Genotypic spectrum of 21-hydroxylase deficiency in an endogamous population.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. METHODS: Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99 years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8 bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. RESULTS: Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. CONCLUSION: Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.

Low Adrenomedullary Function Predicts Acute Illness in Infants With Classical Congenital Adrenal Hyperplasia.

CONTEXT: Youth with classical congenital adrenal hyperplasia (CAH) exhibit abnormal adrenomedullary function with decreased epinephrine levels noted in newborns and young infants. Little is known about how this relates to morbidity during the first year of life. OBJECTIVE: This work aimed to study plasma epinephrine levels in infants with classical CAH and examine the clinical significance of epinephrine deficiency in the first year of life. METHODS: This prospective cohort study comprised participants recruited from a pediatric tertiary care center: 36 infants with classical CAH due to 21-hydroxylase deficiency and 27 age-matched unaffected controls with congenital hypothyroidism. Main outcome measures included plasma epinephrine levels (N = 27), CYP21A2 genotype (N = 15), and incidence of acute illnesses from birth to age 1 year (N = 28). RESULTS: Epinephrine levels in CAH infants independently predicted illness incidence in the first year of life (ß = -0.018, R = -0.45, P = .02) and were negatively correlated with 17-hydroxyprogesterone at diagnosis (R = -0.51, P = .007). Infants with salt-wasting CAH exhibited lower epinephrine levels as newborns than simple-virilizing infants (P = .02). CAH patients had lower epinephrine as newborns than did controls (P = .007) and showed decreases in epinephrine from birth to age 1 year (P = .04). Null genotype was associated with lower newborn epinephrine and more illness in the first year of life, compared to less severe mutation categories. CONCLUSION: Lower epinephrine levels are associated with increased risk of illness among CAH infants. While not currently part of clinical standard of care, measuring epinephrine levels and assessing genotype may help predict acute illness in the first year of life.

Chronic social defeat stress causes retinal vascular dysfunction.

PURPOSE: The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss. METHODS: Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy. RESULTS: No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD. CONCLUSIONS: We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BACKGROUND: Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. METHODS: Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. SUMMARY: Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. CONCLUSIONS: CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Cardiovascular Disease Risk Factors and Metabolic Morbidity in a Longitudinal Study of Congenital Adrenal Hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) are exposed to hyperandrogenism and supraphysiologic glucocorticoids, both of which can increase risk of metabolic morbidity. OBJECTIVE: Our aim was to evaluate cardiovascular and metabolic morbidity risk in a longitudinal study of patients with CAH spanning both childhood and adulthood. DESIGN AND SETTING: Patients with classic CAH followed for a minimum of 5 years during both childhood and adulthood (n = 57) at the National Institutes of Health were included and compared with the US general population using NHANES data. MAIN OUTCOME MEASURES: Obesity, hypertension, insulin resistance, fasting hyperglycemia, and dyslipidemia. RESULTS: Compared to the US population, patients with CAH had higher (P < 0.001) prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein (HDL) during childhood and obesity (P = 0.024), hypertension (P<0.001), and insulin resistance (P < 0.001) during adulthood. In our cohort, obesity, hypertension, fasting hyperglycemia, and hypertriglyceridemia began prior to age 10. During childhood, increased mineralocorticoid dose was associated with hypertension (P = 0.0015) and low HDL (P = 0.0021). During adulthood, suppressed androstenedione was associated with hypertension (P = 0.002), and high low-density lipoprotein (P = 0.0039) whereas suppressed testosterone (P = 0.003) was associated with insulin resistance. Elevated 17-hydroxyprogesterone, possibly reflecting poor disease control, was protective against high cholesterol (P = 0.0049) in children. Children whose mothers were obese (maternal obesity) had increased risk of obesity during adulthood (P = 0.0021). Obesity, in turn, contributed to the development of hypertension, insulin resistance, and hypertriglyceridemia in adulthood. CONCLUSION: Patients with CAH develop metabolic morbidity at a young age associated with treatment-related and familial factors. Judicious use of glucocorticoid and mineralocorticoid is warranted.

Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia.

BACKGROUND/PURPOSE: Although it is known that there is generally a good correlation between genotypes and phenotypes, the number of studies reporting discrepancies has recently increased, exclusively between milder genotypes and their phenotypes due to the complex nature of the CYP21A2 gene and methodological pitfalls. This study aimed to assess CYP21A2 genotyping in children with 21-hydroxylase deficiency (21-OHD) and establish their predictive genotype-phenotype correlation features using a large cohort in Southeastern Anatolia's ethnically diverse population. METHODS: The patients were classified into three groups: salt-wasting (SW), simple virilizing (SV) and non-classical (NC). The genotypes were categorized into six groups due to residual enzyme activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. RESULTS: A total of 118 unrelated children with 21-OHD were included in this study (61% SW, 24.5% SV and 14.5% NC). The pathogenic variants were found in 79.5% of 171 mutated alleles (60.2%, 22.2%, and 17.6% in SW, SV and NC, respectively). Patient distribution based on genotype groups was as follows: null-16.1%, A-41.4%, B-6.0%, C-14.4%, E-22%). In2G was the most common pathogenic variant (33.9% of all alleles) and the most common variant in the three phenotype groups (SW-38.8%, SV-22.2% and NC-23.3%). The total genotype-phenotype correlation was 81.5%. The correlations of the null and A groups were 100% and 76.1%, respectively, while it was lower in group B and poor in group C (71.4% and 23.5%, respectively). CONCLUSION: This study revealed that the concordance rates of the severe genotypes with their phenotypes were good, while those of the milder genotypes were poor. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

Incidental Finding of Bilateral Ovarian Adrenal Rest Tumor in a Patient With Congenital Adrenal Hyperplasia: A Case Report and Brief Review.

Ovarian adrenal rest tumors (OART) are tumors that develop in females with congenital adrenal hyperplasia (CAH). In contrast to their counterpart in testicles, they are exceptional and few cases have been reported in the literature. In this report, we present clinicopathological findings of a female patient with CAH due to 21-hydroxylase deficiency who was incidentally diagnosed with OART with a review of the literature. The 14-year-old patient, who was raised as a boy, developed a virilizing syndrome with high testosterone levels that were attributed to non adherence to her replacement corticosteroid therapy. She consulted for sex reassignment surgery. Pelvic ultrasound was normal. She underwent hysterectomy and bilateral adnexectomy. No abnormalities were noticed during the operation. Grossly, both ovaries were variegated with well circumscribed and lobulated, brownish-yellow nodules. Histologically, the nodules were composed of nests of large polygonal cells with centrally located nuclei and prominent nucleoli. There was mild atypia and no crystals of Reinke. Thus, the findings of the histopathological examination were consistent with bilateral OART. Histological differential diagnosis of OART can be challenging particularly with leydig cell tumor, stromal luteoma and steroid cell tumors, not otherwise specified. OART must be considered in women with CAH and persistent virilizing symptoms despite negative imaging results.

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

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.

Disorders of Sex Development of Adrenal Origin.

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11ß-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3ßHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia.

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. Clinical consequences of gonadal dysfunction include menstrual disturbances in females and hypogonadism and impaired fertility in males and females. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. In females, gonadal dysfunction can result from an overproduction of adrenal androgens including 11-oxygenated C-19 androgens and progestins, and rarely from ovarian adrenal rest tumours. In all patients with CAH, optimal hormonal control is the key for adequate gonadal function. Therefore, regular measurements of adrenal steroids and/or their metabolites should be performed. In addition, markers of the hypothalamus-pituitary-gonadal axis need to be assessed. In females, the regularity of the menstrual cycle should be evaluated. In males, regular evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. When TART is present, counselling on cryopreservation of semen should be offered.

Reproductive and Perinatal Outcomes in Women with Congenital Adrenal Hyperplasia: A Population-based Cohort Study.

CONTEXT: Reduced fertility has been reported for women with congenital adrenal hyperplasia (CAH), especially for those with the salt-losing form. However, data are sparse on reproductive and perinatal outcomes in these women. OBJECTIVE: To investigate reproductive and perinatal outcomes in women with CAH. DESIGN AND SETTING: Population-based and nationwide study using the National CAH Register, the Total Population Register, and the Medical Birth Register of Sweden. PARTICIPANTS: A total of 272 women with CAH due to 21-hydroxylase deficiency and 27 200 controls matched by sex, age, and place of birth. The median age was 31 years. MAIN OUTCOME MEASURES: The proportion of CAH women that have given birth, and reproductive and perinatal outcomes. RESULTS: Of the 272 women with CAH, 69 gave birth to at least 1 child (25.4%), which was a lower frequency than for the controls (45.8%) (P < .001). Furthermore, women with CAH had fewer children than controls and were slightly older at birth of their first child. More women with CAH were diagnosed with gestational diabetes than controls, 4.9% versus 1.4% (P < .05), and more women with CAH were delivered through cesarean section, 51.4% versus 12.3% (P < .05). There was no difference in Apgar score or frequency of small-for-gestational age between children born to mothers with CAH and controls. CONCLUSIONS: This is, to our knowledge, the largest cohort designed to investigate reproductive and perinatal outcomes in women with CAH. We found the birth rate to be lower in women with CAH; gestational diabetes and cesarean section were more common, but perinatal outcomes were comparable with controls.

Comment on: Adrenal hypoplasia congenita in identical twins.

[No Abstract Available].

Growth Trajectory and Adult Height in Children with Nonclassical Congenital Adrenal Hyperplasia.

BACKGROUND: Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH). OBJECTIVE: The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH. METHODS: The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models. RESULTS: The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and <0.001). PG was higher in males than in females (22.59 ± 5.74 vs. 20.72 ± 17.4 cm, p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children. CONCLUSIONS: The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.

STAR mutations causing non­classical lipoid adrenal hyperplasia manifested as familial glucocorticoid deficiency.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by single cortisol deficiency but normal aldosterone and renin levels. Beginning from the discovery of the disease to that of the pathogenic genes over a period of 30 years, the development of gene detection technology has identified a large number of FGD­related genes. Despite the fact that the genetic defect underlying this disease is known for approximately 70% of the patients diagnosed with FGD, there are still several unknown factors causing it. FGD is divided into type 1, type 2 and non­classical type according to the mutant gene. The case described in the present study reported two patients, who were siblings, having skin hyperpigmentation and undergone treatment in adulthood. The gonadal development was normal and the proband had a 10­year­old son. Laboratory tests suggested glucocorticoid deficiency and a mild lack of mineralocorticoid, indicating hyponatremia and hypotension in the proband. In addition, cortisol deficiency was not affected by adrenocorticotropic hormone treatment, while the adrenal glands in the two patients did not show any hyperplasia. Gene analysis revealed two compound heterozygote mutations c.533T>A (p. Leu178Gln) and c.737A>G (p. Asp246Gly) in the steroid hormone acute regulatory protein (STAR) gene in both patients, which may have been obtained from their parents and the proband passed one of the mutations to her son. The present study results revealed that STAR mutations cause non­classic congenital lipoid adrenal hyperplasia in China.

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report.

Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

Identity, Sexuality, and Parenthood in Women with Congenital Adrenal Hyperplasia.

STUDY OBJECTIVE: To explore how women with congenital adrenal hyperplasia (CAH) describe their experiences of gender role behavior, psychosexual development, and intimate relationships. CAH results in increased androgen exposure in affected females, and is the most common reason for unclear sex at birth. Women with CAH have been studied to find answers to the role of androgens in psychosexual development. Nevertheless, factors that may account for the variability of outcomes in women with CAH are unclear. DESIGN, SETTING AND PARTICIPANTS: This was a qualitative study with 13 Swedish women (aged ≥18 years) with CAH. Semi-structured interviews were analyzed using inductive content analysis. MAIN OUTCOME MEASURES: Direct quotes of patients' experiences derived from interview transcripts were sorted in categories, subcategories, and according to latent theme. RESULTS: The main categories were "forming identity" and "establishing relationships." Forming identity encompasses that of a girl, a tomboy, and/or a woman. Establishing relationships focuses on intimate relationships, pregnancy, and parenthood. A latent theme was interpreted as "shifting perspectives," with CAH being the main focus of some participants' lives but a side issue for others. CONCLUSION: These women's experiences are varied and describe shifting perspectives on how much CAH affects their lives. Health care providers can play an important role in helping women with CAH to separate what is caused by the condition and what is not. The long-term goal is to help girls and women to feel in control of their condition across their whole life.

Congenital Adrenal Hyperplasia with Salt Wasting Crisis: A Case Report.

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficiencies of enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiency which can be classical or non-classical. The severe form also called Classical Congenital Adrenal Hyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is not diagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. We report a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia. The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and life long oral Prednisolone and Fludrocortisone were prescribed. Keywords: 21-hydroxylase, congenital adrenal hyperplasia, case report.

How do mutations affect the structural characteristics and substrate binding of CYP21A2? An investigation by molecular dynamics simulations.

Congenital adrenal hyperplasia (CAH) is one of the most frequent inborn errors of metabolism, inherited as an autosomal recessive trait. Above 95% of CAH cases are caused by mutations in cytochrome P450 21A2 (CYP21A2). It is a pity that how these mutations affect the structural characteristics and substrate binding of CYP21A2 is still unclear. To this end, molecular dynamics (MD) simulations and binding free energy calculations are performed to investigate the effects of single point mutations (L108R, G292C, G292S, G293D, and T296N) in CYP21A2. The results indicate that mutations could cause the local conformational changes of CYP21A2, affecting the substrate binding by changing the interaction between the protein and heme, changing the charge environment of residues, or introducing steric hindrance. In addition, our work gives a wonderful explanation of the phenomenon that though the substrate binding ability increases, the reaction activity decreases in T296N. The present study provides detailed atomistic insights into the structure-function relationships of CYP21A2, which could contribute to further understanding about 21-hydroxylase deficiency and also provide a theoretical basis for CAH prediction and treatment.

A rare CYP21A2 haplotype clarifies the phenotype-genotype discrepancy in an Italian patient with Non Classical Congenital Adrenal Hyperplasia (NC-CAH).

RCCX haplotypes with two copies of the CYP21A2 gene and one copy of the CYP21A1P pseudogene have been widely described in different populations. In most cases, the CYP21A2-like gene downstream of the TNXA gene showed a wild-type sequence or the c.293-13A/C > G variant while the CYP21A2 gene next to TNXB carried the p.(Gln319Ter) variant. Here is the discovery of a novel rare CYP21A2 haplotypes detected in an Italian patient with Non Classical Congenital Adrenal Hyperplasia (NC-CAH). The molecular family study was performed clarifying the previously found phenotype-genotype discrepancy.