11β-hydroxylase deficiency overview
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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 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.