Non-classical Form Of Congenital Adrenal Hyperplasia Research Articles

Cardiovascular risk in women with nonclassical congenital adrenal hyperplasia.

The outcomes related to cardiovascular risk (CVR) in patients with nonclassical form of congenital adrenal hyperplasia (NCAH) are unknown, especially those related to therapeutic options, including low doses of glucocorticoids (GCs) or oral contraceptive pills. to analyze CVR by markers of atherosclerosis in females with nonclassical form according to therapeutic options. a cross-sectional study at a tertiary center. Forty-seven females with NCAH (33.4 ± 10 years) were subdivided into: G1 (n = 28) treated with dexamethasone (0.14 ± 0.05 mg/m2/day); G2 (n = 19) with oral contraceptive pills; and G3 (30 matched controls). CVR was analyzed through serum lipids, HOMA-IR, inflammatory cytokines levels and quantitative image evaluations (pulse wave velocity-PWV, endothelial function by flow mediated dilatation-FMD, carotid intima media thickness-CIMT and visceral fat-VAT by abdominal tomography. There were no statistically significant differences in BMI, HOMA-IR, HDL-cholesterol, or triglyceride levels among groups (p > 0.05). Serum interleukin-6 levels ​​were higher in G1 than in G2 (p = 0.048), and interleukin-8 levels were higher in G1 than in G2/3 (p = 0.008). There were no statistically significant differences in VAT, PWV, FMD or CIMT among groups (p > 0.05). In multivariable regression analysis, there was no statistically significant association between glucocorticoid dose and evaluated outcomes. Adult females with NCAH did not show increased CVR using methodologies for detection of precocious atherosclerosis. Although patients receiving dexamethasone therapy had increased IL-6 and 8 levels, these data were not associated with radiological markers of atherosclerosis. Our cohort was composed of young adults and should be reevaluated in a long-term follow-up.

Syndrome of hyperandrogenism in adolescent girls

The diagnosis of hyperandrogenism may be based on clinical manifestations or on determining the blood level of androgens. Causes of hyperandrogenism in the peripubertal period are polycystic ovary syndrome (PCOS), non-classical forms of congenital adrenal hyperplasia (NCCAH), androgen-producing tumors, obesity, idiopathic hirsutism, and other rare causes. Physiological hyperandrogenism of peripubertal period passes within 2 years. PCOS affects from 4 to 21% of women of reproductive age and from 6 to 18% of adolescent girls. To date, there is no consensus on the diagnostic criteria for PCOS in teenage girls. At least, three symptoms are necessary: menstrual disorders, clinical and biochemical hyperandrogenism and polycystic ovaries. Diagnosis of NCCAH includes measurement of the level of 17-hydroxyprogesterone and a test with adrenocorticotropic hormone. The purpose of the treatment of these diseases is to reduce the manifestations of hyperandrogenism, regulate the menstrual cycle and improve the quality of life. Effective methods of pharmacotherapy are combined oral contraceptives and antiandrogens. An important stage is lifestyle changes in PCOS and obesity patients.

Rare Coexistence of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency and Turner Syndrome: A Case Report and Brief Literature Review

The coexistence of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and Turner syndrome (TS) is rare. We report on a 6-year-old Portuguese girl with mosaic TS [45,XO(39)/47,XXX(21)] presenting with premature pubarche at the age of 5 years. Laboratory findings showed elevated 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and total testosterone, and her sex-determining region Y (SRY) was negative. CYP21A2 gene analysis revealed two mutations (c.[844G>T]; [CYP21A2del]), consistent with the non-classical form of CAH. Complete deletion of CYP21A2 allele occurred de novo. At 6 years and 4 months, she presented with accelerated growth velocity and hydrocortisone at a dose of 5 mg/m2/day was initiated. This case highlights the need to perform global examinations looking for virilization signs in TS patients’ follow-ups. It also supports the reported genetic combination of TS and CAH. Therefore, CAH should be kept in mind in TS patients with SRY negative and virilization signs, even in the absence of short stature.

Testicular adrenal rest tumors in boys with 21-hydroxylase deficiency, timely diagnosis and follow-up.

BackgroundTesticular adrenal rest tumors (TARTs) are found in 30–94% of adult males with congenital adrenal hyperplasia (CAH). We sought to explore TART appearance through yearly ultrasound examination of testes in young boys with CAH, and its association with metabolic control and genetic mutations.MethodsTwenty-five boys with 21-hydroxylase deficiency in the age group 4–18 years diagnosed during the period 2001–2016 were included in the study. ACTH, 17-hydroxyprogesterone, androstenedione and testosterone were measured at 4-month intervals. Growth and BMI were assessed at the time of evaluation. PCR/ACRS method was used for CYP21A2 gene analysis. Testicular ultrasound examination was performed yearly.ResultsTARTs were detected by ultrasound in 8 children at the age of 6–16 years (13.2 years average). Five had salt-wasting form, two had simple virilizing form and one had non-classic form of CAH. Significant differences in the17OHP and androstenedione levels were detected between the boys, adherent and non-adherent to therapy. Inadequate metabolic control was not different in boys with and without TART (11/17 and 5/8 respectively). No significant difference was detected in the distribution of genetic mutations or adherence to therapy between patients with and without TARTs. One patient had a mutation not reported thus far in TART and another developed leukemia.ConclusionTART is not rare in young boys with CAH, irrespective of the specific mutation or metabolic control. Ultrasound screening helps timely diagnosis and adjustment of therapy.

Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia

Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37-13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3-progesterone, indicating that C-H bond breaking is a rate-limiting step over a 104-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.

Association of HLA alleles and haplotypes with CYP21A2 gene p. V282L mutation in the Croatian population.

The CYP21A2 mutations that are in linkage disequilibrium with particular HLA-A, -B, -DRB1 alleles/haplotypes, cause deficiency of the 21-hydroxylase enzyme (21-OHD) and account for the majority of congenital adrenal hyperplasia (CAH) cases. The aim of this study was to investigate those associations with the p.V282L mutation linked to the non-classical (NC) form of CAH among Croatians. The study included parents of patients with the NC form of CAH, positive for the p.V282L mutation (N = 55) and cadaveric donor samples (N = 231). All subjects were HLA-A, -B, and -DRB1 typed and tested for the presence of the p.V282L mutation. Among parents of patients, 92.73% of subjects were positive for the B*14:02 allele and almost half of them carried the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype. Among cadaveric samples 77 out of 96 subjects positive for the B*14:02 allele had the p.V282L mutation. Among them, 37 were positive for the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype, 23 had the HLA-A*33:01-B*14:02-DRB1*03:01 haplotype, 8 had the B*14:02-DRB1*01:02 combination and 5 were carrying the HLA-A*68:02-B*14:02-DRB1*13:03 haplotype. Only 4 of these subjects were positive for the B*14:02 allele. HLA-B*14:02 was the only single allele with association that reached statistically significant P value (RR = 12.00; P = 0.0024). Haplotypes B*14:02-DRB1*01:02 (P < 0.001) and HLA-A*68:02-B*14:02-DRB1*13:03 (P < 0.001) as well as HLA-A*33:01-B*14:02-DRB1*01:02 and HLA-A*33:01-B*14:02-DRB1*03:01 showed high relative risks (RR = 45.00, RR = 41.63 and RR = 36.96, respectively). Our data support the previously documented association of the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype with the p.V282L mutation, but also point out a high frequency of the p.V282L mutation among Croatians with HLA-A*33:01-B*14:02-DRB1*03:01 and HLA-A*68:02-B*14:02-DRB1*13:03 haplotypes.

Congenital Adrenal Hyperplasia: Unresolved Issues.

Congenital adrenal hyperplasia (CAH) describes a family of disorders that comes from enzymatic deficiencies in cortisol production, with 21-hydroxylase deficiency causing ∼90% of cases. Distinction is made between the severe classical form and milder nonclassical form of CAH. Molecular genetic analysis is used to confirm the hormonal diagnosis. A high rate of genotype-phenotype disconcordance has been found in 21-hydroxylase deficiency. The goal of treatment is to replace with synthetic glucocorticoids and mineralocorticoids and suppress adrenal androgen production. The treatment of patients affected with nonclassical CAH, particularly males, remains controversial. Variable synthetic glucocorticoids are used and new modes of glucocorticoid delivery are under investigation. To improve height, growth hormone and other adjuvant therapies are employed. Long-term outcomes of genital surgery using modern techniques in females affected with classical CAH continue to be investigated. Prenatal treatment with dexamethasone is available to avoid ambiguous genitalia in these females. Although studies have shown its safety to mother and fetus, prenatal treatment is still regarded as experimental. Currently, prenatal diagnosis of CAH can only be obtained through invasive methods. Recently, the detection of cell-free fetal DNA in maternal plasma has made it possible to make this diagnosis earlier and noninvasively.

A CYP21A2 gene mutation in patients with congenital adrenal hyperplasia

Objectives:The aim of this study is to determine congenital adrenal hyperplasia (CAH) with the pattern of CYP21A2 gene-mutations in Saudi children.Methods:Between January 2011 and March 2014 at King Fahad Military Complex, Dhahran, Saudi Arabia, we thoroughly examined 11 patients with CAH and 2 asymptomatic individuals with a history of affected siblings. Additionally, we sequenced the full coding regions of the CYP21A2 gene and screened the gene for deletion(s)/duplication(s) using the multiplex ligation-dependent probe amplification (MLPA) technique.Results:Nine patients had classic CAH and presented with ambiguous genitalia and/or salt losing crisis. Two patients had the non-classic form of CAH and presented with precocious puberty. The remaining 2 subjects were asymptomatic. Screening the CYP21A2 gene, we detected p.Gln318X mutation in 4 patients, c.290 -13 C>G (IVS2-13C>G) in another 4, and a common deletion, involving exons 6 and 8 in 3 patients.Conclusion:Our strategy of Sanger sequencing followed by MLPA was very successful in detecting CYP21A2 mutations in all patients with CAH.

17-Hydroxyprogesterone in children, adolescents and adults

17-Hydroxyprogesterone (17-OHP) is an intermediate steroid in the adrenal biosynthetic pathway from cholesterol to cortisol and is the substrate for steroid 21-hydroxylase. An inherited deficiency of 21-hydroxylase leads to greatly increased serum concentrations of 17-OHP, while the absence of cortisol synthesis causes an increase in adrenocorticotrophic hormone. The classical congenital adrenal hyperplasia (CAH) presents usually with virilisation of a girl at birth. Affected boys and girls can have renal salt loss within a few days if aldosterone production is also compromised. Diagnosis can be delayed in boys. A non-classical form of congenital adrenal hyperplasia (NC-CAH) presents later in life usually with androgen excess. Moderately raised or normal 17-OHP concentrations can be seen basally but, if normal and clinical suspicion is high, an ACTH stimulation test will show 17-OHP concentrations (typically >30 nmol/L) above the normal response. NC-CAH is more likely to be detected clinically in females and may be asymptomatic particularly in males until families are investigated. The prevalence of NC-CAH in women with androgen excess can be up to 9% according to ethnic background and genotype. Mutations in the 21-hydroxylase genes in NC-CAH can be found that have less deleterious effects on enzyme activity. Other less-common defects in enzymes of cortisol synthesis can be associated with moderately elevated 17-OHP. Precocious puberty, acne, hirsutism and subfertility are the commonest features of hyperandrogenism. 17-OHP is a diagnostic marker for CAH but opinions differ on the role of 17OHP or androstenedione in monitoring treatment with renin in the salt losing form. This review considers the utility of 17-OHP measurements in children, adolescents and adults.

Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p=7.13×10(-16)). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p=1.61×10(-14)). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6%; p=1.08×10(-4)). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.

Overview of Genetic Defects in Endocrinopathies in the Island of Cyprus; Evidence of a Founder Effect

Hereditary endocrinopathies in Cyprus exhibit evidence of a founder effect and display the influence of past migration patterns. The genetic frequency and mutation pattern of a specific disorder of sex development (DSD), which is classified as 46,XX DSD or 46,XY DSD, and the non-classic form of congenital adrenal hyperplasia (NC-CAH) outline a type of genetic drift. Not only the high prevalence of the NC-CAH p.V281L mutation but also the rarity of CAH large lesions present a genetic diversity similar to that observed in the Middle Eastern countries. In addition, both the high frequency of the 5-alpha steroid reductase deficiency (5αSRD) IVS1-2A>G mutation and the carrier frequency of the 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD-3) p.R80Q mutation are good examples of a founder effect. p.R80Q can be considered a founder mutation, even though it has been identified in patients of Dutch, Brazilian, and Portuguese origin. This has led to the speculation that it has a Phoenician origin. Phoenicians as ancient traders migrated around 750 BC from present day Syria, Lebanon, and Israel toward Portugal, Spain, and also to nearby Cyprus. While the 5αSRD IVS1-2A>G mutation has already been extensively reported in Turkish patients, it is very common in the Eastern Mediterranean region. This short article portrays clearly, through specific endocrine genetic disorders, the past migration trends in Cyprus that shaped the present-day gene pool of the Greek-Cypriot population.

CYP21A2 gene mutationsin the women with recurrent miscarriage

Miscarriage is one of the major problems of modern reproduction. Total frequency of micarrieges is estimated as 15–27 % of total pregnancies. Recurrent Miscarriage (RM) (three or more spontaneous abortions) is responsible for almost 20 % of total miscarrieges. The population frequency of RM fluctuates from 2 % to 5 %. One of the important causes of abortion in the first trimester are hormonal disturbances in the mother, including adrenal hyperandrogenism, which results in congenital adrenal hyperplasia (CAH). In 95 % of cases, this pathology is caused by mutations in the 21-hydroxylase gene (CYP21A2), encoding for 21-hydroxylase. A non-classical form of CAH is the leading factor in 30 % of RM in women with hyperandrogenia. The aim of this study was to investigate the role of the most common mutations in the CYP21A2 gene in women with RM for more accurate diagnosis of this pathology. The level of 17-OH-progesterone was measured in women with RM and with mutations in the gene CYP21A2. The frequency of mutations in the CYP21A2 gene in RM women was significantly higher than in the group of women who don’t have these mutations (14.4 ± 3.3 % and 2 ± 1.4 %, respectively, p &lt;0,05 df = 1). According to the odds ratio the risk of RM in CYP21A2 mutations carriers is 8 times higher than in the women without these mutations (OR = 8.4 (1.9–37.6)). The level of 17-OH-progesterone is not associated with mutations in CYP21A2 gene in the women with RM

Genetic disorders of adrenal hormone synthesis.

Steroid 21-hydroxylase is the enzyme involved in 90-95% of cases of congenital adrenal hyperplasia (CAH). The general feature of CAH, which results from an enzymatic block at any stage in the synthesis of cortisol, is increased serum adrenocorticotropin and thus stimulated adrenal synthesis of steroids proximal to the block. All enzyme defects causing CAH are autosomal recessive traits. The early steps in cortisol synthesis are common to adrenal and gonadal steroid pathways, thus CAH caused by dysfunction of the enzymes supporting these steps is also characterized by insufficient production of gonadal hormones, causing impaired genital development in the genetic male. The absence of or severe reduction of steroid 21-hydroxylase activity also causes prenatal hypersecretion of androgens by the adrenal cortex, which results in external genital ambiguity in genetic females. This paper discusses the classical and nonclassical forms of CAH, their aetiology, diagnosis and treatment, and also describes recent advances in prenatal diagnosis and treatment which avoids the need for corrective genital plastic surgery in infancy.