11β-hydroxylase deficiency overview: Difference between revisions

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Latest revision as of 17:27, 3 August 2017

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 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.

Historical Perspective

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.

Classification

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.

Pathophysiology

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.

Causes

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

11β-hydroxylase deficiency from other Diseases

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.

Epidemiology and Demographics

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.

Risk Factors

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

Screening

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

Natural history, Complications and Prognosis

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.

History and Symptoms

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.

Physical Examination

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

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

CT

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

MRI

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

Ultrasound

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.

Other Imaging Findings

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

Other Diagnostic Studies

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.

Medical Therapy

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.

Surgery

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

Prevention

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

Reference

@@ Line 1: / Line 1: @@
 __NOTOC__
-{{Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency}}
+{{11β-hydroxylase deficiency}}
-{{CMG}}; {{AE}} {{Ammu}}
+{{CMG}}; {{AE}} {{MJ}}
 ==Overview==
-'''11β-Hydroxylase deficient congenital adrenal hyperplasia''' ('''11β-OH CAH''') is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] for the [[enzyme]] which mediates the final step of [[cortisol]] synthesis in the [[adrenal gland|adrenal]]. 11β-OH CAH results in [[hypertension]] due to excessive [[mineralocorticoid]] effects. It also causes excessive [[androgen]] production both before and after birth and can [[virilization|virilize]] a genetically female fetus or a child of either sex.
+β-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 [[Deoxycortisol|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|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]].
+==Historical Perspective==
+β-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.
+==Classification==
+β-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.
 ==Pathophysiology==
-''Congenital adrenal hyperplasia'' (CAH) refers to any of several [[autosomal]] [[recessive]] diseases resulting from defects in steps of the [[synthesis]] of [[cortisol]] from [[cholesterol]] by the [[adrenal gland]]s.  All of the forms of CAH involve excessive or defective production of [[sex steroid]]s and can pervert or impair development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in affected infants, children, and adults.  Many also involve excessive or defective production of [[mineralocorticoid]]s, which can cause [[hypertension]] or salt wasting.
+β-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 [[Deoxycortisol|11-deoxycortisol]] to [[cortisol]] and [[11-deoxycorticosterone]]. Lack of [[11β-hydroxylase]] enzyme in different amounts results in accumulation of [[Deoxycortisol|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]].
+==Causes==
+Mutations in the [[CYP11B1]] gene cause 11β-hydroxylase deficiency, classic type. The responsible mutation in non-classic type is unknown.
-β-Hydroxylase mediates the final step of the [[glucocorticoid]] pathway, producing [[cortisol]] from 11-deoxycortisol.  It also catalyzes the conversion of 11-deoxycorticosterone (DOC) to [[corticosterone]] in the [[mineralocorticoid]] pathway.
+==11β-hydroxylase deficiency from other Diseases==
+β-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]].
-===Genetics===
-The enzyme which mediates 11β-hydroxylase activity is now known as P450c11β since it is one of the [[cytochrome P450 oxidase]] enzymes located in the inner [[mitochondrion|mitochondrial]] membrane of cells of the adrenal cortex. It is coded by a gene at 8q21-22. Like the other forms of CAH, a number of different defective alleles for the gene have been identified, producing varying degrees of impaired 11β-hydroxylase activity.  Also like the other forms of CAH, 11β-OH CAH is inherited as an [[Dominance relationship#Autosomal recessive gene|autosomal recessive disease]].
-==Differentiating 11β-Hydroxylase deficient congenital adrenal hyperplasia from other Diseases==
-β-OH CAH resembles [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]] in its [[androgen]]ic 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.
-==Natural History, Complications, and Prognosis==
-===Complications===
-====Sex steroid effects of 11β-OH CAH====
-Because 11β-hydroxylase activity is not necessary in the production of [[sex steroid]]s ([[androgen]]s and [[estrogen]]s), the hyperplastic adrenal cortex produces excessive amounts of [[DHEA]], [[androstenedione]], and especially [[testosterone]].
-These [[androgen]]s produce effects that are similar to those of [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]]. In the severe forms, XX (genetically female) fetuses can be markedly virilized, with [[ambiguous genitalia]] that look more male than female, though internal female organs, including [[ovary|ovaries]] and [[uterus]] develop normally.
-XY fetuses (genetic males) typically show no signs of excess androgens.
-In milder mutations, androgen effects in both sexes appear in mid-childhood as early pubic hair, overgrowth, and accelerated bone age. Although "nonclassic" forms causing [[hirsutism]] and menstrual irregularities and appropriate steroid elevations have been reported, most have not had verifiable mutations and mild 11β-hydroxylase deficient CAH is currently considered a very rare cause of hirsutism and infertility.
-All of the issues related to virilization, neonatal assignment, advantages and disadvantages of genital surgery, childhood and adult virilization, gender identity and sexual orientation are similar to those of 21-hydroxylase CAH and elaborated in more detail in [[Congenital adrenal hyperplasia]].
-==Diagnosis==
-===Symptoms===
-====Mineralocorticoid aspects of 11β-OH CAH====
-[[Mineralocorticoid]] manifestations of severe 11β-hydroxylase deficient CAH can be biphasic, changing from deficiency (salt-wasting) in early infancy to excess ([[hypertension]]) in childhood and adult life.
-Salt-wasting in early infancy does not occur in most cases of 11β-OH CAH but can occur because of impaired production of [[aldosterone]] aggravated by inefficiency of salt conservation in early infancy. When it occurs it resembles the salt-wasting of severe [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]]: poor weight gain and vomiting in the first weeks of life progress and culminate in life-threatening [[dehydration]], [[hyponatremia]], [[hyperkalemia]], and [[metabolic acidosis]] in the first month.
-Despite the inefficient production of aldosterone, the more characteristic mineralocorticoid effect of 11β-OH CAH is [[hypertension]]. Progressive adrenal hyperplasia due to persistent elevation of ACTH results in extreme overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. DOC is a weak mineralocorticoid, but usually reaches high enough levels in this disease to cause effects of mineralocorticoid excess: salt retention, volume expansion, and [[hypertension]].
-==Treatment==
-===Pharmacotherapy===
-As with other forms of CAH, the primary therapy of 11β-hydroxylase deficient CAH is life-long [[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 [[congenital adrenal hyperplasia|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.
-==Related Chapters==
-*[[Congenital adrenal hyperplasia]] for an overview of CAH, and a more detailed discussion of management issues related to the common forms of 21-hydroxylase deficiency. Nearly all of the sex steroid-related issues are the same for both 11β-hydroxylase and 21-hydroxylase deficient CAH.
-*[[Lipoid congenital adrenal hyperplasia]]
-*[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency]]
-*[[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency]]
-*[[Intersex]] and [[ambiguous genitalia]]
-*[[Adrenal insufficiency]]
+==Epidemiology and Demographics==
+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.
+==Risk Factors==
+The most potent [[risk factor]] in the development of 11β-hydroxylase deficiency is the presence of [[family history]] of 11β-hydroxylase deficiency..
+==Screening==
+There is insufficient evidence to recommend routine screening for 11β-hydroxylase deficiency.
+==Natural history, Complications and Prognosis==
+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.
+==History and Symptoms==
+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]].
+==Physical Examination==
+Patients with 11β-hydroxylase deficiency usually appear healthy. Physical examination of patients with 11β-hydroxylase deficiency is usually remarkable for [[Gynaecomastia|gynecomastia]], [[hyperpigmentation]], [[hypertension]], and [[ambiguous genitalia]].
+==Laboratory Findings==
+Laboratory findings consistent with the diagnosis of 11β-hydroxylase deficiency include elevated [[17-Hydroxyprogesterone|17-hydroxyprogesterone]], elevated [[androstenedione]], elevated urinary 17-ketosteroids, and decreased [[renin]].
+==CT==
+On abdominal [[CT scan]], 11β-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the [[adrenal glands]].
+==MRI==
+On abdominal [[MRI]], 11β-hydroxylase deficiency is characterized by bilateral symmetric enlargement of the [[adrenal glands]].
+==Ultrasound==
+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.
+==Other Imaging Findings==
+There is no other imaging studies available for the diagnosis of 11β-hydroxylase deficiency.
+==Other Diagnostic Studies==
+[[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 sampling|chorionic villus biopsies]]; and utilize fetal [[DNA]] extracted from maternal blood through noninvasive methods.
+==Medical Therapy==
+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 tumor|adrenal rest tumors]].
+==Surgery==
+In patients with 11β-hydroxylase deficiency, girls with [[ambiguous genitalia]] mostly undergo [[reconstructive surgery]] such as clitoroplasty and [[vaginoplasty]].
+==Prevention==
+[[Prenatal diagnosis]] of 11β-hydroxylase deficiency is conducted to prevent complication of the disease in future life and treated with prenatal [[dexamethasone]] treatment.
+==Reference==
+{{Reflist}}
+[[Category:Disease]]
 [[Category:Pediatrics]]
 [[Category:Endocrinology]]
 [[Category:Genetic disorders]]
 [[Category:Intersexuality]]
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