Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia 

Congenital Adrenal Hyperplasia is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones

CAH is a mitochindrial disease.

CAH effects the adrenal glands located at the top of each kidney.

Congenital adrenal hyperplasia (CAH) is a spectrum of disorders resulting from a deficiency or complete lack of one of the enzymes in the cortisol synthesis pathway.

These autosomal recessive genetic disorders are usually characterized by cortisol deficiency and virilization, with or without salt wasting.

Synonyms

  • CAH
  • 21-Hydroxylase deficiency (mutations/deletions in CYP21A2)
  • 11β-Hydroxylase deficiency
  • 3β-Hydroxysteroid dehydrogenase deficiency17a-Hydroxylase/17, 20 lyase deficiency
  • p450 Oxidoreductase deficiency
  • Steroidogenic acute regulatory protein (StAR) deficiency (Lipoid CAH)
  • Adrenal virilism
  • Adrenogenital syndrome
  • Virilizing adrenal hyperplasia

Subtypes of Congenital Adrenal Hyperplasia

  1. Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  2. Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
  3. Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
  4. Classic congenital lipoid adrenal hyperplasia due to STAR deficency
  5. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency
  6. Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
  7. Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency
  8. Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
  9. Congenital lipoid adrenal hyperplasia due to STAR deficency
    Non-classic congenital lipoid adrenal hyperplasia due to STAR deficency

Epidemiology & Demographics

  • •Approximately 95% of cases of CAH are caused by 21-hydroxylase deficiency, of which 75% are the salt-wasting form. The below table summarizes genotype-phenotype correlations in CAH owing to 21-hydroxylase deficiency.
  • •The newborn screen uses serum 17-hydroxyprogesterone assays to screen for CAH due to 21-hydroxylase deficiency. Screening a second sample later improves sensitivity and positive predictive value.
  • •Autosomal recessive inheritance.
  • •The “classic” form presents with more severe symptoms of hyperandrogenism and consists of salt-wasting and non–salt-wasting simple virilizing types, and the “nonclassic” form is the mild, late-onset non–salt-wasting form.
  • •Worldwide incidence of the classic form ranges from 1:14,000 to 1:18,000 live births, and the incidence of the nonclassic form ranges from 1:500 to 1:1000. Increased prevalence exists in small, genetically isolated groups.
  • •Most common cause of ambiguous genitalia in 46,XX individuals.

Genotype-Phenotype Correlations in Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

Adapted from Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

SeverityClassic salt wastingClassic simple virilizingNonclassic
21-Hydroxylase enzyme activity (% normal)01-220-50
CYP21A2 mutations (phenotype generally corresponds to the least affected allele)Gene deletionMutation in Intron 2Exon 3 del 8 bp
Exon 6 cluster
Q318X
R356W
I172NMutation in Intron 2P30LV281L
P453S
Aldosterone synthesisLowNormalNormal
Age at diagnosis (without newborn screening)InfancyInfancy (46,XX individuals)Childhood (46,XY individuals)Childhood to adulthood, or asymptomatic
VirilizationSevereModerate to severeNone to mild

Symptoms of CAH

Very Common Symptoms

  • Abnormality of metabolism/homeostasis 
  • Accelerated skeletal maturation 
  • Cryptorchidism 
  • Female pseudohermaphroditism 
  • Hypercortisolism 
  • Hypertension 
  • Hypospadias 

Common Symptoms

  • Failure to thrive in infancy 
  • Feeding difficulties in infancy 

Clinical Presentation

“Classic” salt-wasting form (impaired cortisol and aldosterone synthesis):

  • •Adrenal crisis in first wks of life with poor feeding, vomiting, weight loss or poor weight gain, lethargy, dehydration, hyponatremia, hyperkalemia, elevated plasma renin activity, and potentially fatal hypovolemia and shock if untreated or not diagnosed by newborn screen.
  • •46,XX infants are born with ambiguous genitalia, which often leads to diagnosis before adrenal crisis occurs.
  • •Males may have greater penile size and smaller testes during childhood, making early diagnosis more difficult based on physical exam.
  • •Males may develop ectopic islands of adrenal cortical tissue in the testes, or testicular adrenal rest tumors (TART), as early as adolescence, which can cause infertility and gonadal dysfunction. TARTs are located in the rete testis and are bilateral in 80% of cases.
  • •Untreated children and adolescents with open growth plates and high androgen concentrations for age may exhibit rapid linear growth in childhood and accompanying early epiphyseal closure resulting in short stature in adulthood.
  • •Precocious puberty is common in both males and females.

“Classic” simple virilizing form:

  • •46,XX individuals present with ambiguous genitalia at birth.
  • •The normal appearance of male genitalia in the simple virilizing form makes this a difficult diagnosis in 46,XY infants.
  • •Characterized by precocious puberty, short stature, and TART.

“Nonclassic” or mild, late-onset form (varying degrees of androgen excess):

  • •Usually presents in adolescence or adulthood and is not detected on newborn screening
  • •Often asymptomatic but can be associated with mild virilization
  • •PCOS-like symptoms occur in women (hirsutism, oligomenorrhea, acne, infertility, insulin resistance, and abnormal menses)
  • •Associated with infertility in males

Etiology

In 21-hydroxylase deficiency, the pathways for aldosterone synthesis (from the conversion of progesterone to deoxycorticosterone) and cortisol synthesis (from the conversion of 17-hydroxyprogesterone to 11-deoxycortisol) by the cP450 enzyme 21-hydroxylase are interrupted. The production of ACTH is thus stimulated by negative feedback, leading to adrenal hyperplasia. The steroid precursors are shunted to the androgen biosynthesis pathway. Biallelic loss-of-function mutations and/or deletions in CYP21A2 cause 21-hydroxylase deficiency. Importantly, there is a pseudogene, and gene recombination events are a common cause of loss of function, and therefore interpretation of genetic results requires specific expertise.

Differential Diagnosis

  • •Precocious puberty
  • •Polycystic ovarian syndrome (PCOS)
  • •Androgen resistance syndromes
  • •Mixed gonadal dysgenesis
  • •Testicular carcinoma
  • •Leydig cell tumors
  • •Adrenocortical carcinoma
  • •Addison disease
  • •Adrenal hypoplasia

Laboratory Tests

  • •Prenatal: Chorionic villus sampling (CVS) or amniocentesis with genetic testing, especially with known family history. Cell-free fetal DNA (cffDNA) testing may be discordant with results on anatomy ultrasound, prompting further evaluation/prenatal counseling.
  • •Serum 17-hydroxyprogesterone concentration, which is included in the newborn screen in all states, is the first-line test for suspected CAH. A positive newborn screen should be followed by a confirmatory serum 17-hydroxyprogesterone concentration and serum electrolytes.
  • •Adrenocorticotropin (ACTH) stimulation test is the next step to confirm the diagnosis if the serum 17-hydroxyprogesterone is not diagnostic of classic, salt-wasting CAH and to differentiate 21-hydroxylase deficiency from other enzyme defects.
  • •Additional tests that may be useful include plasma renin activity, aldosterone, ACTH, and electrolytes.

Imaging Studies

  • •Adults with classic CAH do not warrant routine adrenal imaging. Evaluation of adrenal glands should be reserved for individuals with poor disease control, lack of response to intensified treatment, or prolonged lapse in treatment.
  • •Ultrasound to identify a uterus in cases of newborn individuals with ambiguous genitalia.
  • •Periodic ultrasounds to evaluate males for TART should be initiated in adolescence.

 Treatment

Pharmacologic Therapy

  • •Treatment of classic CAH (salt-wasting and simple virilizing):
    • 1.Daily glucocorticoids to replace deficient cortisol and to partially suppress adrenal androgen secretion.
      • a.In children, hydrocortisone (10-15 mg/m2/day PO divided tid) is preferred because of its short half-life, which decreases the risk of iatrogenic short stature.
      • b.Adolescents and adults: Hydrocortisone (15-25 mg/day PO divided tid) remains the preferred treatment. Longer-acting glucocorticoids can be utilized, including prednisolone (4 to 6 mg/day divided bid) or dexamethasone (0.25 to 0.5 mg once a day).
    • 2.During periods of physiologic stress glucocorticoid supplementation needs to be increased (stress dosing). All patients with CAH who are on daily glucocorticoids require oral or parental stress dosing with fever >38.5o C, vomiting, general anesthesia, or major trauma (30-50 mg/m2/day of hydrocortisone divided every 6 hr).
      • a.Every patient with classic CAH should have a glucocorticoid injection kit and be provided education on parenteral administration.
      • bStress doses of parenteral hydrocortisone: Infants/preschool children 25 mg, school-age children 50 mg, and adults 100 mg administered every 6 hr.
    • 3.Mineralocorticoids (fludrocortisone 0.05-0.2 mg/day) to replace aldosterone deficiency and normalize electrolytes and decrease plasma renin activity.
      • a.Infants require sodium chloride supplementation.
    • 4.Additional pharmacologic therapy information and adjuncts:
      • a.Oral contraceptive pills (OCP) containing drospirenone may serve as an adjunct for treatment of clinical and biochemical hyperandrogenism in women (OCPs alone cannot replace treatment with glucocorticoids or mineralocorticoids if required).
      • b.Spironolactone is contraindicated as an androgen antagonist in classic salt-wasting CAH due to mineralocorticoid antagonism.
      • cNewer medications are currently under development.
  • •Treatment of nonclassic form:
    • 1.Nonpregnant individuals with asymptomatic nonclassic CAH do not warrant therapy.
    • 2.Glucocorticoid treatment is recommended for children with rapid progression of pubarche and bone age and/or adolescents with overt virilization. Individuals requiring daily glucocorticoids also warrant stress-dose precautions and parenteral administration education.
    • 3.In most adult males, no treatment is necessary unless they have TARTs or infertility.
    • 4.In adult women who have patient-important hyperandrogenism or infertility glucocorticoid treatment is recommended.
      • a.OCP containing drospirenone may be utilized alone for treatment of clinical and biochemical hyperandrogenism in women, if desired.
  • •Management of classic and nonclassic CAH during pregnancy.
    • 1.Avoid using glucocorticoids that traverse the placenta, including dexamethasone.
    • 2.Women should be evaluated for increases in glucocorticoid therapy during the second and third trimester and administration of stress doses of glucocorticoids during labor and delivery.

Nonpharmacologic Therapy

  • •Parents and patients should be informed about surgical options. Surgical correction of ambiguous genitalia is controversial, especially clitoroplasty. Vaginoplasty or revision may be warranted if a urogenital sinus,vaginal stenosis, or abnormalities in menstruation are present.
  • •Monitoring: Serum 17-hydroxyprogesterone and androstenedione concentrations, plasma renin activity, electrolytes, blood pressure, Tanner staging, growth velocity, weight. Annual bone age assessments until near-adult height is attained.
  • •Mental health team members with specific expertise should ideally be involved.
  • •Patients with CAH who require glucocorticoid treatment should wear or carry medical identification indicating they have adrenal insufficiency.

 Pearls & Considerations

Comments

  • •Consider the diagnosis of classic salt-wasting CAH in infants with failure to thrive.
  • •Pharmacological management of classic CAH is a balance between hypercortisolism (Cushing syndrome) and hyperandrogenism.
  • •Patients with CAH may experience gender dysphoria and sexual dysfunction. Patients and families should be made aware of surgical options.
  • •The below table summarizes diagnosis and treatment of different types of CAH.

Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Adapted from Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

DisorderAffected Gene and ChromosomeSigns and SymptomsLaboratory FindingsTherapeutic Measures
21-Hydroxylase deficiency, classic formCYP21A2 6p21.3Glucocorticoid deficiency↓︎ Cortisol, ↑︎ACTH↑︎↑︎ Baseline and ACTH-stimulated 17-hydroxy-progesteroneGlucocorticoid (hydrocortisone) replacement
Mineralocorticoid deficiency (salt-wasting crisis)Hyponatremia, hyperkalemia↑︎ Plasma renin activityMineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation
Ambiguous genitalia in 46,XX individuals↑︎ Serum androgensVaginoplasty and/or clitoroplasty (controversial)
Postnatal virilization↑︎ Serum androgensSuppression with glucocorticoids +/- surgical intervention or revision when desired
21-Hydroxylase deficiency, nonclassic formCYP21A2 6p21.3May be asymptomatic; precocious adrenarche, hirsutism, acne, menstrual irregularity, infertility↑︎ Baseline and ACTH-stimulated 17-hydroxyprogesterone↑︎ Serum androgensSuppression with glucocorticoids
11β-Hydroxylase deficiencyCYP11B1 8q24.3Glucocorticoid deficiency↓︎ Cortisol, ↑︎ ACTHGlucocorticoid (hydrocortisone) replacement
↑︎↑︎ Baseline and ACTH-stimulated 11-deoxycortisol and deoxycorticosterone
Ambiguous genitalia in 46,XX individuals↑︎ Serum androgensVaginoplasty and/or clitoroplasty (controversial)
Postnatal virilization↑︎ Serum androgensSuppression with glucocorticoids
Hypertension↓︎ Plasma renin, hypokalemiaSuppression with glucocorticoids
3β-Hydroxysteroid dehydrogenase deficiency, classic formHSD3B2 1p13.1Glucocorticoid deficiency↓︎ Cortisol, ↑︎ ACTH↑︎↑︎ Baseline and ACTH-stimulated Δ5 steroids (pregnenolone, 17-hydroxy-pregnenolone, DHEA)Glucocorticoid (hydrocortisone) replacement
Mineralocorticoid deficiency (salt-wasting crisis)Hyponatremia, hyperkalemia↑︎ Plasma renin activityMineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation
Ambiguous genitalia in XX and XY individuals↑︎ DHEA, ↓︎ androstenedione, testosterone, and estradiolGenitoplasty (controversial) and sex hormone replacement
Precocious adrenarche, disordered puberty↑︎ DHEA, ↓︎ androstenedione, testosterone, and estradiolSuppression with glucocorticoids
17α-Hydroxylase/17,20-lyase deficiencyCYP17A1 10q24.3Cortisol deficiency (corticosterone is an adequate glucocorticoid)↓︎ Cortisol, ↑︎ ACTH↑︎ DOC, corticosterone
Low 17α-hydroxylated steroids; poor response to ACTH
Glucocorticoid (hydrocortisone) administration
Ambiguous genitalia in 46,XY individuals↓︎ Serum androgens; poor response to hCGOrchidopexy or removal of intraabdominal testes (if desired)
Sex steroid deficiency↓︎ Serum androgens or estrogensSex hormone replacement
Hypertension↓︎ Plasma renin; hypokalemiaSuppression with glucocorticoids
Congenital lipoid adrenal hyperplasiaStAR 8p11.2Glucocorticoid deficiency↑︎ ACTH
Low concentrations of all steroid hormones, with decreased or absent response to ACTH
Glucocorticoid (hydrocortisone) replacement
Mineralocorticoid deficiency (salt-wasting crisis)Hyponatremia, hyperkalemia↓︎ Aldosterone, ↑︎ plasma renin activityMineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation
Ambiguous genitalia in 46,XY individualsDecreased or absent response to hCGOrchidopexy or removal of intraabdominal testes (if desired); sex hormone replacement
Poor pubertal development or premature ovarian failure in 46,XX individuals↑︎ FSH, ↑︎ LH, ↓︎ estradiol (after puberty)Estrogen replacement
P450 oxidoreductase deficiencyPOR 7q11.3Glucocorticoid deficiency↓︎ Cortisol, ↑︎ ACTH ↑︎ Pregnenolone, ↑︎ progesteroneGlucocorticoid (hydrocortisone) replacement
Ambiguous genitalia in XX and XY individuals↑︎ Serum androgens prenatally, ↓︎ androgens and estrogens at pubertyGenitoplasty (controversial) and sex hormone replacement
Maternal virilization
Antley-Bixler syndrome
Decreased ratio of estrogens to androgens

↓︎, Decreased; ↑︎, increased; ↑︎↑︎, markedly increased; ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone.

Prevention

  • •Prenatal: Consider CVS or amniocentesis, especially with a known family history. Prenatal glucocorticoid therapy is considered experimental, and no specific treatment protocols are recommended.
  • •Genetic counseling: Consider preimplantation genetic evaluation.

Seek Additional Information

  • Merke D.P., Auchus R.J.: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 2020; 383: pp. 1248-1261.
  • Miller W.L.: Mechanisms in endocrinology: rare defects in adrenal steroidogenesis. Eur J Endocrinol 2018; 179: pp. R125-R141.
  • New M.I., et al.: Genotype-phenotype correlation in 1507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. PNAS 2013; 10 (7): pp. 2611-2616.
  • Speiser P.W., et al.: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2018; 103: pp. 4043-4088.
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