11β-hydroxylase deficiency differential diagnosis

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

Overview

11β-hydroxylase deficiency must be differentiated from diseases that cause ambiguous genitalia such as 21-hydroxylase deficiency, 17 alpha-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency and Gestational hyperandrogenism.

Differentiating 11β-hydroxylase deficiency from other diseases

11-hydroxylase deficiency must be differentiated from diseases that cause ambiguous genitalia:

Disease name	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

11β-hydroxylase deficiency 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 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

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	Due to excess 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

Other differentials

11- beta hydroxylase deficiency should be differentiated from other diseases causing hypertension and hypokalemia for example:

• Renal artery stenosis
• Cushing's syndrome
• Congenital adrenal hyperplasia (CAH)
  • 17 alpha hydroxylase deficiency
  • Hyperaldosteronism
• Liddle's syndrome
• Diuretic use
• Licorice ingestion
• Renin-secreting tumors

Hypertension and Hypokalemia

Plasma renin activity

Normal or High (Plasma Renin/Aldosterone ratio <10

Suppressed (Plasma Renin/Aldosterone ratio >20

*Renin-secreting tumors *Diuretic use *Renovascular hypertension *Coarctation of aorta *Malignant phase hypertension

Urinary aldosterone

Elevated

Normal

Low

Conn's syndrome (Primary aldosteronism)

Profound K+ depletion

• 17 alpha hydroxylase deficiency • 11 beta hydroxylase deficiency • Liddle's syndrome • Licorice ingestion • Deoxycortisone producing tumor

Add Mineralocrticoid antagonist for 8 weeks

BP response

No BP response

• Deoxycorticosterone excess( Tumor, 17 alpha hydroxylase and 11 beta hydroxylase deficiency) • Licorice ingestion •Glucocorticoid resistance

Liddle's syndrome)

Differential Diagnoses	Clinical features											History Findings	Laboratory Findings
	Headache and hypertension	Nausea and vomiting	Palpitations	Shortness of breath	Diminished pulses	Fatigue	Constipation	Visual abnormalities	Pruritis	Polyuria	Ambiguous genitalia
Renin-Secreting tumors	✔ (Due to hypertension)	✔	✔	✔	-	-	-	-	-	-	-	Drug-resistant hypertension Chronic headaches	Normal renal function tests Normal liver function tests Metabolic alkalosis (pH > 7.45) Hypokalemia Plasma renin-aldosterone ratio <10
Coarctation of aorta	✔	✔	✔	✔	✔	✔	-	-	-	-	-	Young patients (neonates) may have history of: Failure to thrive Poor feeding Lethargy Turner's syndrome Familial predisposition Ventricular septal defects Adults may have a history of: Claudication Epistaxis	Bicuspid aortic valves Notching of ribs Metabolic alkalosis (pH > 7.45) Hyperkalemia Plasma renin-aldosterone ratio <10
11-beta hydroxylase deficiency	✔ (Hypertensive crisis due to increased 11-deoxycorticosterone-11-DOC)	✔	✔	-	-	✔	-	-	-	-	✔	Females: Clitoral enlargement Labioscrotal fusion Males: Penile enlargement (If not diagnosed at birth, may present as premature adrenarche, developing body odor with axillary and pubic hair development)	Hypokalemia Increased 11-DOC levels Increased androgens Low urinary aldosterone level
17-alpha hydroxylase deficiency	✔	✔	✔	-	-	-	-	-	-	-	✔	Phenotypically females at birth Lack of pubertal development in females Incompletely developed external genitalia in males	Increased serum mineralocorticoids Decreased androgen levels Hypokalemia Low urinary aldosterone level
Uremia		✔	✔	✔	-	✔	✔	-	✔	-	-	Patients have chronic kidney disease and maybe on dialysis Features of uremic neuropathy: Autonomic features with postural hypotension, Impaired sweating Diarrhea Impotence Paraesthesia Delayed deep tendon reflexes Muscle wasting Encephalopathy	Increased blood urea nitrogen (BUN) and creatinine (Cr) Hyperkalemia Decreased serum vitamin 1,25 dihydroxy vitamin D3 level
Liddle's syndrome	✔	✔	✔	-	-	-	✔	-	-	-	-	Family history of Liddle's syndrome (autosomal dominant inheritance) Nephropathy Arrythmias SCNN1B or SCNN1G gene mutation	Hyporeninemic hypoaldosteronism Hypertension Hypokalemia Enhanced erythrocyte sodium influx  Low urinary aldosterone