Congenital adrenal hyperplasia

This page contains general information about Congenital adrenal hyperplasia. For more information on specific types, please visit the pages on 21-hydroxylase deficiency, 17 alpha-hydroxylase deficiency, 11β-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, cytochrome P450-oxidoreductase (POR) deficiency (ORD), congenital lipoid adrenal hyperplasia.

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Congenital adrenal hyperplasia main page
Overview
Classification 21-hydroxylase deficiency
11β-hydroxylase deficiency
17 alpha-hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Lipoid congenital adrenal hyperplasia
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Synonyms and keywords: Congenital adrenal hyperplasia; CAH; Adrenal hyperplasia.

Overview

Congenital adrenal hyperplasia consists of several disorders resulting from defective enzymes and proteins involved in steroid and cortisol synthesis pathways. Defects in steroid biosynthesis are caused by several genetic mutations and may lead to delayed puberty, precocious puberty or ambiguous genitalia in specific disorders. The decrease in cortisol level leads to the release of the inhibitory feedback on corticotropin (ACTH) production. The high ACTH level causes increase cortisol precursors and overproduction of other hormones. The most common cause of congenital adrenal hyperplasia is a 21-hydroxylase deficiency, which accounts for more than 95% of cases. Other causes include 17 alpha-hydroxylase deficiency, 11β-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, Cytochrome P450-oxidoreductase (POR) deficiency (ORD), and congenital lipoid adrenal hyperplasia.

Classification

Congenital adrenal hyperplasia (CAH) is classified into seven types based on the genetic causes that lead to hyperplasia and hormonal imbalance. CAH is hyperplasia of different layer of Adrenal cortex. Within the adrenal cortex, there are three layers named zones; each of them has a distinct cell type and secrete specific hormones.

Adrenal cortex zones based on the hormonal synthesis ability and location:

• Zona glumerulosa:
  • The outer layer of adrenal cortex.
  • Laying directly under the adrenal capsule.
  • Secretion: Aldosterone synthesis.
• Zona fasciculate:
  • The middle part of adrenal cortex
  • Laying under zona glumerulosa
  • Secretion: Cortisol synthesis
• Zona reticularis:
  • The inner part of adrenal cortex
  • Laying between zona fasciculate and adrenal medulla
  • Secretion: Androgen synthesis

Adrenal cortex zones - By Jpogi - https://commons.wikimedia.org/wiki/File:Adrenal_gland_%28cortex%29.JPG, CC0, https://commons.wikimedia.org/w/index.php?curid=37838551

Impairment of each pathway and enzyme may lead to a specific subtype of congenital adrenal hyperplasia include:

• 21-hydroxylase deficiency
• 17 alpha-hydroxylase deficiency
• 11β-hydroxylase deficiency
• 3 beta-hydroxysteroid dehydrogenase deficiency
• Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
• Congenital lipoid adrenal hyperplasia

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes

Summary and important Characteristics of the different congenital adrenal hyperplasia subtypes:

Disease		History and symptoms		Laboratory findings						Defective gene
		Blood pressure	Genitalia	Cortisol	Aldosterone	Androgens	Estrogens	Increased hormone precursors	Potassium levels
21-hydroxylase deficiency	Classic type, salt-wasting	↓	Female: Ambiguous genitalia Male: Normal or scrotal pigmentation and large phallus	↓	↓↓	↑	Relatively low	17-hydroxyprogesterone	↑	CYP21A1 and CYP21A2 gene
	Classic type, non-salt-wasting	Normal	Female: Ambiguous genitalia Male: normal or scrotal pigmentation and large phallus	↓	↓	↑	Relatively low	17-hydroxyprogesterone	Normal	CYP21A1 and CYP21A2 gene
	Non-classic type	Normal	Female: Virilization after puberty Male: Normal appearance	Normal	Normal	↑	Relatively low	17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone response to ACTH	Normal	CYP21A1 and CYP21A2 gene
17-α hydroxylase deficiency		↑	Female: Normal Male: Ambiguous genitalia	Normal corticosterone Normal cortisol	↑	↓	↓	Deoxycorticosterone Progesterone	↓	CYP17A1
11-β hydroxylase deficiency		↑	Female: Ambiguous genitalia Male: Normal or scrotal pigmentation and large phallus	↓	↑	↑	Relatively low	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	↓	CYP11B1
3 beta-hydroxysteroid dehydrogenase deficiency		↓	Both male and female: Ambiguous genitalia	↓	↓	Male:↓ Female:↑	↓	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	↑	HSD3B2
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)		Normal	Both male and female: Ambiguous genitalia	↓	Normal	↓	↓	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Normal	Mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase).
Congenital lipoid adrenal hyperplasia		↓	Female: Normal, delayed puberty in females Male: Ambiguous genitalia	↓	↓	↓	↓	None of precursors increased	↓	Gene mutations on chromosome 8, codes for a protein called steroid acute regulatory protein (StAR)

Differential Diagnosis

Congenital adrenal hyperplasia can present with different symptoms such as:

• Ambiguous genitalia
• Virilization and hirsutism in female
• Primary amenorrhea
• Low reninemic hypertension

Differential diagnosis for each of these symptoms are described in below tables.

Congenital adrenal hyperplasia must be differentiated from diseases that cause ambiguous genitalia:

Disease	Steroid status		Important clinical findings
	Increased	Decreased
Classic type of 21-hydroxylase deficiency	17-hydroxyprogesterone Progesterone Androstenedione DHEA	Aldosterone Corticosterone (salt-wasting) Cortisol (virilization)	Ambiguous genitalia in female Virilization in female Salt-wasting Hypotension and hyperkalemia
11-β hydroxylase deficiency	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone (mild elevation)	Cortisol Corticosterone Aldosterone	Ambiguous genitalia in female Hypertension and hypokalemia Virilization
17-α hydroxylase deficiency	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair
3 beta-hydroxysteroid dehydrogenase deficiency	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	Vomiting, volume depletion, hyponatremia, and hyperkalemia 46-XY infants often show undervirilization, due to a block in testosterone synthesis
Gestational hyperandrogenism	Maternal serum androgen concentrations (usually testosterone and androstenedione) are high If virilization is caused by exogenous hormone administration, the values may be low because the offending hormone is usually a synthetic steroid not measured in assays for testosterone or other androgens		Androgen excess in mother History of androgen containing medication consumption during pregnancy in mother Virilization in a 46,XX individual with normal female internal anatomy Causes include maternal luteoma or theca-lutein cysts, and placental aromatase enzyme deficiency

Congenital adrenal hyperplasia must be differentiated from diseases that cause virilization and hirsutism in female:

Disease	Steroid status	Other laboratory	Important clinical findings
Non-classic type of 21-hydroxylase deficiency	Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone in response to ACTH	Low testosterone levels	No symptoms in infancy and male Virilization in females
11-β hydroxylase deficiency	Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone	Low testosterone levels	Hypertension and hypokalemia Virilization
3 beta-hydroxysteroid dehydrogenase deficiency	Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone	Low testosterone levels	Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes.
Polycystic ovary syndrome	High DHEAS and androstenedione levels	Low testosterone levels	Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis
Adrenal tumors	Variable levels depends on tumor type	Low testosterone level	Older age Rapidly progressive symptoms
Ovarian virilizing tumor	Variable levels depends on tumor type	Testosterone is high	Older age Rapidly progressive symptoms
Cushing's syndrome	Increase cortisol & metabolites Variable other steroids	Variable mineralocorticoid excess	Cushingoid appearance
Hyperprolactinemia	Normal levels of most of steroids	Increased prolactin	Infertility galactorrhea

Some types of congenital adrenal hyperplasia must be differentiated from diseases with primary amenorrhea:

Disease	Cause	Differentiating
		Findings	Uterus	Breast development	Testosterone	LH	FSH	Karyotyping
3 beta-hydroxysteroid dehydrogenase deficiency	HSD3B2 gene mutation	Undervirilization in 46,XY individuals due to a block in testosterone biosynthesis. Mild virilization in 46,XX individuals	Yes in female	Yes in female	↓	Normal	Normal	XY and XX
17-alpha-hydroxylase deficiency	CYP17A1 gene mutation	Female external genitalia Primary amenorrhea Hypertension Absence of secondary sexual characteristics Minimal body hair	No	No	↓	Normal	Normal	XY
Gonadal dysgenesis	Mutations in SRY, FOG2/ZFPM2, and WNT1	Female external genitalia Intact Mullerian ducts Streak gonads	Yes	Yes	↓	↑	↑	XY
Testicular regression syndrome	Loss of testicular function and tissue early in development	Female phenotype with atrophic Mullerian ducts.	No	No	↓	↑	↑	XY
LH receptor defects	LH receptor gene mutation on chromosome 2	Female external genitalia Lack a uterus and fallopian tubes Epididymis and vas deferens may be present Laboratory: Unresponsiveness to hCG Normal levels of testosterone precursors (produced in the adrenal glands).	No	No	↓	↑	↑	XY
5-alpha-reductase type 2 deficiency	Autosomal recessive	Female external genitalia or ambiguous Bilateral testes and normal testosterone formation Impaired external virilization during embryogenesis Defective conversion of testosterone to DHT. Testosterone:DHT ratio is >10:1	No	No	Normal male range	High to normal	High to normal	XY
Androgen insensitivity syndrome	Androgen receptor defect	Female external genitalia Resistant to testosterone	No	Yes	Normal male range	Normal	Normal	XY
Mullerian agenesis	Mutations in WNT4	Normal female genitalia Normal breast development	No	Yes	Normal female range	Normal	Normal	XX
Primary ovarian insufficiency	Genetic defects such as turner syndrome, fragile X syndrome, some other chromosomal defects	Normal female genitalia	Yes	Yes	Normal female range	↑	↑	XX
Hypogonadotropic hypogonadism	Functional, sellar masses	Normal female genitalia, Delayed puberty	Yes	No	Normal female range	Low	Normal	XX
Turner syndrome	Chromosomal	Normal female external genitalia	Yes	Yes	Normal female range	↑	↑	45 XO

17 alpha-hydroxylase deficiency and 11β-hydroxylase deficiency can cause low reninemic hypertension and should be differentiate from other causes of pseudohyperaldosteronism (low renin):

Pseudohyperaldosteronism causes	Disease	Etiology	Clinical features	Labratory				Treatment
				Elevated mineralocorticoid	Renin	Aldosterone	Other
Endogenous causes	17 alpha-hydroxylase deficiency	Mutations in the CYP17A1 gene	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair	Deoxycorticosterone (DOC)	↓	↓	Cortisol ↓	Corticosteroids
	11β-hydroxylase deficiency	Mutations in the CYP11B1 gene	Ambiguous genitalia in female Hypertension and hypokalemia Virilization				Cortisol ↓
	Apparent mineralocorticoid excess syndrome (AME)	Genetic or acquired defect of 11-HSD gene Cortisone decreases and cortisol accumulates and binds to aldosterone receptors	Severe juvenile hypertension Hypercalciuria, nephrocalcinosis, polyuria (due to hypokalemia-induced nephrogenic diabetes insipidus) Renal failure	Cortisol has mineralocorticoid effects	↓	↓	Urinary free cortisone ↓↓	Dexamethasone and/or mineralocorticoid blockers
	Liddle’s syndrome (Pseudohyperaldosteronism type 1)	Mutation of the epithelial sodium channels (ENaC) gene in the distal renal tubules	Hypertension Hypokalemia	No extra mineralocorticoid presents, and mutations in Na channels mimic aldosterone mechanism	↓	↓	Cortisol ↓	Amiloride or triamterene
	Cushing’s syndrome	The main pathogenetic mechanism is linked to the excess of cortisol which saturates 11-HSD2 activity, This allows cortisol to bind mineralocorticoid receptor	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache	Cortisol has mineralocorticoid effects	↓	↓ if excess cortisol saturates 11-HSD2 enzyme activity ↑ in direct activation of renin angiotensin system activation by glucocorticoids	Urinary free cortisol markedly ↑↑	Pasireotide, Cabergoline, Ketoconazole, and Metyrapone Adrenalectomy
	Insensitivity to glucocorticoids (Chrousos syndrome)	Mutations in glucocorticoid receptor (GR) gene	Hypertension Adrenal hyperandrogenism	Deoxycorticosterone (DOC)	↓	↓	Cortisol	Dexamethasone
	Cortisol-secreting adrenocortical carcinoma	Multifactorial	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache	Cortisol has mineralocorticoid effects	↓	↓ if excess cortisol saturates 11-HSD2 enzyme activity ↑ in direct activation of renin angiotensin system activation by glucocorticoids	Urinary free cortisol markedly ↑↑	Surgery
	Geller’s syndrome	Mutation of mineralocorticoid (MR) receptor that alters its specificity and allows progesterone to bind MR	Severe hypertension particularly during pregnancy	Progesterone has mineralocorticoid effects	↓	↓	-	mineralocorticoid blockers
	Gordon’s syndrome (Pseudohypoaldosteronism type 2)	Mutations of at least four genes have been identified, including WNK1 and WNK4	Hypertension Hyperkalemia Normal renal function	No excess mineralocorticoid; an increased activity of the thiazide-sensitive Na–Cl co-transporter in the distal tubule	↓	Normal	Hyperkalemia	thiazide diuretics and/or dietary sodium restriction
Exogenous causes	Corticosteroids with mineralocorticoid activity	Fludrocortisone or fluoroprednisolone can mimic the action of aldosterone,	Hypertension Hypokalemia	Medications such as fludrocortisone	↓	↓	-	Change the treatment
	Licorice ingestion	Glycyrrhetinic acid that binds mineralocorticoid receptor and blocks 11-HSD2 at the level of classical target tissues of aldosterone	Hypertension Hypokalemia	-	↓	↓	Urinary free cortisol Moderate ↑	Discontinue licorice
	Grapefruit	High assumption of naringenin, a component of grapefruit, can also block 11-HSD	Hypertension	-	↓	↓	-	Discontinue grapefruit
	Estrogens	Estrogens can retain sodium and water by different mechanisms, causing: Increased blood pressure values and suppressing the renin aldosterone system, on the other side inducing secondary hyperaldosteronism due to the stimulation of the synthesis of angiotensinogen	Hypertension Headache Edema Weight gain	-	↓	↓	-	Discontinue estrogens

CAH must be differentiated from other causes of irregular menses and hirsutism:

Disease	Differentiating Features
Pregnancy	Pregnancy always should be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy
Hypothalamic amenorrhea	Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution
Primary amenorrhea	Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered
Cushing syndrome	Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing
Hyperprolactinemia	Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bi-temporal hemianopsia
Ovarian or adrenal tumor	Benign ovarian tumors and ovarian cancer are rare causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone
Congenital adrenal hyperplasia	Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnostic assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency
Anabolic steroid abuse	Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatomegaly, alopecia, and aggression Altered liver function test results are seen
Hirsutism	Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present

References