Altered Gray Matter Structure and White Matter Microstructure in Patients with Congenital Adrenal Hyperplasia: Relevance for Working Memory Performance.

Congenital adrenal hyperplasia (CAH) has been associated with brain structure alterations, but systematic studies are lacking. We explore brain morphology in 37 (21 female) CAH patients and 43 (26 female) healthy controls, aged 16-33 years, using structural magnetic resonance imaging to estimate cortical thickness, surface area, volume, subcortical volumes, and white matter (WM) microstructure. We also report data on a small cohort of patients (n = 8) with CAH, who received prenatal dexamethasone (DEX). Patients with CAH had reduced whole brain volume (4.23%) and altered structure of the prefrontal, parietal, and superior occipital cortex. Patients had reduced mean FA, and reduced RD and MD, but not after correcting for brain volume. The observed regions are hubs of the visuospatial working memory and default mode (DMN) networks. Thickness of the left superior parietal and middle frontal gyri was associated with visuospatial working memory performance, and patients with CAH performed worse on this task. Prenatal treatment with DEX affected brain structures in the parietal and occipital cortex, but studies in larger cohorts are needed. In conclusion, our study suggests that CAH is associated with brain structure alterations, especially in the working memory network, which might underlie the cognitive outcome observed in patients.

Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish children and adolescents at risk of congenital adrenal hyperplasia.

Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but potential long-term adverse effects are largely unknown. In this report we intended to explore potential side effects of DEX therapy to enhance the adequacy of future risk benefit analyses of DEX treatment. We investigated the long-term effects of first trimester prenatal DEX treatment on behavioral problems and temperament in children and adolescents aged 7-17 years. The study included 34 children and adolescents, without CAH, who had been exposed to DEX during the first trimester and 67 untreated controls. Standardized parent-completed questionnaires were used to evaluate adaptive functioning and behavioral/emotional problems (CBCL), social anxiety (SPAI-C-P), and temperament (EAS) in the child. Self-reports were used to assess the children's perception of social anxiety (SASC-R). No statistically significant differences were found between DEX-treated and control children and adolescents, suggesting that, in general, healthy children treated with DEX during early fetal life are well adjusted.

Cognitive impairment in adolescents and adults with congenital adrenal hyperplasia.

OBJECTIVE: Impaired cognition has been reported in patients with congenital adrenal hyperplasia (CAH), although the findings have been conflicting. It has been hypothesized that the major causes of the deficits are prenatal hormonal imbalances and/or excessive glucocorticoid treatment. DESIGN: An observational study investigating cognition in patients with CAH. PATIENTS: A total of 55 patients with CAH and 58 control subjects from the general population, aged 16-33 years. Nine CAH subjects had been treated prenatally with dexamethasone. SETTING: Singel research institute. MEASUREMENTS: Standardized neuropsychological tests (Wechsler Scales and Stroop Interference Test) and questionnaires (Barkley Deficit in Executive Functioning Scale) were used. RESULTS: Compared to controls, patients with CAH had impaired performance in tests measuring verbal working memory (P = .024), visual-spatial working memory (P = .005 and P = .003) and inhibition (P = .002). In measures of fluid intelligence/nonverbal logical reasoning, males with CAH performed poorer than control males (P = .033). Patients with salt-wasting CAH performed equally compared to patients with simple virilizing CAH. However, patients with a null genotype performed poorer than patients with a non-null genotype and significantly worse on fluid intelligence/nonverbal logical reasoning (P = .042). Prenatally-treated women performed worse on most cognitive measures than women with CAH not treated prenatally. CONCLUSIONS: Patients with CAH had normal psychometric intelligence but impaired executive functions compared with population controls. A null CAH genotype was associated with poorer general cognitive capacity.

Combined external and intracavitary irradiation in treatment of advanced cervical carcinomas: predictive factors for treatment outcome and early and late radiation reactions.

OBJECTIVE: The objective of this study was to find out predictive factors of tumor control as well as acute and late radiation reactions in treatment of advanced cervical carcinomas. METHODS: In a series of 134 primary cervical carcinomas in International Federation of Gynecology and Obstetrics stages I to IV treated with combined external pelvic and intraluminal cervical-vaginal brachytherapy, predictive and prognostic factors were analyzed with regard to tumor control, recurrences, survival data, and adverse effects. Concomitant chemotherapy was given to 48 patients (35.8%). The external beam therapy was given with a 4-field technique (50-60 Gy) and brachytherapy was given with a high-dose rate (iridium-192) afterloading technique using a ring applicator set. A computed tomographically based 3-dimensional dose-planning system was used for the external beam therapy and for the brachytherapy planning. The mean age of the patients was 65 years. A total of 110 tumors were squamous cell carcinomas and 24 were adenocarcinomas or adenosquamous carcinomas. A total of 111 tumors were in International Federation of Gynecology and Obstetrics stages I to II; 23 tumors, in stages III to IV. RESULTS: The primary control rate of the complete series was 92.5%. Tumor size, the brachytherapy dose, the combined external and brachytherapy dose, as well as the number of days of interruption (delay) of irradiation were all significant predictive factors for local tumor control. Forty recurrences (30%) were recorded. Early radiation reactions were recorded in 67% (mostly grade 1) and were associated with the widths of the anterior-posterior and lateral pelvic fields. Serious late radiations reactions (grade 3-4) were noted in 11%. CONCLUSIONS: The width of the lateral pelvic fields, left point A and B doses, dose to the rectal reference point, as well as asymmetry of the dose distribution were associated with late severe reactions. Prior abdominal and pelvic surgery was also a high-risk factor for late tissue reactions. Concomitant chemotherapy did not increase the risk for acute or late toxicity.

Intraoperative Radiation Therapy Delivered by Brachytherapy in Breast Cancer: An Interim Analysis of a Phase 2 Trial.

PURPOSE: Intraoperative breast cancer radiotherapy (IORT) offers an alternative to external beam radiotherapy (EBRT) after breast-conserving surgery (BCS). The Intraoperative brachytherapy (IOBT) trial applies high dose rate (HDR) brachytherapy with a new applicator prototype as IORT after BCS. In this interim analysis of the IOBT trial, we present the oncological safety and toxicity of the method METHODS: Eligible patients were women, ≥ 50 years old with an unifocal nonlobular, estrogen-receptor-positive, HER2-negative breast cancer, cN0, ≤ 3 cm, treated with BCS and sentinel node biopsy (SNB). Toxicity was registered according to the LENT-SOMA scale. Cumulative incidence of local (LR) and regional recurrence (RR) were calculated through cumulative incidence function whereas overall survival (OS) was illustrated through Kaplan-Meier curve. RESULTS: Until February 2023, 155 women (median age 68 years) were included in the trial. Twenty-nine women (18.7%) received supplemental EBRT, mostly due to positive SNB. Three-year cumulative incidence of LR and RR were 1.0% (CI 95 % 0.1%-2.3%) and 2.1% (CI 95% 0.8%-4.2%) respectively. Five- year cumulative incidence of LR and RR were 3.9% (CI 95% 1.8%-6.4%) and 2.1% (CI 95% 0.8%-4.2%) respectively. Five-year OS was 96.3% (CI 95% 93.6%-98.4%). Side effects were limited, low grade, and transient. CONCLUSION: Acknowledging the short median follow-up time at interim analysis, our initial results indicate that delivering IORT through HDR brachytherapy in carefully selected breast cancer patients is feasible and oncological safe so far. A long-term follow-up is essential to confirm the initial results.

Brain activity during visuospatial working memory in congenital adrenal hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) require life-long replacement of cortisol. Problems with cognitive function, especially working memory, have previously been identified, but the long-term effects of this disease on brain function are unknown. OBJECTIVE: We investigate brain activity during working memory in CAH compared to controls. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine individuals with CAH (17 females) and 40 healthy controls (24 females), 16-33 years, from a single research institute, underwent functional magnetic resonance imaging while doing a verbal and visuospatial working memory task. RESULTS: Individuals with CAH responded faster on the verbal task. Although we found no differences in BOLD response over the whole group, there were significant interactions with sex: CAH males had increased activity in the bilateral lateral superior occipital cortex, left supramarginal and angular gyri, left precuneus, left posterior cingulate cortex and bilateral cerebellum during decoding of the visuospatial task, while females showed decreased activity in these regions. CONCLUSIONS: Long-term cortisol imbalances do not seem to have a major impact on the functional brain responses during working memory in CAH. However, activity of the left dorsal visual stream in particular might be affected depending on sex. As the task employed may have been relatively easy, larger studies using more complex tasks are needed to further investigate this.

Effect of controlled hypotensive hemorrhage on plasma sodium levels in anesthetized pigs: An exploratory study.

Perioperative hyponatremia, due to non-osmotic release of the antidiuretic hormone arginine vasopressin, is a serious electrolyte disorder observed in connection with many types of surgery. Since blood loss during surgery contributes to the pathogenesis of hyponatremia, we explored the effect of bleeding on plasma sodium using a controlled hypotensive hemorrhage pig model. After 30-min baseline period, hemorrhage was induced by aspiration of blood during 30 min at mean arterial pressure <50 mmHg. Thereafter, the animals were resuscitated with retransfused blood and a near-isotonic balanced crystalloid solution and monitored for 180 min. Electrolyte and water balances, cardiovascular response, renal hemodynamics, and markers of volume regulation and osmoregulation were investigated. All pigs (n = 10) developed hyponatremia. All animals retained hypotonic fluid, and none could excrete net-free water. Urinary excretion of aquaporin 2, a surrogate marker of collecting duct responsiveness to antidiuretic hormone, was significantly reduced at the end of the study, whereas lysine vasopressin, i.e., the pig antidiuretic hormone remained high. In this animal model, hyponatremia developed due to net positive fluid balance and generation of electrolyte-free water by the kidneys. A decreased urinary aquaporin 2 excretion may indicate an escape from antidiuresis.

An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia.

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Symmetry breaking in core-valence double ionisation of allene.

Conventional electron spectroscopy is an established one-electron-at-the-time method for revealing the electronic structure and dynamics of either valence or inner shell ionized systems. By combining an electron-electron coincidence technique with the use of soft X-radiation we have measured a double ionisation spectrum of the allene molecule in which one electron is removed from a C1s core orbital and one from a valence orbital, well beyond Siegbahns Electron-Spectroscopy-for-Chemical-Analysis method. This core-valence double ionisation spectrum shows the effect of symmetry breaking in an extraordinary way, when the core electron is ejected from one of the two outer carbon atoms. To explain the spectrum we present a new theoretical approach combining the benefits of a full self-consistent field approach with those of perturbation methods and multi-configurational techniques, thus establishing a powerful tool to reveal molecular orbital symmetry breaking on such an organic molecule, going beyond Löwdins standard definition of electron correlation.

Ambulatory Blood Pressure Monitoring in Children and Adults Prenatally Exposed to Dexamethasone Treatment.

CONTEXT: The clinical use of dexamethasone (DEX) prenatally to reduce virilization of external genitalia in female fetuses with congenital adrenal hyperplasia (CAH) is efficient but still controversial. It remains challenging to prevent the excessive exposure of DEX in unborn healthy babies during the first trimester of pregnancy. OBJECTIVE: Since endogenous glucocorticoids contribute to the maintenance of blood pressure (BP) and since events during fetal life may program the fetus and affect future metabolic health, the aim of this study was to analyze ambulatory BP measurements in CAH-unaffected children and adults that were prenatally exposed to DEX treatment. METHODS: Ambulatory BP measurements were analyzed in 33 (16 female) DEX-treated participants aged 5.1 to 26.3 years (19 participants aged ≤ 18 years) and in 54 (28 female) age- and sex-matched apparently healthy controls aged 5.5 to 25.3 years (27 participants aged ≤ 18 years) with ambulatory normotension. RESULTS: Participants' age, height, weight, and body mass index were similar between the DEX-treated group and the control group. Heart rate, 24-hour BP, pulse pressure, and nighttime dipping did not statistically significantly differ between DEX-treated participants and controls. CONCLUSION: Our study suggests that prenatal DEX treatment in CAH-unaffected children and adults does not appear to adversely affect ambulatory BP later in life. Our observations need to be confirmed in larger studies.

Predicting toxicity caused by high-dose-rate brachytherapy single boost for prostate cancer.

PURPOSE: Treating localized prostate cancer (PC) with combination radiotherapy consisting of external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) has been proven to result in better disease outcome than EBRT only. We aimed to evaluate the incidence of toxicities due to combination therapy and identify parameters correlated to acute or late urinary, rectal, and erectile toxicities. MATERIAL AND METHODS: Data on symptoms and tumor/treatment parameters were collected from 359 patients treated between 2008 and 2018 with EBRT (42 Gy in 14 fractions) and HDR-BT (14.5 Gy in one fraction) for localized PC, at the Örebro University Hospital. Urinary, rectal, and erectile symptoms were presented descriptively, and bivariate analyses for correlation between grade ≥ 2 toxicity and potential predictors were performed. To evaluate prognostic models, multivariable analyses were applied. RESULTS: Urinary toxicity grade ≥ 2 was observed in 154 patients (47% of patients without pre-existing symptoms grade ≥ 2), of which 15 were grade 3. Rectal toxicity grade 2 was observed in 22 (6%) patients. Any grade erectile dysfunction was evident in all patients without pre-existing dysfunction (n = 103), whereas only 7 recovered completely. In bivariate analyses age was correlated with higher risk of acute urinary toxicity, and irradiated volume was associated with both urinary and rectal toxicities. However, we found no multivariable model of clinical and statistical significance to predict the risk of urinary or rectal toxicities. CONCLUSIONS: In our study cohort, the severity of toxicities was in general mild or moderate and temporary, whereas the incidence of severe toxicity was considerably low. Although we found no predictive models for toxicities, our findings are reassuring that this treatment approach as curative therapy for localized PC is well-tolerated.

High-dose-rate brachytherapy as monotherapy for low- and intermediate-risk prostate cancer: long-term experience of Swedish single-center.

PURPOSE: Until now, most long-term results for brachytherapy only has been published for low-dose-rate (LDR) seeds. Due to radiobiology reasons, high-dose-rate (HDR) mono-brachytherapy is of growing interest. The aim of the study was to report long-term biochemical control rate and toxicities with HDR monotherapy. MATERIAL AND METHODS: This was a retrospective single-institution experience, including 229 men, clinically staged T1c-T2b, Gleason 3 + 3 (prostate specific antigen (PSA) ≤ 15), or Gleason 3 + 4 (PSA ≤ 10), consecutively treated between 2004 and 2012 with HDR brachytherapy alone, using three different fractionation schedules of 92-95 Gy (EQD(2), α/ß = 3). Group 4F (n = 19) had a single implant of 9.5 Gy in four fractions over 2 days. Group 3F (n = 107) had three separate implants of 11 Gy over 4 weeks. Group 2F (n = 103) had two implants of 14 Gy over 2 weeks. No adjuvant hormonal therapy was allowed. RESULTS: For 4F, 3F, and 2F study groups, median follow-up was 10.2, 7.1, and 6.1 years, respectively, and biochemical failure rate was 10.5%, 4.7%, and 14.6%, respectively. Early and late side effects were followed with common terminology criteria version 2.0 and patient-reported questionnaires. There were a temporary acute urethral toxicity increase, 1-2 grades over baseline lower urinary tract symptoms (LUTS), which usually recovered. About 1/3 of the patients had a remaining one grade over baseline LUTS. Severe grade 3-4 toxicity were only found in 3.5% of patients. No rectal toxicity was observed. Erectile dysfunction (ED) was depending on age and erectile function before treatment. In patients without ED before the treatment, we found a complete ED in 21% of men at the last follow-up. CONCLUSIONS: In the present study, HDR mono-brachytherapy was found to be an effective treatment, with mild long-term side effects difficult to differentiate from aging effects. There were no significant differences in PSA regression, PSA failure rate, and toxicity between the different fraction schedules.

Intraoperative high dose rate brachytherapy during breast-conserving surgery: A prospective pilot study.

PURPOSE: To evaluate feasibility, quality of life, toxicity, and cosmetic outcome for intraoperative breast cancer brachytherapy after breast-conserving surgery using high dose rate brachytherapy. METHODS: Fifty-two consecutive women, ⩾50 years old, diagnosed with a unifocal non-lobular breast cancer ⩽3 cm, N0, underwent breast-conserving surgery and sentinel node biopsy. Twenty-five women received intraoperative brachytherapy pre-pathology at primary surgery and the others post-pathology, during a second procedure. An applicator, connected to a high dose rate afterloader, was used. Two of the women were excluded due to metastases found per-operatively at a frozen section from the sentinel node. Quality of life was evaluated using two validated health questionnaires. Treatment toxicity was documented according to the LENT-SOMA scale by two oncologists. The cosmetic result was evaluated using the validated freely available software BCCT.core 2.0. RESULTS: The clinical procedure worked out well logistically. Seven women received supplementary external radiotherapy due to insufficient margins and, in one case, poor adaptation of the breast parenchyma to the applicator. No serious adverse effects from irradiation were registered. The results from the health questionnaires showed no major differences compared with reference groups from the Swedish population. Only two women were registered as having a "poor" cosmetic result while a majority of the women had a "good" outcome. CONCLUSIONS: This pilot study shows that intraoperative brachytherapy is a feasible procedure and encourages further trials evaluating its role in treatment of early breast cancer.

Wire Laser Metal Deposition Additive Manufacturing of Duplex Stainless Steel Components-Development of a Systematic Methodology.

A systematic four-stage methodology was developed and applied to the Laser Metal Deposition with Wire (LMDw) of a duplex stainless steel (DSS) cylinder > 20 kg. In the four stages, single-bead passes, a single-bead wall, a block, and finally a cylinder were produced. This stepwise approach allowed the development of LMDw process parameters and control systems while the volume of deposited material and the geometrical complexity of components increased. The as-deposited microstructure was inhomogeneous and repetitive, consisting of highly ferritic regions with nitrides and regions with high fractions of austenite. However, there were no cracks or lack of fusion defects; there were only some small pores, and strength and toughness were comparable to those of the corresponding steel grade. A heat treatment for 1 h at 1100 °C was performed to homogenize the microstructure, remove nitrides, and balance the ferrite and austenite fractions compensating for nitrogen loss occurring during LMDw. The heat treatment increased toughness and ductility and decreased strength, but these still matched steel properties. It was concluded that implementing a systematic methodology with a stepwise increase in the deposited volume and geometrical complexity is a cost-effective way of developing additive manufacturing procedures for the production of significantly sized metallic components.

Perturbed Beta-Cell Function and Lipid Profile After Early Prenatal Dexamethasone Exposure in Individuals Without CAH.

BACKGROUND: Prenatal treatment with dexamethasone (DEX) reduces virilization in girls with congenital adrenal hyperplasia (CAH). The treatment is effective but may result in long-lasting adverse effects. In this study we explore the effects of DEX on metabolism in individuals not having CAH but treated with DEX during the first trimester of fetal life. METHOD: All DEX-treated participants (n = 40, age range 5.1-26.4 years) and controls (n = 75, age range 4.5-26.6 years) were assessed with fasting blood samples to measure blood count, renal function, glucose homeostasis, and serum lipid profiles. RESULTS: There were no significant differences between DEX and control participants for birth parameters, weight and height, or body mass index at the time of testing. Analyzing the entire cohort, we found no significant effects of DEX on blood count, renal function, or serum lipid profiles. However, a lower HOMA-ß index in the DEX-treated individuals (U = 893.0; P = 0.049) was observed. Post hoc analyses revealed an effect in girls (U = 152.5; P = 0.024) but not in boys (U = 299.5; P = 0.550). The effect on HOMA-ß persisted (U = 117.5; P = 0.048) after analyzing data separately in the participants < 16 years of age. In addition, we observed higher plasma glucose levels (F = 14.6; P = 0.001) in the DEX-treated group. The participants ≥ 16 years of age in the DEX-treated group had significantly higher total plasma cholesterol (F = 9.8; P = 0.003) and higher low-density lipoprotein cholesterol levels (F = 7.4; P = 0,009). CONCLUSION: Prenatal DEX exposure in early pregnancy has negative effects on beta-cell function and lipid profile in individuals without CAH already at a young age.

Cognitive Function of Children and Adolescents With Congenital Adrenal Hyperplasia: Importance of Early Diagnosis.

CONTEXT: Patients with classic congenital adrenal hyperplasia (CAH) are treated postnatally with lifelong glucocorticoid (GC) replacement therapy. Previous results on general cognitive ability in individuals with CAH have been conflicting. OBJECTIVE: To evaluate long-term cognitive effects of GC replacement therapy and the impact of early diagnosis in children with CAH. DESIGN AND SETTING: Observational study with patients from a single research institute. PATIENTS: 32 children with CAH (mean age 11.5 years) identified through the Swedish national neonatal screening program for CAH and 52 matched population controls (mean age 10.7 years). Eleven (6 female) children with CAH who were treated prenatally with dexamethasone (DEX), (CAH-DEX) (mean age 11.7 years). INTERVENTION: GC replacement therapy, neonatal screening for CAH. MEASURES: Cognitive abilities assessed with standardized neuropsychological tests (Wechsler scales, Span Board Test, Stroop Interference Test, NEPSY list learning). RESULTS: Children with CAH (not prenatally treated) performed equally well as population controls on a series of tests assessing general intellectual ability and executive functions. No significant differences were observed in cognitive performance between patients with different genotypes (null, non-null). Patients with salt-wasting CAH performed poorer than patients with simple virilizing CAH in a test assessing visuo-spatial working memory (P = 0.039), although the performance was within the normal range for the population. Prenatally DEX-treated girls with CAH had lower verbal intellectual ability compared with CAH girls not exposed to prenatal treatment (P = 0.037). CONCLUSION: Children and adolescents with CAH who were diagnosed early via a neonatal screening program and treated with hydrocortisone had normal psychometric intelligence and executive functions.

First Trimester DEX Treatment Is Not Associated with Altered Brain Activity During Working Memory Performance in Adults.

CONTEXT: Prenatal dexamethasone (DEX) treatment is sometimes used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in female fetuses with CAH. In boys and in fetuses not having CAH, there is no benefit of early DEX treatment and the risks of this therapy must be thoroughly investigated. High doses of prenatal glucocorticoid might alter the developmental trajectory of the brain into adulthood, even for CAH unaffected subjects treated with DEX for a short term during the first trimester. OBJECTIVE: The present study investigated brain activation during working memory performance in DEX-treated subjects compared with controls. DESIGN, SETTING, AND PARTICIPANTS: We tested 18 participants who were exposed to DEX during the first trimester of fetal life but did not have CAH (8 females; mean age 20.78 [standard deviation (SD), 2.67] years) and 40 control participants (24 females; mean age 20.53 [SD, 2.64]) from a single research institute. Participants underwent functional magnetic resonance imaging on a 3T scanner during a verbal and visuospatial working memory task. RESULTS: We did not observe any differences in brain activity during working memory performance. However, DEX-treated subjects responded faster during the experimental condition of the verbal WM task. CONCLUSIONS: First trimester DEX treatment did not seem to result in altered working memory-related brain activity at adult age. Our findings contribute to the risk-benefit assessment of prenatal DEX treatment in the context of CAH.

The Success of a Screening Program Is Largely Dependent on Close Collaboration between the Laboratory and the Clinical Follow-Up of the Patients.

Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and death. The screening laboratory can also play an important role in increasing the general awareness of the disease and act as the source of information and education for clinicians to facilitate improved initial care, ensure prompt and correct glucocorticoid dosing to optimize the long-term outcome for the patients. A National CAH Registry and CYP21A2 genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described.

Update on the Swedish Newborn Screening for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Congenital adrenal hyperplasia (CAH) was the fourth disorder added to the national Swedish neonatal screening program in 1986, and approximately 115,000 newborns are screened annually. Dried blood spot (DBS) screening with measurement of 17-hydroxyprogesterone (17OHP) is also offered to older children moving to Sweden from countries lacking a national DBS screening program. Here, we report an update on the CAH screening from January 2011 until December 2019. Results: During the study period, 1,030,409 newborns and 34,713 older children were screened. In total, 87 newborns were verified to have CAH, which gives an overall positive predictive value (PPV) of 11% and 21% for term infants. Including the five missed CAH cases identified during this period, this gives an incidence of 1:11,200 of CAH in Sweden. Among the older children, 12 of 14 recalled cases were found to be true positive for CAH. All patients were genotyped as part of the clinical follow-up and 70% of the newborns had salt wasting (SW) CAH and 92% had classic CAH (i.e., SW and simple virilizing (SV) CAH). In the group of 12 older children, none had SW CAH and two had SV CAH. Conclusion: The incidence of classic CAH is relatively high in Sweden. Early genetic confirmation with CYP21A2 genotyping has been a valuable complement to the analysis of 17OHP to predict disease severity, make treatment decisions and for the follow-up and evaluation of the screening program.

Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia.

Patients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. Our pilot study investigates genome-wide DNA methylation in patients with CAH to determine whether there is preliminary evidence for epigenomic reprogramming as well as any relationship to patient outcome. Here, we analysed CD4 + T cell DNA from 28 patients with CAH (mean age = 18.5 ±â€¯6.5 years [y]) and 37 population controls (mean age = 17.0 ±â€¯6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs and glucose homeostasis, blood lipid profile, and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age = 19.1, ±6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment. We identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho = 0.58, adjusted p = 0.027) and cg02404636 (located in the SFI1 gene; rho = 0.58, adjusted p = 0.038). cg02404636 was also associated with genotype (rho = 0.59, adjusted p = 0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p = 0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p = 0.044 and p = 0.034) and genotype (p = 0.044 and p = 0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p = 0.035). In conclusion, in this pilot study, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH, although the data must be interpreted with caution due to the small sample size. Additional studies in larger cohorts are therefore warranted.