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Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

ABSTRACT: 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3'untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers-Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.

SUBMITTER: Paragliola RM

PROVIDER: S-EPMC9267771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mortality in children with classic congenital adrenal hyperplasia and 21-hydroxylase deficiency (CAH) in Germany.

Project description:BackgroundAdrenal crises in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are life-threatening and have the potential to death.MethodsA survey was performed among Paediatric Endocrinologists in Germany to report on deceased children with CAH. Our survey covered the whole of Germany.ResultsThe participating centres reported 14 cases of death (9 female, 5 male) from 1973 until 2004, but no deaths thereafter. 11 children had the SW form and 3 the simple virilizing (SV) form. All patients were on glucocorticoid replacement, and the SW forms additionally on mineralocorticoid replacement. The age at death varied between 6 weeks and 16.5 years. Seven children died before introduction of general neonatal screening, and 7 children thereafter. Before death, the clinical signs of impending crisis were nonspecific. Five patients developed hypoglycaemia and convulsions with cerebral oedema. Half of the deceased patients died at home. The hydrocortisone dosage was only doubled in two of the 14 cases.ConclusionsAccording to the assessments by the attending centres, almost all deaths could be related to an inadequate administration of stress doses of hydrocortisone. Since no deceased CAH children were reported in Germany from 2005 on, we assume the effectiveness of educational programs over the past years.

| S-EPMC5994009 | biostudies-literature

Characteristics of In2G Variant in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Project description:Substantial research has been performed during the last decades on the clinical and genetic variability of congenital adrenal hyperplasia (CAH) and its most common form, 21-hydroxylase deficiency (21OHD). CAH is one of the most prevalent autosomal recessive diseases in humans, and it can be divided into classic-further subdivided into salt wasting (SW) and simple virilizing (SV)-and non-classic (NC) forms. Pathogenic variants of CYP21A2 gene, encoding the 21-hydroxylase enzyme, have been reported with variable prevalence in different populations. NM_000500.9:c.293-13C/A>G (In2G) variant represents the most common CYP21A2 gene changes related to the classic 21OHD form. However, the phenotype of In2G carriers is variable depending on the variant homozygous/heterozygous status and combination with other CYP21A2 pathogenic variants. In addition, identical genotypes, harboring the homozygous In2G variant, can present with variable phenotypes including the SW and SV or rarely NC form of the disease. Here, we analyze and present the clinical aspects, genotype/phenotype correlations, and other characteristics related to the CYP21A2 In2G variant.

| S-EPMC8818746 | biostudies-literature

Quality of Life in Men With Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Project description:Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p<0.05). Patients treated with dexamethasone or prednisone scored higher on the physical health, psychological health, and social relationships domains, but not on the environmental domain. In conclusion, QoL domain scores appeared to be comparable to healthy reference populations and higher compared to patients with a chronic illness. QoL was not influenced by genotype, but undertreatment and use of dexamethasone or prednisone were associated with higher QoL.

| S-EPMC8018222 | biostudies-literature

Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:BACKGROUND:Prior studies reveal that bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) is mostly in the osteopaenic range and is associated with lifetime glucocorticoid dose. The forearm, a measure of cortical bone density, has not been evaluated. OBJECTIVE:We aimed to evaluate BMD at various sites, including the forearm, and the factors associated with low BMD in CAH patients. METHODS:Eighty CAH adults (47 classic, 33 nonclassic) underwent dual-energy-x-ray absorptiometry and laboratory and clinical evaluation. BMD Z-scores at the AP spine, total hip, femoral neck, forearm and whole body were examined in relation to phenotype, body mass index, current glucocorticoid dose, average 5-year glucocorticoid dose, vitamin D, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHEAS). RESULTS:Reduced BMD (T-score <-1 at hip, spine, or forearm) was present in 52% and was more common in classic than nonclassic patients (P = 0·005), with the greatest difference observed at the forearm (P = 0·01). Patients with classic compared to nonclassic CAH, had higher 17-hydroxyprogesterone (P = 0·005), lower DHEAS (P = 0·0002) and higher non-traumatic fracture rate (P = 0·0005). In a multivariate analysis after adjusting for age, gender, height standard deviation, phenotype and cumulative glucocorticoid exposure, higher DHEAS was independently associated with higher BMD at the spine, radius and whole body. CONCLUSION:Classic CAH patients have lower BMD than nonclassic patients, with the most affected area being the forearm. This first study of forearm BMD in CAH patients suggests that low DHEAS may be associated with weak cortical bone independent of glucocorticoid exposure.

| S-EPMC4242797 | biostudies-literature

Cardiovascular risk factors in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:ObjectiveThe prevalence of cardiovascular risk factors in congenital adrenal hyperplasia (CAH) varies widely. In the light of recent changes in treatment regimens, we have reassessed the prevalence of these risk factors in our current cohort of patients with CAH due to P450c21 deficiency.MethodsA retrospective cross-sectional study of 107 children (39 m) with CAH aged 9·2 years (range 0·4-20·5 years). Anthropometric, systolic (SBP) and diastolic (DBP) blood pressure data were collected and expressed as standard deviation scores (SDS) using UK growth reference data and the Fourth Task Force data set, respectively. Fasting blood glucose with plasma insulin and lipids was measured, and insulin resistance (HOMA IR) calculated using the homoeostasis assessment model.Results23·6% (33% men; 18% women) of the cohort were obese (BMI SDS>2). BMI SDS was significantly higher (P < 0·001) when compared with the UK population. Nineteen (20·9%) of 91 patients (20% men; 21% women) had systolic hypertension and 8 [8·8% (8·6% men; 8·9% women)] had diastolic hypertension. Mean SBP [108 (SD 13·5)] mm Hg was significantly higher than the normal population (P < 0·001), but mean DBP was not (P = 0·07). Both SBP SDS and DBP SDS were not related to BMI SDS. 9·5% of the subjects had hyperlipidaemia, but HOMA IR was more favourable compared with the normal population.ConclusionDespite a reduction in steroid doses over the last decade, a number of children with CAH are still obese and hypertensive. Whether this reflects general population trends or indicates a need to further optimize treatment regimens remains to be determined.

| S-EPMC4204515 | biostudies-literature

Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:BackgroundGenetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.Study objectiveThe objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients.MethodsTargeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype.ResultsIn our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively.ConclusionsExtensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.

| S-EPMC3038490 | biostudies-literature

Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:INTRODUCTION:21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE:The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS:We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS:The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION:Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed, the CYP3A7*1C allele accounted for 20% of the variability in the cortisone acetate dose. The analysis of genes involved in glucocorticoid metabolism may be useful in the optimization of treatment of 21-hydroxylase deficiency.

| S-EPMC3161212 | biostudies-literature

Phenotype of patients with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Project description: Not available

| S-EPMC4428642 | biostudies-literature

Complement component 4 variations may influence psychopathology risk in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:CYP21A2 defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis. CYP21A2 lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes C4A and C4B have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate C4A and C4B in patients with CAH in relation to CYP21A2 genotype and psychiatric and autoimmune comorbidity. We determined the copy numbers of C4A and C4B in 145 patients with CAH (median age: 15.5 years, IQR: 16.8) and 108 carrier relatives (median age: 41.5 years, IQR: 12.0) and evaluated serum C4 concentrations. Comorbidity was determined by medical record review. Only 30% of subjects had the expected two copies each of the two C4 genes. C4B copy number determined total C4 copy number and serum C4 concentration, negatively correlated with carriership of a 30-kb deletion (P?<?10-?5), and positively correlated with carriership of p.V281L (P?<?10-?5). High C4A copy number (??3) was associated with increased risk of having an externalizing psychiatric condition (relative risk: 2.67, 95% CI: 1.03-6.89, P?=?0.04). No association was found between C4 copy number and autoimmune disease. Mutation-specific C4 structural variations commonly occur in patients with CAH and may have important clinical consequences, including increased risk of psychiatric morbidity. Trial registration NCT00250159 (November 7, 2005).

| S-EPMC6702947 | biostudies-literature

Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Project description:ObjectivesTo test whether dexamethasone (DEX) treatment in pregnancies at risk for congenital adrenal hyperplasia (CAH) impairs cognitive functioning in the offspring.DesignObservational follow-up of prenatally DEX-exposed offspring and controls.MethodsStudy 1 included 140 children aged 512 years: 67 DEX-exposed (long-term: eight CAH girls) and 73 unexposed (with 15 CAH girls). Study 2 included 20 participants aged 11-24 years: seven DEX-exposed (long-term: one CAH woman) and 13 unexposed (with four CAH women). Neuropsychological testing was done in hospital settings or at patients' homes. Data analysis aimed at maximizing detection of the effects of DEX exposure.ResultsThe vast majority of group comparisons were not marginally or conventionally significant. The few significant findings on short-term prenatal DEX exposure suggested more positive than adverse outcomes. By contrast, few significant findings in females with CAH and long-term DEX exposure indicated slower mental processing than in controls on several neuropsychological variables, although partial correlations of DEX exposure duration with cognitive outcome did not corroborate this association.ConclusionsAlthough our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory, our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive after effects of such exposure. Yet, our studies are not definitive, and replications in larger samples are required.

| S-EPMC3383400 | biostudies-literature

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