11-beta-hydroxylase deficiency

Other Names: Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency; Adrenal hyperplasia IV; Adrenal hyperplasia 4; Steroid 11-beta-hydroxylase deficiency; Adrenal hyperplasia hypertensive form; P450c11b1 deficiency; CAH due to 11-beta-hydroxylase deficiency; CYP11B1 deficiency

Congenital adrenal hyperplasia (CAH) due to 11-beta-hydroxylase deficiency is one of a group of disorders (collectively called congenital adrenal hyperplasia) that affect the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with CAH due to 11-beta-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones.

Types

There are two types of CAH due to 11-beta-hydroxylase deficiency, the classic form and the non-classic form. The classic form is the more severe of the two types.

Cause

Mutations in the CYP11B1 gene cause CAH due to 11-beta-hydroxylase deficiency. The CYP11B1 gene provides instructions for making an enzyme called 11-beta-hydroxylase. This enzyme is found in the adrenal glands, where it helps produce hormones called cortisol and corticosterone. Cortisol has numerous functions, such as maintaining blood sugar levels, protecting the body from stress, and suppressing inflammation. Corticosterone gets converted to the hormone aldosterone, which helps control blood pressure by maintaining proper salt and fluid levels in the body.

CAH due to 11-beta-hydroxylase deficiency is caused by a shortage (deficiency) of the 11-beta-hydroxylase enzyme. When 11-beta-hydroxylase is lacking, precursors that are used to form cortisol and corticosterone build up in the adrenal glands and are converted to androgens. The excess production of androgens leads to abnormalities of sexual development, particularly in females with CAH due to 11-beta-hydroxylase deficiency. A buildup in the precursors used to form corticosterone increases salt retention, leading to hypertension in individuals with the classic form of CAH due to 11-beta-hydroxylase deficiency.

The amount of functional 11-beta-hydroxylase enzyme that an individual produces typically determines the extent of abnormal sexual development. Individuals with the classic form of the condition usually have CYP11B1 gene mutations that result in the production of an enzyme with low levels of function or no function at all.

Individuals with the non-classic form of the condition typically have CYP11B1 gene mutations that lead to the production of an enzyme with moderately reduced function. The severity of the signs and symptoms of sexual development do not appear to be related to the severity of the hypertension.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Females with the classic form of CAH due to 11-beta-hydroxylase deficiency have external genitalia that do not look clearly male or female (atypical genitalia). However, the internal reproductive organs develop normally. Males and females with the classic form of this condition have early development of their secondary sexual characteristics such as growth of facial and pubic hair, deepening of the voice, appearance of acne, and onset of a growth spurt. The early growth spurt can prevent growth later in adolescence and lead to short stature in adulthood. In addition, approximately two-thirds of individuals with the classic form of CAH due to 11-beta-hydroxylase deficiency have high blood pressure (hypertension). Hypertension typically develops within the first year of life.

Females with the non-classic form of CAH due to 11-beta-hydroxylase deficiency have normal female genitalia. As affected females get older, they may develop excessive body hair growth (hirsutism) and irregular menstruation. Males with the non-classic form of this condition do not typically have any signs or symptoms except for short stature. Hypertension is not a feature of the non-classic form of CAH due to 11-beta-hydroxylase deficiency.

Dopamine beta-hydroxylase

Common symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of hair growth rate(Abnormality of pace of hair growth)
• Accelerated bone age after puberty
• Adrenocorticotropic hormone excess
• Adrenogenital syndrome
• Congenital adrenal hyperplasia
• Decreased circulating aldosterone level(Low blood aldosterone level)
• Decreased circulating renin level
• Delayed skeletal maturation(Delayed bone maturation)
• Enlarged polycystic ovaries(Enlarged ovaries with cysts)
• Hirsutism(Excessive hairiness)
• Hyperaldosteronism(Elevated plasma aldosterone)
• Increased circulating ACTH level(High blood corticotropin levels)
• Increased circulating androgen level
• Irregular menstruation(Menstrual irregularity)
• Osteoporosis
• Premature adrenarche
• Renal salt wasting(Loss of salt in urine)
• Tall stature(Increased body height)

Less common symptoms

30%-79% of people have these symptoms

• Abnormal circulating aldosterone(Abnormal plasma aldosterone)
• Abnormal EKG(Abnormal ECG)
• Abnormality of prenatal development or birth
• Ambiguous genitalia, female(Atypical appearance of female genitals)
• Aortic root aneurysm(Bulge in wall of root of large artery that carries blood away from heart)
• Clitoral hypertrophy(Enlarged clitoris)
• Decreased circulating cortisol level(Low blood cortisol level)
• Decreased fertility in females(Reduced fertility in females)
• Decreased fertility in males
• Ectopic adrenal gland(Abnormal adrenal gland position)
• Female sexual dysfunction
• Fused labia minora(Fused inner lips)
• Generalized hyperpigmentation
• Hyperpigmented genitalia(Increased genital pigmentation)
• Hypertension
• Hypervolemia(Fluid overload in blood)
• Hypokalemia(Low blood potassium levels)
• Hypoplasia of the vagina(Underdeveloped vagina)
• Long penis(Enlarged penis)
• Short stature(Decreased body height)
• Urogenital sinus anomaly

Diagnosis

Yes. GeneTests lists laboratories offering clinical genetic testing for this condition. Clinical genetic tests are ordered to help diagnose a person or family and to aid in decisions regarding medical care or reproductive issues. Talk to your health care provider or a genetic professional to learn more about your testing options.

11β-OH CAH resembles 21-hydroxylase deficient CAH in its androgenic manifestations: partial virilization and ambiguous genitalia of genetically female infants, childhood virilization of both sexes, and rarer cases of virilization or infertility of adolescent and adult women. The mineralocorticoid effect differs: hypertension is usually the clinical clue that a patient has 11- rather than 21-hydroxylase CAH.

Diagnosis of 11β-OH CAH is usually confirmed by demonstration of marked elevations of 11-deoxycortisol and 11-deoxycorticosterone (DOC), the substrates of 11β-hydroxylase. Management is similar to that of 21-hydroxylase deficient CAH except that mineralocorticoids need not be replaced.

Treatment

As with other forms of CAH, the primary therapy of 11β-hydroxylase deficient CAH is lifelong glucocorticoid replacement in sufficient doses to prevent adrenal insufficiency and suppress excess mineralocorticoid and androgen production.

Salt-wasting in infancy responds to intravenous saline, dextrose, and high dose hydrocortisone, but prolonged fludrocortisone replacement is usually not necessary. The hypertension is ameliorated by glucocorticoid suppression of DOC.

Long term glucocorticoid replacement issues are similar to those of 21-hydroxylase CAH, and involve careful balance between doses sufficient to suppress androgens while avoiding suppression of growth. Because the enzyme defect does not affect sex steroid synthesis, gonadal function at puberty and long-term fertility should be normal if adrenal androgen production is controlled. See congenital adrenal hyperplasia for a more detailed discussion of androgen suppression and fertility potential in adolescent and adult women.

NIH genetic and rare disease info

• NIH info on 11-beta-hydroxylase deficiency

11-beta-hydroxylase deficiency is a rare disease.

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