11β-hydroxylase deficiency

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

11β-hydroxylase deficiency is the second most common type of congenital adrenal hyperplasia. This disease results from a defect in CYP11B1 on chromosome 8. CYP11B1 gene encodes an enzyme called 11β-hydroxylase in the path of steroid biosynthesis. Lack of 11β-hydroxylase enzyme in different amounts results in accumulation of 11-deoxycortisol, and decrease amounts of cortisol and 11-deoxycorticosterone. The most potent risk factor in the development of 11β-hydroxylase deficiency is the presence of family history of 11β-hydroxylase deficiency. Symptoms of 11β-hydroxylase deficiency include female patients with ambiguous genitalia, clitoromegaly, labial fusion, hirsutism, menstrual irregularities, aggressive behavior; male patients present with increased penile size in newborns, acne. Children who are not diagnosed at birth, may present with premature adrenarche, adult body odor, axillary and pubic hair development, faster growth and bone age in premature adrenarche. Laboratory findings consistent with the diagnosis of 11β-hydroxylase deficiency include elevated 17-hydroxyprogesterone, elevated androstenedione, elevated urinary 17-ketosteroids, and decreased renin. Treatment for 11β-hydroxylase deficiency in children is administration of glucocorticoids. The treatment option in women is spironolactone. Girls with ambiguous genitalia mostly undergo reconstructive surgery such as clitoroplasty and vaginoplasty.

11β-hydroxylase deficiency was first described by Dr. Walter Eberlein and Dr. Alfred M. Bongiovanni, American physicians, in 1956 based on the study they conducted on accumulated steroids. In 1999, White was the first to discover the association between homozygous mutation in the CYP11B1 gene and development of 11β-hydroxylase deficiency.

11β-hydroxylase deficiency may be classified according to the clinical presentation into 2 subtypes: the classic form and the non-classic form of the 11β-hydroxylase deficiency.

11β-Hydroxylase deficiency is a type of congenital adrenal hyperplasia resulting from a defect in CYP11B1 on chromosome 8. CYP11B1 gene encodes an enzyme called 11β-hydroxylase in the path of steroid biosynthesis. This enzyme is located in the zona fasciculate, and converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone. Lack of 11β-hydroxylase enzyme in different amounts results in accumulation of 11-deoxycortisol, and decrease amounts of cortisol and 11-deoxycorticosterone. There is an elevation of adrenocorticotropic hormone results in overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. 11-deoxycorticosterone is a weak mineralocorticoid, but because of high amounts in this disease can cause mineralocorticoid excess effects such as salt retention, volume expansion, and hypertension. Non-classic forms mostly doesn’t have verifiable mutations and mild 11β-hydroxylase deficiency is currently considered a very rare cause of hirsutism and infertility.

Mutations in the CYP11B1 gene cause 11β-hydroxylase deficiency, classic type. The responsible mutation in non-classic type is unknown.

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.

The prevalence of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is approximately 1 per 100,000 individuals the United States. Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency affects male and female equally. Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency usually affects individuals of the Jewish race.

The most potent risk factor in the development of 11β-hydroxylase deficiency is the presence of family history of 11β-hydroxylase deficiency..

There is insufficient evidence to recommend routine screening for 11β-hydroxylase deficiency.

If left untreated, patients with 11β-hydroxylase deficiency may progress to develop malignant hypertension. Common complications of 11β-hydroxylase deficiency include muscle weakness, metabolic alkalosis, menstrual irregularities in women, acne, hirsutism, and infertility. Prognosis is generally good with treatment.

Symptoms of 11β-hydroxylase deficiency include female patients with ambiguous genitalia, clitoromegaly, labial fusion, hirsutism, menstrual irregularities, aggressive behavior; male patients present with increased penile size in newborns, acne. Children who are not diagnosed at birth, may present with premature adrenarche, adult body odor, axillary and pubic hair development, faster growth and bone age in premature adrenarche.

Patients with 11β-hydroxylase deficiency usually appear healthy. Physical examination of patients with 11β-hydroxylase deficiency is usually remarkable for gynecomastia, hyperpigmentation, hypertension, and ambiguous genitalia.

Laboratory findings consistent with the diagnosis of 11β-hydroxylase deficiency include elevated 17-hydroxyprogesterone, elevated androstenedione, elevated urinary 17-ketosteroids, and decreased renin.

On abdominal CT scan, 11β-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.

On abdominal MRI, 11β-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the adrenal glands.

On ultrasound, 11β-hydroxylase deficiency is characterized by enlarged, wrinkled, and cerebriform adrenal glands. Also testicular masses can be seen in the setting of classical disease.

There is no other imaging studies available for the diagnosis of 11β-hydroxylase deficiency.

Prenatal diagnosis may be used in diagnosis of 11β-hydroxylase deficiency. Different tests which may be used are: amniotic fluid sampling and oligonucleotide hybridization of deoxyribonucleic acid (DNA) obtained from chorionic villus biopsies; and utilize fetal DNA extracted from maternal blood through noninvasive methods.

Treatment for 11β-hydroxylase deficiency in children is administration of glucocorticoids. The response to therapy should be monitored by laboratory tests and clinical findings. The treatment option in women is spironolactone. If pregnancy is not desired, spironolactone plus oral contraceptive pills can be combined with replacement doses of hydrocortisone. In adult males, replacement doses of hydrocortisone should be administered to avoid the development of adrenal rest tumors.

In patients with 11β-hydroxylase deficiency, girls with ambiguous genitalia mostly undergo reconstructive surgery such as clitoroplasty and vaginoplasty.

Prenatal diagnosis of 11β-hydroxylase deficiency is conducted to prevent complication of the disease in future life and treated with prenatal dexamethasone treatment.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2], Ammu Susheela, M.D. [3]

11β-hydroxylase deficiency was first described by Dr. Walter Eberlein and Dr. Alfred M. Bongiovanni, American physicians, in 1956 based on the study they conducted on accumulated steroids. In 1999, White was the first to discover the association between homozygous mutation in the CYP11B1 gene and development of 11β-hydroxylase deficiency.

• In 1956, Dr. Walter Eberlein and Dr. Alfred M. Bongiovanni, American physicians, were the first who described 11β-hydroxylase deficiency based on the study they conducted on accumulated steroids.^[1]
• In 1999, Dr. Perrin C. White, an American endocrinologist, was the first to discover the association between homozygous mutation in the CYP11B1 gene and development of 11β-hydroxylase deficiency.^[2]

• In 1963 congenital adrenal hyperplasia was categorized as several closely related disorders, each caused by different enzyme abnormalities.
• In 1965, the diagnostic approach of congenital adrenal hyperplasia was established by measuring the levels of adrenal hormones in the amniotic fluid.
• In 1979, Dr. Ariel Rosler was the first to discover that the detection of increased levels of tetrahydro-11-deoxycortisol in the amniotic fluid could be used for the diagnosis of 11β-hydroxylase deficiency.
• In 1982, International Newborn Screening Meeting recommended new born screening for congenital adrenal hyperplasia.^[3][4]

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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]

11β-hydroxylase deficiency may be classified according to the clinical presentation into 2 subtypes: the classic form and the non-classic form of the 11β-hydroxylase deficiency.

There are two types of 11β-hydroxylase deficiency:^[1][2]

• Classic form, most of 11β-hydroxylase deficiency cases.
• Non-classic form, a very rare disease.

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

11β-Hydroxylase deficiency is a type of congenital adrenal hyperplasia resulting from a defect in CYP11B1 on chromosome 8. CYP11B1 gene encodes an enzyme called 11β-hydroxylase in the path of steroid biosynthesis. This enzyme is located in the zona fasciculate, and converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone. Lack of 11β-hydroxylase enzyme in different amounts results in accumulation of 11-deoxycortisol, and decrease amounts of cortisol and 11-deoxycorticosterone. There is an elevation of adrenocorticotropic hormone results in overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. 11-deoxycorticosterone is a weak mineralocorticoid, but because of high amounts in this disease can cause mineralocorticoid excess effects such as salt retention, volume expansion, and hypertension. Non-classic forms mostly doesn’t have verifiable mutations and mild 11β-hydroxylase deficiency is currently considered a very rare cause of hirsutism and infertility.

• 11β-hydroxylase deficiency is a type of congenital adrenal hyperplasia resulting from a defect in CYP11B1 on chromosome 8.
• CYP11B1 gene encodes an enzyme called 11β-hydroxylase in the path of steroid biosynthesis. This enzyme is located in the zona fasciculata, and converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone.
• Cortisol production reduction has a negative feedback on the pituitary and increases corticotropin (ACTH) secretion. This leads to of 11-deoxycortisol precursors and then adrenocortical hyperplasia.
• With intact amount of other pathways, as a result of high ACTH concentrations, some amount of the 11-deoxycortisol precursors are metabolized to adrenal androgens and can cause virilization in a genetically female fetus or a child of either sex.
• Severity of disease depends on the amount of functional 11β-hydroxylase enzyme that an individual produces.
• Aldosterone production is decreased in this disease but there is an elevation of adrenocorticotropic hormone results in overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. 11-deoxycorticosterone is a weak mineralocorticoid, but because of high amounts in this disease can cause mineralocorticoid excess effects such as salt retention, volume expansion, and hypertension.
• Non-classic forms mostly doesn’t have verifiable mutations and mild 11β-hydroxylase deficiency is currently considered a very rare cause of hirsutism and infertility.

• 11β-hydroxylase deficiency is an inherited disease with an autosomal recessive pattern, which means both copies of the gene in each cell have gene mutations.
• Commonly, 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.
• Most CYP11B1 mutations correspond to minimal or absent enzyme activity, resulting in the classic 11β-hydroxylase deficiency phenotype.
• A non-classic form of enzyme deficiency caused by CYP11B1 mutations exists but is very rare.^[2][3][4]

• Hirsutism
• Hypertension
• Testicular tumor

Gross pathology findings in patients with 11β-hydroxylase deficiency are:^[5][6]

• Enlarged adrenal glands
• Wrinkled surface adrenal glands
• Cerebriform pattern adrenal glands (pathognomonic sign)
• Normal ultrasound appearances may also be seen
• Testicular masses may be identified representing adrenal rest tissue

In 11β-hydroxylase deficiency microscopic findings may include:

• Diffuse cortical hyperplasia with smaller cells
• The cell cytoplasm can be vacuolated, and often more basophilic
• Rare mitotic figures may be present
• The hyperplastic cells typically lack features of cellular atypia.^[7]

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

Mutations in the CYP11B1 gene cause 11β-hydroxylase deficiency, classic type. The responsible mutation in non-classic type is unknown.

Mutations in the CYP11B1 gene cause 11β-hydroxylase deficiency, classic type. The responsible mutation in non-classic type is unknown.^[1][2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2] Syed Hassan A. Kazmi BSc, MD [3]

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.

11- beta hydroxylase deficiency should be differentiated from other diseases causing hypertension and hypokalemia for example:^{[5][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]}

• 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

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

Worldwide, the prevalence of 11β-hydroxylase deficiency is 1 per 100,000 persons. 11β-hydroxylase deficiency accounts for 5 percent of all cases of congenital adrenal hyperplasia and it is considered the second most frequent variant after 21-hydroxylase deficiency. The incidence of 11β-hydroxylase deficiency is 1 per 100,000 persons. Also, this disease is more common in Moroccan Jews living in Israel, occurring in approximately 20 in 100,000 newborns. 11β-hydroxylase deficiency affects males and females equally.

• Worldwide, the prevalence of 11β-hydroxylase deficiency is 1 per 100,000 persons.

• 11β-hydroxylase deficiency accounts for 5 percent of all cases of congenital adrenal hyperplasia and it is considered the second most frequent variant after 21-hydroxylase deficiency.
• Worldwide, the incidence of 11β-hydroxylase deficiency is 1 per 100,000 persons.
• 11β-hydroxylase deficiency is more common in Moroccan Jews living in Israel, occurring in approximately 20 in 100,000 newborns.^[1][2]

• 11β-hydroxylase deficiency affects males and females equally.

• 11β-hydroxylase deficiency usually affects individuals of the Jewish race.

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

The most potent risk factor in the development of 11β-hydroxylase deficiency is the presence of family history of 11β-hydroxylase deficiency.

The most potent risk factor in the development of 11β-hydroxylase deficiency is presence of family history of 11β-hydroxylase deficiency.^[1]

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

There is insufficient evidence to recommend routine screening for 11β-hydroxylase deficiency.

There is insufficient evidence to recommend routine screening for 11β-hydroxylase deficiency.

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

If left untreated, patients with 11β-hydroxylase deficiency may progress to develop malignant hypertension. Common complications of 11β-hydroxylase deficiency include muscle weakness, metabolic alkalosis, menstrual irregularities in women, acne, hirsutism, and infertility. Prognosis is generally good with treatment.

If left untreated, patients with 11β-hydroxylase deficiency may progress to develop malignant hypertension.Untreated children progress into isosexual or contra-sexual pseudo-precocious puberty; early puberty in boys, acne and hirsutism in girls, menstrual irregularities in women, and infertility .^[1][2]

• Vascular hemorrhage
• Renal insufficiency
• Left ventricular hypertrophy
• Hypertensive retinopathy
• Stroke

• Muscle weakness
• Metabolic alkalosis
• Paralytic ileus

• Early puberty in boys
• Acne
• Hirsutism in girls
• Menstrual irregularities in women
• Azoospermia
• Oligospermia
• Infertility

• The prognosis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is generally good with treatment.^[1][2]