Classic Congenital Adrenal Hyperplasia Research Articles

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.

Infants with Congenital Adrenal Hyperplasia Exhibit Thalamic Discrepancies in Early Brain Structure

Introduction: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study the brain structure in infants with CAH compared to healthy controls. Methods: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency (8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age [PCA] 42.2 ± 3.0 weeks) and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses (mean, 95% confidence interval [CI]). The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex. Results: Infants with CAH had significantly smaller thalamic volumes (8,606 mm3, 95% CI [8,209, 9,002]) compared to age-matched control infants (9,215 mm3, 95% CI [8,783, 9,647]; β = −609; p = 0.02) which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH (66,817 mm3, CI [65,957, 67,677]) compared to controls (65,616 mm3, CI [64,680, 66,551]; β = 1,202, p = 0.03). The brain regions most differentiated between CAH versus controls were the thalamus (22%) and parietal lobe (10%). Conclusions: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8–14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.

Clinical and functional analyses of the novel STAR c.558C>A in a patient with classic lipoid congenital adrenal hyperplasia.

Objective: Congenital lipid adrenal hyperplasia (LCAH) is the most serious type of congenital adrenal hyperplasia and is caused by steroid-based acute regulatory (STAR) protein mutations. Herein, we report compound heterozygous mutations c.558C>A (p.S186R) and c.772C>T (p.Q258*) in a newborn 46 XY patient diagnosed with classic LCAH and explore their clinical and functional characteristics. Methods: Peripheral blood samples were collected from LCAH patient and their families. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. The functional consequence and ability to convert cholesterol into progesterone of the identified STAR Q258* and S186R mutations were analyzed by cell transfection and in vitro assays. Results: The proband was presented with severe glucocorticoid and mineralocorticoid deficiency, high adrenocorticotropic hormone, and enlarged adrenals. Heterozygous mutations p. S186R and p. Q258* in the STAR gene were identified in the patient, and her parents were carriers, which is consistent with an autosomal recessive disorder. The STAR p. Q258* mutation has been reported and generates a truncated protein. The p. S186R mutation is a novel variant that disrupts STAR. The residual STAR activities of p. S186R, p. Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins. Conclusion: Our findings reveal the molecular mechanisms underlying LCAH pathogenesis, further expanding the genotype and clinical spectrum of LCAH.

Electrolyte abnormalities and stress dosing predict illness-related hospitalizations among infants and toddlers with congenital adrenal hyperplasia.

Infants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for morbidity/mortality arising from life-threatening adrenal crisis. Management of acute illnesses in CAH requires an understanding of factors leading to emergency department (ED) visits and hospitalizations in the first few years of life. We, therefore, examined adrenal crisis at prehospital and ED stages of illness in young children with CAH as they related to medical outcomes. Retrospective cohort study of 39 children with CAH due to 21-hydroxylase deficiency (0-4 years of age) and 27 age-matched controls. ED visit, acute illness symptoms (fever, vomiting, diarrhoea) and other characteristics (hospitalizations, administration of stress-dose hydrocortisone, electrolyte abnormalities). CAH infants and toddlers had significantly higher rates of ED visits (0.50 [0.25-0.88] per person-year) than controls (0 [0-0] per person-year; p < .001). Moreover, CAH children under 6 months old had significantly higher rates of ED visits compared with older ages. Only 50% (51/102) of illness-related ED visits in CAH children were preceded by the administration of either oral (46/51) or intramuscular (11/51) stress dosing by parents. A total of 10.8% of ED visits resulted in hospital admission. Controlling for age and 17-hydroxyprogesterone at diagnosis, electrolyte abnormalities and administration of parenteral hydrocortisone in the ED significantly predicted hospital admission. Receiving a hydrocortisone injection before the ED was a significant predictor of having electrolyte abnormalities. Infants and toddlers with classical CAH are at high risk for acute illness and hospitalizations and often do not receive adequate stress dosing before the ED.

Promene u dijagnostici i lečenju kongenitalne adrenalne hiperplazije - iskustvo tercijernog centra

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases caused by a deficiency of enzymes responsible for the steroidogenesis. There are three forms of CAH due to 21-hydroxylase deficiency: the classic form with salt loss, the classic virilizing and the non-classic form. The aim of the paper was to analyze the changes in the diagnosis and treatment of children with CAH during previous 15 years. Material and methods: This retrospective cohort study includes patients who were diagnosed with CAH due to 21-hydroxylase deficiency in the period from 2007 to 2021 in endocrinology department of the Institute for Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic". Respondents were divided into two groups - a group whose diagnosis was made in the period between 2007 and 2014 and another group of those whose diagnosis was made in the period between 2015 and 2021. Statistical analysis using Hi-square and Mann Whitney U test was conducted using the software IBM SPSS ver. 22, and p values &lt;0.05 were considered significant. Results: Out of the total of 55 patients included in the study, 46 patients (83.6%) had 46, XX karyotype. The diagnosis was made in all patients on the basis of biochemical analyzes. In the second group the diagnosis was confirmed by genetic analysis in statistically significantly higher number of children (p &lt;0.05). 49 patients (89.1%) received hydrocortisone and 16 patients received fludrocortisone. In patients from the second group a statistically significantly higher frequency of fludrocortisone therapy was noticed in patients with classic CAH. Conclusion: Having in mind the constant advancement in the field, frequent improvements in clinical care of children with CAH are needed.

Treatment patterns and unmet needs in adults with classic congenital adrenal hyperplasia: A modified Delphi consensus study.

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive condition characterized by cortisol deficiency and excess androgen production. The current standard of care is glucocorticoid (GC) therapy, and sometimes mineralocorticoids, to replace endogenous cortisol deficiency; however, supraphysiologic GC doses are usually needed to reduce excess androgen production. Monitoring/titrating GC treatment remains a major challenge, and there is no agreement on assessment of treatment adequacy. This study surveyed expert opinions on current treatment practices and unmet needs in adults with classic CAH. A modified two-round Delphi process with adult endocrinologists was conducted via online questionnaire. Survey questions were organized into three categories: practice characteristics/CAH experience, GC management, and unmet needs/complications. Anonymized aggregate data from Round 1 were provided as feedback for Round 2. Responses from both rounds were analyzed using descriptive statistics. Consensus was defined a priori as: full consensus (100%, n=9/9); near consensus (78% to <100%, n=7/9 or 8/9); no consensus (<78%, n<7/9). The same nine panelists participated in both survey rounds; five (56%) were based in North America and four (44%) in Europe. Most panelists (78%) used hydrocortisone in the majority of patients, but two (22%) preferred prednisone/prednisolone. Panelists agreed (89%) that adequate control is best evaluated using a balance of clinical presentation and androgen/precursor laboratory values; no consensus was reached on optimal timing of collecting samples for androgen testing or laboratory values indicating good control. Despite lack of consensus on many aspects of CAH management, panelists agreed on the importance of many disease- and GC-related complications, and that there is a large unmet need for new treatments. With currently available treatments, panelists reported that 46% of classic CAH patients did not have optimized androgen levels, regardless of GC dose. The limited areas of consensus obtained in this study reflect the variability in treatment practices for adults with classic CAH, even among clinicians with expertise in treating this population. However, all panelists agreed on the need for new treatments for classic CAH and the importance of many disease- and GC-related complications, which are difficult to manage with currently available treatments.

PSAT095 Examination of Treatment Patterns in Patients with Classic Congenital Adrenal Hyperplasia (CAH) Compared to Treatment Guidelines

Abstract Introduction Classic congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder, usually due to a deficiency in the 21-hydroxylase enzyme, that results in impaired cortisol synthesis and excess androgen production. Recommended guidelines for management of CAH include assessment of androgen control by routine clinical investigations and patient examination for treating both disease-related and drug-related symptoms. The objective of this study was to identify treatment patterns in patients with classic CAH with reference to guideline-directed care in the United States (US). Methods A retrospective analysis of real-world data on patients with classic CAH was carried out using claims data between Oct 2012 and July 2020 (8 years) from the EVERSANA open claims database of 290 million US citizens. The initial cohort included patients with two or more CAH-related ICD 9/ICD 10 codes at least 28 days apart, and two or more oral glucocorticoids (GCs) prescribed at least 28 days apart within one year of CAH diagnosis. The final CAH cohort combined unique patients identified from two sub-cohorts based on GC adherence (sensitivity 1: patients with 60% proportion of days covered and sensitivity 2: patients with five or more GC prescriptions from date of diagnosis to end of study period or available data for that patient). Information on demographic and clinical characteristics, comorbidities, prescribed medications (including corticosteroids), procedures, and referrals were analysed. Results The final cohort included 11,765 patients (overall mean age 28.7 years) of which 36.9% (n=4,338) were pediatric (0-17 years of age; mean age 8.4 years) and 63.1% were adults (n=7,427; mean age 40.5 years). The majority of CAH patients (62%; n=7,260) reported hydrocortisone use, with a higher proportion of pediatric patients on hydrocortisone (96%; n=4,158) compared to adults (42%; n=3,102). Other frequently prescribed corticosteroids were prednisone (30% pediatric; 68% adults), fludrocortisone (65% pediatric; 34% adults), dexamethasone (25% pediatric; 50% adults), and methylprednisolone (6% pediatric; 43% adults). Among diagnostic procedures and labs, total testosterone (47% pediatric; 46% adults), thyroid stimulating hormone (29% pediatric; 55% adults), 17-hydroxyprogesterone (62% pediatric; 33% adults), androstenedione (55% pediatric; 20% adults), glycated hemoglobin (18% pediatric; 41% adults) and free thyroxine (23% pediatric; 36% adults) were most common. Furthermore, bone age studies were reported in 19% of pediatric patients (51% of pediatric CAH patient population). Only 44% of adult CAH patients and 34% of pediatric CAH patients visited an endocrinologist or pediatric endocrinologist between Oct 2012 and July 2020. Conclusions In line with guidelines, most pediatric patients received short-acting hydrocortisone. However, a large proportion of patients with classic CAH were not treated by an endocrinologist and did not receive guideline-recommended therapy or laboratory testing or bone age assessments, putting them at risk for poor disease control and GC-related adverse events. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT097 Patient Preference Research: Preferred Adjunctive Medication Attributes of Adult Patients with Classic Congenital Adrenal Hyperplasia

Abstract Background People with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic doses of glucocorticoids (e.g., hydrocortisone, dexamethasone) to treat cortisol deficiency and excess androgen production. Healthcare providers and patients continually try to balance androgen control with side effects from supraphysiologic glucocorticoids. This study aimed to understand the preferences of adults with classic CAH regarding benefits of a potential new adjunctive medication that may provide better androgen control and allow for lower glucocorticoid doses. Methods Discrete choice experiment (DCE) methodology was used to calculate the relative stated preferences for the additional therapy's hypothetical benefits (attributes). Seven attributes were developed for the DCE after review of relevant data and qualitative literature, interviews with eight adults with classic CAH and input from two endocrinologists. The online DCE survey was piloted via interviews with three adults with classic CAH and a soft launch, which confirmed survey content and functioning. Preference data and subgroup differences were analyzed using conditional logit and scale assessment modelling, respectively. Results US adults with classic CAH (N=118, 75% female, age 19–69) valued avoidance of glucocorticoid-induced weight gain by twice the magnitude of other treatment attributes (all coefficients p&amp;lt;0.001 compared to baseline levels of no avoidance/decrease/improvement): complete avoidance of weight gain from glucocorticoids (1.109); moderate decrease in risk of developing health conditions from long-term glucocorticoids: type 2 diabetes (0.540), osteopenia, osteoporosis, fractures (0.521) and cardiovascular disease (0.502); moderate improvement in: fatigue (0.439), fertility (0.437) and excessive body hair (females only) and acne (0.410). Avoidance of glucocorticoid-induced weight gain remained the most preferred attribute across all subgroup analyses. Avoidance of glucocorticoid-induced weight gain was relatively much more important to females (n=89) than males (n=28) and participants with a body mass index ≥30 (n=70) than &amp;lt;30 (n=48). Improvement in fertility was more important to males than females, was valued by participants aged 18–45 (n=82) but was not a significant preference in participants &amp;gt;45 (n=36) and was relatively more important to participants with fertility problems (n=31) than without (n=87). Improvement in hirsutism and acne was highly valued by participants with excessive hair growth (n=38) but had the lowest preference among those without (n=80). Improvement in fatigue was a significant preference for participants with energy problems (n=73) but was not significant for those without (n=45). Conclusions The strong and consistent preference for avoiding glucocorticoid-induced weight gain suggests that patients with classic CAH would most value a novel adjunctive therapy that helps mitigate glucocorticoid-induced weight gain. In relation to other potential adjunctive therapy benefits, reduced risk of glucocorticoid-driven side effects may be valued more than improvement in fatigue or androgen-driven adverse events (fertility and hirsutism/acne). However, subgroup analyses indicated that individuals’ characteristics impact their treatment preferences and priorities, after avoidance of glucocorticoid-induced weight gain. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP046 Initial Lessons from a Prescreening Protocol to Identify Participants with Classic CAH Potentially Eligible for Gene Therapy Treatment with BBP-631, an Adeno-associated Virus (AAV) Serotype 5-Based Recombinant Vector Encoding the Human CYP21A2 Gene

Abstract Here we present the design and early findings from CAH-300 /NCT05101902, a prescreening protocol to identify participants who are potentially eligible for the CAH-301 Phase 1/2 treatment trial with BBP-631, an AAV5-based gene therapy for classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). The CYP21A2 gene encodes the 21-hydroxylase enzyme that plays a critical role in glucocorticoid and mineralocorticoid synthesis by the adrenal cortex. CYP21A2pathogenic variants cause 21OHD, the most common form of CAH, characterized by variable degrees of adrenal insufficiency and androgen excess. Standard treatment of classic CAH due to 21OHD usually consists of daily replacement doses of glucocorticoid (GC) and mineralocorticoid. However, supraphysiologic GC doses are often required to mitigate the androgen excess and it is difficult to dose exogenous GCs in a manner that provides adequate disease control while avoiding overtreatment. A gene therapy approach offers the potential to restore cortisol and aldosterone production from the adrenal glands in a physiologically regulated manner. To assess potential eligibility for the gene therapy trial CAH-301, participants in the prescreening protocol CAH-300 undergo initial assessments for the presence of exclusionary anti-21OH antibodies and anti-AAV5 antibodies, as well as for characterization of CYP21A2 genotype. After the participant meets initial eligibility criteria, referral to a treatment trial center may be arranged. To address the challenges in recruiting participants with this rare disorder, prescreening assessments are performed at the participant's home allowing for recruitment from broad geographic areas including those without proximity to a tertiary care center. Home assessments have also provided flexibility for participants during the COVID pandemic. Additional assessments during prescreening that further impact eligibility for the gene therapy trial include review of participant medical history and collection of hormonal biomarkers including 17-hydroxyprogestone, androstenedione, cortisol, and ACTH. Preliminary laboratory data show the expected presence of low cortisol (measured by both gas chromatography-mass spectrometry and immunoassay) with concomitant elevated ACTH, confirming the potential to detect meaningful changes in endogenous cortisol production after BBP-631 dosing. In summary, our prescreening approach with home assessments has enabled the efficient identification of participants potentially eligible for the CAH-301 gene therapy trial. Preliminary data have confirmed the presence of low cortisol and thus potential for detecting meaningful increases in endogenous cortisol production after gene therapy with BBP-631. Presentation: No date and time listed

RF33 | PSAT68 Gonadotropin-Releasing Hormone Agonist Therapy Does Not Affect Bone Mineral Density in Congenital Adrenal Hyperplasia: a Clinical Study

Abstract Background Children with congenital adrenal hyperplasia (CAH) are at risk for early central puberty, and gonadotropin-releasing hormone analogs (GnRHa) are frequently used aiming to improve adult height. However, their effect on bone health among the CAH population has not been previously studied. GnRHa reduce sex steroid levels and delay central puberty, which may negatively affect the achievement of peak bone mass. In healthy children, bone mass increases with time, reaching its peak between the second and third decades of life. The purpose of this study was to investigate the short-term and long-term effect of GnRHa therapy on the bone mineral density (BMD) of patients with classic CAH. Methods Sixty patients with classic CAH due to 21OH deficiency were followed longitudinally at our institution with DXA scans at the time they achieved adult height. Adult height was considered attained when bone age exceeded 15 years in girls and 17 years in boys. Twenty-one patients treated with GnRHa (81% male, 57% salt wasting, treated for mean ± SD: 4.3 ±2 years) were compared to 39 patients not treated with GnRHa (49% male, 79.5% salt wasting). BMD z scores, adjusted for height and age, were evaluated at the time they reached adult height and on average 8.3 years later. Results There was no difference between GnRHa groups in total body (p=0.96), femoral neck (p=0.24), lumbar spine (p=0.59), forearm (p=0.38), and total hip (p= 0.31) z scores at adult height attainment. In multivariable analyses, there was no effect of GnRHa on BMD z scores at any site. In reduced models, increased 17-hydroxyprogesterone (17-OHP) levels correlated with higher BMD z scores for total body (p=0.003), lumbar spine (p&amp;lt;0.001), and forearm (p&amp;lt;0.001). Higher BMI (p=0.014) and no treatment with dexamethasone (p=0.022) were also associated with higher femoral BMD z score. Overall, the follow up DXA during young adulthood (n=28) showed significant decreases in z scores at total body (p=0.019), femoral neck (p=0.036), lumbar spine (p&amp;lt;0.001), forearm (p&amp;lt;0.001), and total hip (p=0.024), and use of GnRHa did not contribute. Interestingly, when adjusting for midparental height, those treated with GnRHa had lower adult height z scores than those without GnRHa (p=0.037). Conclusion Treatment with GnRHa for approximately 4 years does not impact BMD in adolescents and young adults with CAH, and exposure to adrenal androgens may play a protective role. In patients with CAH, BMD decreases with time and during the second and third decades of life, which may reflect the effect of long-term supraphysiologic glucocorticoid therapy. Although intended to preserve height, children with CAH who experience early puberty have loss of adult height, despite treatment with GnRHa. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:54 p.m. - 12:59 p.m.

ODP028 Association Between Serum Steroid Profile and Metabolic Risks in Adults with Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract Objective In adult patients with congenital adrenal hyperplasia (CAH), long-term health outcomes, including metabolic and cardiovascular health, are a priority for the management of CAH. The enzyme 21-hydroxylase deficiency, which accounts for a majority of CAH, leads to a large perturbation in serum steroid profile under glucocorticoid replacement therapy. Serum levels of several adrenal steroids, including 17-hydroxyprogesterone and androstenedione, are associated with disease severity and sexual dysfunction of CAH patients. However, the association between the serum steroid profiles with metabolic risk in CAH patients is not elucidated yet. We aimed to investigate the serum steroid profile of adult CAH patients using liquid chromatography-mass spectrometry (LC-MS) and their association with metabolic risk. Methods Adult patients with classic CAH due to 21-hydroxylase deficiency were included in this study (36 females and 27 males). A multi-steroid panel composed of 25 steroids and their metabolites was applied to morning serum samples of study subjects using LC-MS. An unsupervised clustering algorithm was applied to the serum steroid panel to discover any unique pattern which divides CAH subjects into clusters. The association between serum steroid profiles and clinical characteristics, including age, sex, body mass index (BMI), subtypes (simple virilizing and salt wasting), glucocorticoid dose, and the presence of hypertension, diabetes mellitus (DM), and metabolic syndrome (MetS) was analyzed. The discriminatory power of each steroid or a combination of steroids was estimated using the area under the curve of receiver operating characteristics (AUROC) for metabolic diseases. Results Fifteen steroids including pregnenolone sulfate, 17α-hydroxyprogesterone, cortisol, cortisone, 21-deoxycortisol, 20α-dihydrocortisol, 20α-dihydrocortisone, α-cortolone, β-cortolone, tetrahydrocortisone, dehydroepiandrosterone sulfate, testosterone, androstenedione, 11β-hydroxytestosterone, and 11β-hydroxyandrostenedione were successfully quantified in all subjects. The median age of subjects was 28 years (interquartile range: 25-35). The prevalence of DM, hypertension, and MetS was 3.2% (2/63), 15.8% (10/63), and 28.6% (18/63), respectively. The subjects were divided into two clusters based on the pattern of serum steroid profile using unsupervised hierarchical clustering. The prevalence of MetS was significantly different between the two clusters (cluster 1, 37.8% [17/45] vs. cluster 2, 5.6% [1/18], P = 0. 011). The prevalence of HTN was numerically higher in cluster 1 than cluster 2 (20. 0% [9/45] vs. 5.6% [1/18], P = 0.257). Other clinical characteristics, including age, sex, BMI, subtypes, and glucocorticoid dose, were not different between the two clusters. Among fifteen steroids, the level of tetrahydrocortisone showed the highest discriminatory power for MetS (AUROC 0.795, 95% confidence interval: 0.675-0.914). The multivariate logistic regression model of all 15 steroids showed AUROC of 0.832 (95% CI: 0.732-0.933) for MetS. Conclusion The serum steroid profiles of CAH patients were significantly associated with the presence of MetS. This suggests that serum steroid signatures can guide the optimal management of adult CAH patients to minimize the risk of MetS. Presentation: No date and time listed

RF09 | PSAT70 Comparison of Prednisolone Versus Modified-release Hydrocortisone (Efmody) in the Treatment of Congenital Adrenal Hyperplasia (CAH)

Abstract Background Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ∼1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy3. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one. Methods We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC3: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range (&amp;lt;36 nmol/l) and A4 into the reference range. After 24 weeks, 31 patients from the prednis(ol)one prior therapy group participated in an ongoing MHRC single arm extension study with 28 patients completing 18 months follow up. Control of CAH was defined as a 0900h 17OHP &amp;lt;36 nmol/l. Results Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment. At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively. Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusions Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients.

Growth and Metabolic Syndrome (MetS) criteria in young children with classic Congenital Adrenal Hyperplasia (CAH) treated with corticosteroids (CS).

Treatment of children with congenital adrenal hyperplasia (CAH) with corticosteroids (CS) may increase the risk for developing different components of metabolic syndrome (MetS). Aim: We assessed the occurrence of cardiometabolic risk factors in children with CAH on treatment with CS since early infancy. Data of 30 children with CAH were analyzed retrospectively. They have received hydrocortisone (HC; n = 11) or prednisolone (P; n= 19) and fludrocortisone (0.1- 0.15 mg once daily) since early infancy. The different cardiometabolic criteria including blood pressure (BP), fasting glucose, low-density lipoprotein (LDL), and serum cholesterol concentrations were studied and compared with the data for 66 age-matched obese children. Children with CAH on treatment for > 5 years had a high rate of obesity and overweight (60%) and short stature (23.3%), respectively. They had higher occurrences of abnormal cardio-metabolic components including high LDL and triglyceride and BP as well as increased carotid intima-media thickness (CIMT). Females had higher body mass index (BMI) and BP compared to males. The less controlled group was older and had faster linear growth compared to the controls. In the CAH group, BP and CIMT were correlated significantly with BMI-SDS and weight-standard deviation score (Wt-SDS). Neither the level of 17-hydroxy-Progesterone (17-OHP), nor the HC dose was correlated with BP, CIMT or BMI. These findings suggest the role played by excessive weight gain on the increased cardiometabolic risk factors in children with CAH on treatment with CS.

Evaluation of a New Laboratory Protocol for Newborn Screening for Congenital Adrenal Hyperplasia in New Zealand.

Between 2005 and 2021, 49 cases of classical congenital adrenal hyperplasia were diagnosed in New Zealand, 39 were detected in newborns and 10 were not detected by screening. For every case of CAH detected by screening, 10 false-positive tests are encountered. Second-tier liquid chromatography-tandem mass spectrometry (LCMSMS) has the potential to improve screening sensitivity and specificity. A new laboratory protocol for newborn screening for CAH was evaluated. Birthweight-adjusted thresholds for first- and second-tier 17-hydroxyprogesterone, second-tier 21-deoxyicortisol and a steroid ratio were applied to 4 years of newborn screening data. The study was enriched with 35 newborn screening specimens from confirmed CAH cases. Newborn screening was conducted on 232,542 babies, and 11 cases of classical CAH were detected between 2018 and 2021. There were 98 false-positive tests (specificity 99.96%, PPV = 10.1%) using the existing protocol. Applying the new protocol, the same 11 cases were detected, and there were 13 false-positive tests (sensitivity > 99.99%, PPV = 45.8%, (X2 test p < 0.0001). Incorporating the retrospective specimens screening sensitivity for classical CAH was 78% (existing protocol), compared to 87% for the new protocol (X2 test p = 0.1338). Implementation of LCMSMS as a second-tier test will improve newborn screening for classical CAH in New Zealand.

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.

Syrian females with congenital adrenal hyperplasia: a case series

BackgroundOne of the most common types of congenital adrenal hyperplasia is an autosomal recessive disorder with 21-hydroxylase deficiency. The classical form, defined by cortisol insufficiency, is accompanied by prenatal androgen excess causing variable masculinization degrees of external genitalia in babies with a 46, XX karyotype.Cases presentationThese five case reports highlight the management of Syrian females aged between 0 and 32 years with congenital adrenal hyperplasia. Two of the patients have been raised as males, while two had reconstructive surgery and one had hormonal therapy. Becoming mother was achieved by two patientsConclusionThe integrated treatment of females with classical congenital adrenal hyperplasia CAH, which includes appropriate surgical procedures and controlled hormonal therapy, gives these females the opportunity to live as they are, and perhaps as mothers in the future.

Gender-role behaviour and gender identity in girls with classical congenital adrenal hyperplasia

Brief Summary: This questionnaire-based case control study showed that girls with classical congenital adrenal hyperplasia (CAH) had more masculinized gender-role behaviour (GRB) and a tendency for ambiguous gender-identity (GI) compared to healthy children. The most likely contributor was prenatal androgen exposure.

Tildacerfont in adults with classic Congenital Adrenal Hyperplasia: Results from two phase 2 studies

J Clin Endocrinol Metab. 2021; 106(11): e4666-e4679. PMID: 34146101https://pubmed.ncbi.nlm.nih.gov/34146101/

Low adrenomedullary function predicts acute illness in infants with classical Congenital Adrenal Hyperplasia

Low adrenomedullary function predicts acute illness in infants with classical Congenital Adrenal Hyperplasia

Characteristics of growth in children with classic Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency during adrenarche and beyond

Characteristics of growth in children with classic Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency during adrenarche and beyond