Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency - Gen CYP11B1

Congenital adrenal hyperplasia (CAH) due to the deficiency of 11-β-hydroxylase is one of a set of adrenal steroidogenesis alterations that cause a decrease in cortisol biosynthesis that causes a compensatory increase in the secretion of corticotropic hormone (ACTH). The increase in the concentration of ACTH stimulates the biosynthesis of steroids, which leads to an increase in the synthesis of those steroids prior to blockade, that is, those whose synthesis is not altered by the enzymatic deficiencies that cause congenital adrenal hyperplasia. Thus, the result is a diversity of clinical pictures dependent on the deficiency of cortisol and hormones distal to the blockade and of the excess of hormones and metabolites proximal to the blockade.

Two types of CAH have been described due to the 11-β-hydroxylase deficiency, designated as the classic form (the most severe) and the non-classical form. Women with the classic form have ambiguous genitalia. However, the internal reproductive organs develop normally. Both men and women with the classic form of this disease manifest an early development of their secondary sexual characteristics, such as the growth of facial and pubic hair, thickening of the voice, the appearance of acne and early growth. In addition, approximately 66% of individuals with the classic form have hypertension, which usually develops in the first year of life. For their part, women with the non-classic form of CAH due to 11-beta-hydroxylase deficiency have normal female genitalia. As affected women get older, they may have hirsutism and irregular menstruation. Males with the non-classical form usually have no signs or symptoms except for short stature. Hypertension is not a characteristic of the non-classical form of CAH due to the deficiency of 11-beta-hydroxylase.

This process is due to mutations in the CYP11B1 gene (cytochrome P450 family 11 subfamily B member 1), located on the long arm of chromosome 8 (8q24.3), which encodes the enzyme 11-β-hydroxylase, belonging to the family of cytochrome P450 enzymes. This enzyme is found in the adrenal glands, where it helps synthesize cortisol and corticosterone. Cortisol has numerous functions, such as maintaining blood glucose levels, protecting the body from stress, and suppressing inflammation. Corticosterone is converted to the hormone aldosterone, which helps control blood pressure by maintaining the proper salt concentration and fluid levels in the body.

 More than 80 mutations in the CYP11B1 gene have been identified in people with congenital adrenal hyperplasia (CAH) due to 11-β-hydroxylase deficiency. Most of these mutations change amino acids in the enzyme 11-β-hydroxylase and decrease the function of the enzyme. Mutations of CYP11B1 genes that reduce or eliminate the function of the enzyme in an intense way, generally give rise to the classical form, while mutations that allow a certain function of the enzyme, usually give rise to the non-classical form of the illness. All mutations result in a decrease in the synthesis of cortisol and the consequent increase in the secretion of ACTH. As a result of the blockage, 11-deoxycortisol becomes androgens, causing the virilization of female fetuses. On the other hand, the accumulation of deoxycortisone causes retention of salt and water, suppression of renin and aldosterone and increase in blood pressure, although it can manifest itself after several years.

Some mutations that cause the classical form of CAH fuse sections of the CYP11B1 gene with sections of the CYP11B2 gene. As a consequence, the CYP11B1 gene is regulated by the promoter region of the CYP11B2 gene rather than by its own promoter region. In addition, the fusion generally removes parts of the CYP11B1 gene. These changes in the regulation and structure of the gene decrease the production of 11-beta-hydroxylase.

The molecular characterization of the various forms in which congenital adrenal hyperplasia occurs -see Congenital Adrenal Hyperplasia caused by 21-hydroxylase deficiency and Congenital Adrenal Hyperplasia caused by deficiency of 17-α-hydroxylase-, can guide its diagnosis and enable a rational genetic advice to patients and relatives of the most severe forms of the disease. In addition, molecular and sequencing techniques allow prenatal genetic diagnosis through earlier methods, which allows earlier treatment and greater adjustment of individualized treatment, necessary in any case to normalize the rate of growth and other alterations caused by this pathology. In fact, prenatal diagnosis allows treatment to be started before week 7 of gestation, in which the differentiation of the external genitalia occurs, with a notable improvement in the efficiency of the treatment.

This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have the mutations so that the alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we performed the detection of mutations associated with congenital adrenal hyperplasia due to 11-β-hydroxylase deficiency, by complete PCR amplification of the exons of the CYP11B1 gene, and subsequent sequencing.

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).