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, 17a-Hydroxylase deficiency, 11β-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase, Cytochrome P450-oxidoreductase (POR) deficiency (ORD), congenital lipoid adrenal hyperplasia, cholesterol side-chain cleavage enzyme deficiency .

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 (CAH) refers to any of several autosomal recessive conditions resulting from biochemical paths of the steroidogenesis of cortisol from cholesterol by the adrenal glands. Most of these conditions involve greater or lesser production of sex steroids and can alter development of primary or secondary sex characteristics in affected infants, children, and adults. Only a small minority of people with CAH can be said to have an intersex condition, but this attracted American public attention in the late 1990s and many accounts of varying accuracy have appeared in the popular media. Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency. Prenatal diagnosis can be made in both of these disorders by chorionic villous sampling, but this can only be done at 8-10 weeks. In order to prevent the deleterious effect of excess androgens on genital (and brain!) development, therapy must be started earlier. This is most often considered if there is an affected sibling. Treatment is dexamethasone, which is not degraded by the placenta, but is associated with significant maternal weight gain, hypertension, and edema.

Classification

Congenital adrenal hyperplasia is classified into seven types based on the genetic causes that lead to hyperplasia and hormonal imbalance. There are three zones of hormonal synthesis in adrenal cortex that are shown below, and impairment of each pathway may lead to a specific subtype of congenital adrenal hyperplasia.

Disease		History and symptoms		Laboratory findings			Defective gene
		Blood pressure	Genitalia	Increased	Decreased	K levels
21-hydroxylase deficiency	Classic type	Low in salt-wasting Normal in non-salt-wasting	Female: ambiguous Male: normal or scrotal pigmentation and large phallus	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	Cortisol Corticosterone Aldosterone	High in salt wasting type Normal in non salt wasting	CYP21A1 and CYP21A2 gene
	Non-classic type	Normal	Female: virilization after puberty Male: normal appearance	17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone response to ACTH	Cortisol Aldosterone	Normal	CYP21A1 and CYP21A2 gene
17-α hydroxylase deficiency		Hypertension	Female: normal Male: ambiguous	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Low	CYP17A1
11-β hydroxylase deficiency		Hypertension	Female: ambiguous Male: normal or scrotal pigmentation and large phallus	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	Cortisol Corticosterone Aldosterone	Low	CYP11B1
3 beta-hydroxysteroid dehydrogenase deficiency		Hypotension	Both male and female: ambiguous genitalia	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	High	HSD3B2
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Congenital lipoid adrenal hyperplasia
Cholesterol side-chain cleavage enzyme deficiency

Differential Diagnosis

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

Disease name	Laboratory tests		Important clinical findings
	Increased	Decreased
Classic type of 21-hydroxylase deficiency	17-hydroxyprogesterone Progesterone Androstenedione DHEA	Aldosterone Corticosterone (salt-wasting) Cortisol (simple virilizing)	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
3β-Hydroxysteroid Dehydrogenase	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 sign and symptoms 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 name	Steroid status	Other laboratory	Important clinical findings
Non-classic type of 21-hydroxylase deficiency	Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone 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
3β-Hydroxysteroid Dehydrogenase	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 and female external genitalia.

Disease name	Cause	Differentiating
		Findings	Uterus	Breast development	Testosterone	LH	FSH	Karyotyping
Pregnancy		HCG positive
3-beta-hydroxysteroid dehydrogenase type 2 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	Low	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	Low	Normal	Normal	XY
Gonadal dysgenesis	Mutations in SRY, FOG2/ZFPM2, and WNT1	Female external genitalia Intact Mullerian ducts Streak gonads karyotyping	Yes	Yes	Low	High	High	XY
Testicular regression syndrome	Loss of testicular function and tissue early in development	Female phenotype with atrophic Mullerian ducts.	No	No	Low	High	High	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	Low	High	High	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	High	High	XX
Hypogonadotropic hypogonadism	Functional, sellar masses	Normal female genitalia, No puberty	Yes	No	Normal female range	Low	Normal	XX
Turner syndrome	Chromosomal	Female external genitalia	Yes	Yes	Normal female range	High	High	45 XO

References