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.

Adrenal insufficiency
Adrenal gland

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 result from defective enzymes and proteins involving in steroid and cortisol biosynthesis. Defects in steroid biosynthesis is caused by several genetic mutations and may lead to delayed, precocious puberty or ambiguous genitalia in each specific disorder. Decreasing cortisol level leads to releasing the inhibitory feedback on corticotropin (ACTH) production and high ACTH level causes cortisol precursor accumulation and overproduction of other hormones. The most common cause of congenital adrenal hyperplasia is 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 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
				Elevated mineralocorticoid	Renin	Aldosterone	Other	Treatment
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

References