase deficiency: caused by mutations in CYP11B2 gene
  • Steroidogenic acute regulatory protein (StAR) deficiency: caused by mutations in STAR gene

Pathophysiology

Normal adrenal hormone synthesis

  • The adrenal cortex, which is made up of 3 layers, is the major site of steroid synthesis.
    • Zona glomerulosa (outer layer): site of synthesis of the mineralocorticoid aldosterone
    • Zona fasciculata (middle layer): site of synthesis of the glucocorticoids, including cortisol
    • Zona reticularis (inner layer): site of adrenal androgen synthesis, including dehydroepiandrosterone (DHEA)
  • Adrenocorticotropic hormone (ACTH) is secreted by the anterior pituitary.
  • ACTH stimulates the adrenal cortex (zona fasciculata) to produce cholesterol.
  • Cholesterol is converted into pregnenolone.
  • Pregnenolone is a substrate for both the mineralocorticoids and glucocorticoids pathways, which produce aldosterone and cortisol, respectively.
    • Aldosterone helps regulate salt and water levels in the body by increasing sodium reabsorption and potassium excretion through the urine.
    • Cortisol affects energy levels, blood pressure levels, blood sugar levels, and the body’s response to stress, illness, and injury.
  • Metabolic intermediates from these 2 pathways are also used as substrates for the androgen pathway in the production of testosterone.

Impaired hormone synthesis in CAH

  • Deficient enzymes in steroidogenesis pathway cause: 
    • Low levels of cortisol
    • Low levels of aldosterone
    • Overproduction of androgens such as testosterone
  • Low levels of cortisol produce a lack of negative feedback to the pituitary, which then excessively secretes ACTH.
  • This secretion results in adrenal hyperplasia and increased synthesis of adrenal precursor steroids.

21-hydroxylase deficiency

  • 2 subforms:
    • Salt wasting (approximately 75% of cases): no enzyme activity
    • Simple virilizing/non-salt wasting (approximately 25% of cases): very low, but detectable enzyme activity allowing for some aldosterone production
  • Causes inability to convert 17-hydroxyprogesterone to 11-deoxycortisol
  • Only affects adrenal steroidogenesis
  • Does not affect gonadal/sex hormone synthesis
  • Cortisol is not or only partially produced.
  • Result is a deficiency of cortisol and aldosterone with an accumulation of intermediate products that are used for androgenic synthesis.
21-hydroxylase deficiency

21-hydroxylase deficiency: diagram of the pathophysiology of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Image by Lecturio.

11β-hydroxylase deficiency

  • Enzyme mediates the final step of cortisol synthesis.
  • Impairs ability to convert 11-deoxycorticosterone (DOC) and 11-deoxycortisol to corticosterone and cortisol, respectively
  • Only affects adrenal steroidogenesis
  • No effects on gonadal hormone synthesis
  • DOC has aldosterone-like activity and in increased amounts inhibits renin and aldosterone production.
  • Results in deficiency of cortisol and aldosterone but an excess of androgens and mineralcorticoids (DOC)
11β-hydroxylase deficiency

11β-hydroxylase deficiency: diagram of the pathophysiology of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Image by Lecturio.

17α-hydroxylase deficiency

  • Rare
  • Inhibits metabolization of pregnenolone, progesterone, and their 17-hydroxy derivatives, thereby limiting steroidogenesis to only progesterone, DOC, corticosterone, and 18-oxygenated derivatives
  • Affects adrenal (cortisol and aldosterone) synthesis and gonadal (sex hormone) synthesis, resulting in decreased synthesis of both cortisol and sex steroids
  • Increase in DOC production results in a decrease in renin and aldosterone production.
17α-hydroxylase deficiency

17α-hydroxylase deficiency: diagram of the pathophysiology of congenital adrenal hyperplasia due to 17α-hydroxylase deficiency

Image by Lecturio.

P450 oxidoreductase deficiency

  • Rare
  • Abnormal electron transport causes deficiency and decreased function of 21-hydroxylase, 17α-hydroxylase, and aromatase enzymes.
  • Increased androgens before birth
  • Decreased androgens after birth
  • Decreased glucocorticoids
  • Equivocal mineralcorticoids
  • Impairs production of cholesterol and normal bone formation

3β-hydroxysteroid dehydrogenase deficiency

  • Very rare
  • Impairs synthesis of all active steroids
  • Affects adrenal (cortisol) synthesis and gonadal (sex hormone) synthesis
  • Results in higher levels of 17α-hydroxypregnenolone, which stimulates adrenal corticosteroid synthesis
3β-hydroxysteroid dehydrogenase deficiency (3BHSD)

3β-hydroxysteroid dehydrogenase deficiency: diagram of the pathophysiology of congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency

Image by Lecturio.

Aldosterone synthase deficiency

  • Very rare
  • Enzyme is involved in the final 3 steps of aldosterone synthesis.
  • Deficiency results in decreased or no aldosterone synthesis.
  • ↑ Sodium excretion and potassium retention

Steroidogenic acute regulatory protein deficiency

  • Rarest and most severe form of CAH
  • Also known as congenital lipoid adrenal hyperplasia
  • StAR is responsible for the transport of free cholesterol from outside to inside the mitochondrial membrane.
  • Deficiency impairs the 1st step in initiating steroid synthesis (conversion of cholesterol to pregnenolone).
  • Affects adrenal (cortisol) synthesis and gonadal (sex hormone) synthesis
Table: Enzyme deficiencies
Enzyme deficiencyGene mutatedCortisolAldosterone11-deoxycorticosteroneAndrogens
21-hydroxylaseCYP21A2DecreasedDecreasedDecreasedIncreased
11β-hydroxylaseCYP11B1Increased
17α-hydroxylaseCYP17A1Decreased
3BHSDHSD3B2Decreased

Clinical Presentation

General clinical features

  • Hypoglycemia 
  • Failure to thrive 
  • Hyperpigmentation in areas not exposed to sunlight

21-hydroxylase deficiency

There is a classic form of CAH due to 21-hydroxylase deficiency and a non-classic form. The classic form has 2 different types: simple virilizing and salt wasting.

Classical CAH is the most severe form of 21-hydroxylase deficiency.

  • Presents in neonatal period/infancy
  • Ambiguous genitalia/pseudohermaphroditism noted at birth in girls
    • Virilzation of female external genitalia
    • Clitoromegaly
    • Labioscrotal fusion
    • Urogenital sinus
  • Normal external genitalia in genotypic boys but may have hyperpigmentation of the scrotum and/or increased penile size
  • Boys with salt-wasting type often become symptomatic at 7–14 days of life. 
    • Failure to thrive
    • Severe dehydration
    • Hyponatremia
    • Hyperkalemia
    • Salt-wasting crisis (adrenal crisis) may occur:
      • Vomiting
      • Diarrhea
      • Hypotension
      • Hypoglycemia
      • Metabolic acidosis
      • Hypovolemic shock
  • Boys with simple virilizing form often present with symptoms at 2–4 years of age with early virilization (pubic hair, growth spurt, adult body odor).
  • Precocious puberty (premature onset of puberty occurs < 8 years of age in girls and < 9 years of age in boys)
  • Infertility in both genders
  • Adrenal rest tumors (mostly testicular, rarely ovarian)
    • Noted in childhood or adolescence
    • Present as testicular masses with adrenal-like tissue
    • Typically bilateral
    • Increases likelihood of infertility
    • More common in those with salt-wasting type versus simple virilizing type

Nonclassic CAH is the milder, more common form of 21-hydroxylase deficiency.

  • Onset of symptoms occurs during late childhood, adolescence, or adulthood
  • Normal genitalia at birth
  • Precocious puberty
  • Accelerated bone age
  • Irregular menstrual cycles
  • Hirsutism
  • Acne
  • Possible fertility issues
  • Post-pubertal boys typically asymptomatic
Ambiguous genitalia caused by congenital adrenal hyperplasia

Appearance of ambiguous genitalia in a patient with congenital adrenal hyperplasia

Image: “A rare combination: congenital adrenal hyperplasia due to 21 hydroxylase deficiency and Turner syndrome” by Kendirci HN, Aycan Z, Çetinkaya S, Baş VN, Ağladıoğlu SY, Önder A. License: CC BY 2.5

11β-hydroxylase deficiency

  • Ambiguous genitalia noted at birth in girls
  • Normal external genitalia in genotypic boys but may have increased penile size
  • Hypertension (due to mineralocorticoid DOC accumulation)
  • Hypokalemia
  • Premature adrenarche (axillary and pubic hair development and body odor)
  • Accelerated growth and bone age
  • Precocious pseudopuberty
  • Acne in men
  • Hirsutism and irregular menstrual cycles in women
  • Vulnerable to adrenal crisis
  • Boys may have adrenal rest tumors.

17α-hydroxylase deficiency

  • Genotypic female individuals with normal female external genitalia
  • Genotypic male individuals with pseudohermaphroditism
    • Female external genitalia with blind-ending vagina 
    • Intra-abdominal testes present
  • Primary amenorrhea
  • Delayed puberty or failure to develop secondary sexual characteristics seen in both genders
  • Hypertension
  • Hypokalemia

P450 oxidoreductase deficiency

  • Mild maternal virilization during pregnancy
  • Undervirilization of genitalia in boys 
  • Hypospadias
  • Virilized/ambiguous genitalia in girls
  • Cystic ovaries
  • Pattern of craniofacial and limb abnormalities (Antley-Bixler syndrome)
  • Vulnerable to adrenal crisis

3β-hydroxysteroid dehydrogenase deficiency

  • Salt wasting in infancy
  • Ambiguous genitalia in both boy and girls 
    • Virilization in girls
    • Undervirilization in boys
  • Hypotension
  • Hyperkalemia
  • Girls may have precocious puberty, hirsutism, acne, and menstrual irregularities
  • Fertility may be impaired.

Aldosterone synthase deficiency

  • Salt wasting in infancy
  • Normal external genitalia in both sexes
  • Hyponatremia
  • Stress-induced hyperkalemia
  • Metabolic acidosis
  • Postural hypotension in adults

Steroidogenic acute regulatory protein deficiency

  • Severe adrenal insufficiency/crisis in infancy
    • Vomiting
    • Diarrhea
    • Volume depletion/dehydration
    • Hyponatremia
    • Hyperkalemia
  • All are phenotypically female individuals.
  • Boys (46,XY karyotype) have female external genitalia (male pseudohermaphroditism).
  • Girls have normal-appearing genitalia.
  • Girls may have impaired pubertal development.

Diagnosis

  • History and clinical examination
    • Suspicion raised by the appearance of ambiguous genitalia at birth
    • Salt-wasting crisis
  • Newborn screening: In the United States, every infant is screened for 21-hydroxylase deficiency by the detection of elevated levels of 17α-hydroxyprogesterone.
  • Postnatal diagnosis: 
    • Electrolyte abnormalities
    • Hormone analysis 
      • Hypocortisolism (seen in all types of CAH)
      • Increase in specific steroid precursors in blood/urine (according to type of CAH; see table below)
    • Cosyntropin (ACTH) stimulation test: gold standard to diagnose all forms of CAH
    • Magnetic resonance imaging (MRI) or ultrasound of genitalia to look for Müllerian duct malformations
    • Adrenal ultrasound may show bilateral enlarged adrenal glands.
    • Genetic testing is considered if diagnosis is still uncertain and hormonal analysis is equivocal, or for purposes of genetic counseling.

The following table outlines important findings in the 3 most common types of CAH.

Table: Important findings in the 3 most common types of CAH
Type of CAHSteroids/precursorsElectrolytes
21-hydroxylase
  • ↑↑ 17-hydroxyprogesterone
  • ↓ DOC and corticosterone
  • Hyponatremia
  • Hyperkalemia
  • Metabolic acidosis
11β-hydroxylase
  • ↑ 17-hydroxyprogesterone
  • ↑ 11-deoxycortisol and DOC
  • ↓ Corticosterone
  • ↓ Cortisol and aldosterone
  • ↑ Sndrogens
  • Hypernatremia
  • Hypokalemia
  • Metabolic alkalosis
17α-hydroxylase
  • ↓ 17-hydroxyprogesterone
  • ↑ Progesterone
  • ↑ DOC and corticosterone
  • ↓ Cortisol, aldosterone, renin
  • ↓ Androgens and estrogens

Management

Prenatal prevention

  • Dexamethasone during pregnancy can prohibit the virilization of an affected child.
  • Intake is stopped upon proof of male gender or exclusion of CAH.

General management

The general treatment goals are to mitigate the effects of respective steroid deficiencies and excessive amounts of steroids and to aid secondary sexual development.

  • Often require lifelong glucocorticoid (hydrocortisone) replacement therapy
  • Extra steroids may be needed when sick or hospitalized.
  • Genital reconstruction surgery may be considered in children with ambiguous genitalia according to gender identity.
  • Genetic counseling

21-hydroxylase deficiency

  • Lifelong fludrocortisone therapy to substitute aldosterone
  • High-salt diet and/or sodium chloride supplements
  • Glucocorticoid therapy and/or surgery for adrenal rest tumors
  • Glucocorticoid therapy may also help with infertility and gonadal dysfunction.

11β-hydroxylase deficiency

  • Children typically treated only with glucocorticoid (hydrocortisone) to lower ACTH secretion
  • Spironolactone (blocks mineralocorticoid receptors) may be added in women to treat hypertension, hypokalemia, and androgen excess.
  • Spironolactone should be avoided in male individuals as it can cause gynecomastia and sexual dysfunction; alternatives are eplerenone or triamterene.
  • Low-sodium diet

17α-hydroxylase deficiency

  • Spironolactone may be used in women to block mineralocorticoid receptors.
  • Low-sodium diet
  • Estrogen replacement therapy in early puberty for girls
  • Testosterone replacement may be given to boys.

P450 oxidoreductase deficiency

  • Management depends on degree of glucocorticoid deficiency and degree of cortisol response to ACTH.
  • Ranges from no need for glucocorticoids to lifelong replacement with hydrocortisone
  • Appropriate sex hormone replacement therapy at pubertal age
  • Spironolactone/eplerenone to treat hypertension if needed
  • Surgery may be needed for craniofacial and limb abnormalities.

3β-hydroxysteroid-dehydrogenase

  • Glucocorticoid replacement therapy with hydrocortisone
  • Mineralocorticoid replacement therapy with fludrocortisone
  • Appropriate sex hormone replacement therapy at pubertal age

Aldosterone synthase deficiency

  • Fludrocortisone therapy to substitute aldosterone
  • Low-sodium diet
  • Clinical severity improves with age; adults may not need replacement therapy.

StAR deficiency

  • Approximately 2⁄3 of infants with classical (complete) form of this condition die during infancy.
  • Glucocorticoid and mineralocorticoid replacement needed for survivors
  • Estrogen replacement therapy in puberty to induce secondary sexual characteristics

Differential Diagnosis

  • Androgen insensitivity syndrome: an X-linked recessive condition affecting individuals with a 46,XY karyotype in which the function of androgen receptors is impaired, with resulting resistance to testosterone. Phenotypes vary and include phenotypic female, virilized female, undervirilized male, or phenotypic male individuals. Hormonal analysis, imaging, and genetic testing help make the diagnosis. Management varies depending on the degree of androgen sensitivity and gender identity, and may involve hormone replacement and surgery.
  • Steroid 5-alpha reductase deficiency: an autosomal recessive genetic condition affecting individuals with a 46,XY karyotype. External genitalia most often appear female, but may also appear male or ambiguous. Affected individuals have testes and normal testosterone production. However, there is impairment in the ability to convert testosterone to dihydrotestosterone (DHT), causing undervirilization. Hormonal and genetic testing help make the diagnosis. Management depends on phenotype and gender identity and may involve hormone replacement and surgery.
  • Polycystic ovarian syndrome: a common ovarian disorder affecting women associated with excess androgens and difficulty conceiving. Individuals are born with normal female genitalia and may develop irregular menstrual cycles, hirsutism, and acne. Laboratories and pelvic ultrasound aid in diagnosis. Treatment involves lifestyle changes and medications such as oral contraceptives, metformin, and spironolactone to manage symptoms.

References

  1. Podgórski R, Aebisher D, Stompor M, Podgórska D, Mazur A. (2018). Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods. Acta Biochim Pol. 65(1):25-33. Epub 2018 Mar 15. PMID: 29543924. https://doi.org/10.18388/abp.2017_2343
  2. White, P.C., & Speiser, P.W. (2000). Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. Endocrine Reviews. 21(3): 245–291. https://doi.org/10.1210/edrv.21.3.0398
  3. Hui, E., Yeung, M.C., Cheung, P.T. et al. (2014). The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene. BMC Endocr Disord 14 (29). https://doi.org/10.1186/1472-6823-14-29
  4. Merke, D. P. (2020). Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
  5. Nieman, L. K. (2020). Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2021, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
  6. Merke, D.P. & Auchus, R.J. (2020). Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency-in-infants-and-children
  7. Hannah-Shmouni, F., Morissette, R., Sinali, N., et al. (2017). Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med.  19(11): 1276–1279. doi: 10.1038/gim.2017.46
  8. Auchus, R. J. (2020). Uncommon congenital adrenal hyperplasias. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/uncommon-congenital-adrenal-hyperplasias
  9. Chan, Y. & Levitsky, L.L. (2020). Causes of differences of sex development. UpToDate. Retrieved January 22, 2021, from https://www.uptodate.com/contents/causes-of-differences-of-sex-development

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