Congenital adrenal hyperplasia

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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
Illu adrenal gland.jpg
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 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:

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

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes [1]

Summary and important Characteristics of the different congenital adrenal hyperplasia subtypes: [2][3][4]

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 ↓↓ Relatively low

CYP21A1 and CYP21A2 gene

Classic type, non-salt-wasting Normal
  • Male: normal or scrotal pigmentation and large phallus
Relatively low Normal CYP21A1 and CYP21A2 gene
Non-classic type Normal Normal Normal Relatively low Normal

CYP21A1 and CYP21A2 gene

17-α hydroxylase deficiency Normal corticosterone

Normal cortisol

CYP17A1
11-β hydroxylase deficiency
  • Male: Normal or scrotal pigmentation and large phallus
Relatively low CYP11B1
3 beta-hydroxysteroid dehydrogenase deficiency Male:↓

Female:↑

HSD3B2
Cytochrome P450-oxidoreductase (POR) deficiency (ORD) Normal Normal Normal Mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase).
Congenital lipoid adrenal hyperplasia 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:

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

Congenital adrenal hyperplasia must be differentiated from diseases that cause ambiguous genitalia:[5][6]

Disease Steroid status Important clinical findings
Increased Decreased
Classic type of 21-hydroxylase deficiency
11-β hydroxylase deficiency
17-α hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Gestational hyperandrogenism

Congenital adrenal hyperplasia must be differentiated from diseases that cause virilization and hirsutism in female:[7][6][8]

Disease Steroid status Other laboratory Important clinical findings
Non-classic type of 21-hydroxylase deficiency Increased:
  • No symptoms in infancy and male
11-β hydroxylase deficiency Increased:

Decreased:

3 beta-hydroxysteroid dehydrogenase deficiency Increased:

Decreased:

Polycystic ovary syndrome
Adrenal tumors
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Ovarian virilizing tumor
  • Variable levels depends on tumor type
  • Older age
  • Rapidly progressive symptoms
Cushing's syndrome
Hyperprolactinemia

Some types of congenital adrenal hyperplasia must be differentiated from diseases with primary amenorrhea:[9][2][3][4][10][11][12][13]

Disease Cause Differentiating
Findings Uterus Breast development Testosterone LH FSH Karyotyping
3 beta-hydroxysteroid dehydrogenase deficiency

Yes in female

Yes in female

Normal

Normal

XY and XX

17-alpha-hydroxylase deficiency

No

No

Normal

Normal

XY

Gonadal dysgenesis
  • Mutations in SRY, FOG2/ZFPM2, and WNT1

Yes

Yes

XY

Testicular regression syndrome
  • Loss of testicular function and tissue early in development

No

No

XY

LH receptor defects

No

No

XY

5-alpha-reductase type 2 deficiency

No

No

Normal male range

High to normal

High to normal

XY

Androgen insensitivity syndrome 

No

Yes

Normal male range

Normal

Normal

XY

Mullerian agenesis

No

Yes

Normal female range

Normal

Normal

XX

Primary ovarian insufficiency

Yes

Yes

Normal female range

XX

Hypogonadotropic hypogonadism
  • Functional, sellar masses

Yes

No

Normal female range

Low

Normal

XX

Turner syndrome

  • Chromosomal

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 Deoxycorticosterone (DOC) Cortisol Corticosteroids
11β-hydroxylase deficiency Mutations in the CYP11B1 gene Cortisol
Apparent mineralocorticoid excess syndrome (AME) Genetic or acquired defect of 11-HSD gene 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 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,

Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Cortisol has mineralocorticoid effects
  • ↓ if excess cortisol saturates 11-HSD2 enzyme activity
Urinary free cortisol markedly ↑↑
  • Adrenalectomy
Insensitivity to glucocorticoids (Chrousos syndrome) Mutations in glucocorticoid receptor (GR) gene Deoxycorticosterone (DOC) Cortisol Dexamethasone
Cortisol-secreting adrenocortical carcinoma Multifactorial

Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity)

Cortisol has mineralocorticoid effects
  • ↓ if excess cortisol saturates 11-HSD2 enzyme activity
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
  • 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, 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 - Urinary free cortisol Moderate ↑ Discontinue licorice
Grapefruit High assumption of naringenin, a component of grapefruit, can also block 11-HSD - - 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
- - 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
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
Cushing syndrome
Hyperprolactinemia
Ovarian or adrenal tumor
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
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

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  3. 3.0 3.1 Heremans GF, Moolenaar AJ, van Gelderen HH (1976). "Female phenotype in a male child due to 17-alpha-hydroxylase deficiency". Arch. Dis. Child. 51 (9): 721–3. PMC 1546244Freely accessible. PMID 999330. 
  4. 4.0 4.1 Biglieri EG (1979). "Mechanisms establishing the mineralocorticoid hormone patterns in the 17 alpha-hydroxylase deficiency syndrome". J. Steroid Biochem. 11 (1B): 653–7. PMID 226795. 
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  8. Melmed, Shlomo (2016). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 978-0323297387. =
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