Classic Congenital Adrenal Hyperplasia Research Articles

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

CAHQL: A patient reported outcome instrument to assess health-related quality of life in congenital adrenal hyperplasia.

Measuring health-related quality of life (HRQoL) is a crucial aspect of evaluating health care outcomes. Patients with congenital adrenal hyperplasia (CAH) often self-report deficiencies in HRQoL. The aim of our study was to develop a disease-specific patient reported outcome (PRO) instrument to evaluate the HRQoL of patients >16 years old with classic congenital adrenal hyperplasia (CAH). Following the FDA guidelines for developing PRO instruments, we developed a conceptual framework for the instrument. A preliminary instrument was created after interviewing a representative sample of 12 patients with CAH between 16 to 68 years old and 3 parents, and obtaining expert feedback from 4 endocrinologists. The instrument was edited after cognitive interviews with 6 patients. Internal consistency of the instrument was evaluated using Cronbach's alpha. Validity was assessed by comparing the scores of our instrument with scores from widely used validated instruments for HRQoL and PRO not specific to CAH. Sixty-nine patients 16 to 75 years old participated in validating our preliminary instrument. The final questionnaire consists of 44 questions within 7 domains: General Health, Adrenal Insufficiency, Glucocorticoid Excess, Physical Functioning, Mental Health and Cognition, Social Functioning, and Sexual Functioning, with acceptable internal consistency (Chronbach's alpha≥0.6) and validity (r = -0.350 to 0.866). CAHQL is the first validated PRO instrument to capture disease specific HRQoL outcomes in CAH. In addition to its anticipated use in the clinical setting, the instrument could be used to assess the efficacy of novel treatments in development.

Fertility outcomes in women with classic and non-classic congenital adrenal hyperplasia on modified-release hydrocortisone (MR-HC)

Fertility outcomes in women with classic and non-classic congenital adrenal hyperplasia on modified-release hydrocortisone (MR-HC)

Baseline characteristics of children and adolescents with classic congenital adrenal hyperplasia enrolled in CAHtalyst pediatric, a phase 3 Study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of children and adolescents with classic congenital adrenal hyperplasia enrolled in CAHtalyst pediatric, a phase 3 Study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Landscape of congenital adrenal hyperplasia cases in adult endocrinology clinics of Türkiye-a nation-wide multicentre study.

Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive pattern. The clinical and biochemical manifestations of the disorder are diverse, ranging from varying degrees of anomalies of the external genitalia to life-threatening adrenal insufficiency. This multicenter study aimed to determine the demographics, biochemical, clinical, and genetic characteristics besides the current status of adult patients with CAH nationwide. The medical records of 223 patients with all forms of CAH were evaluated in the study, which included 19 adult endocrinology clinics. A form inquiring about demographical, etiological, and genetic (where available) data of all forms of CAH patients was filled out and returned by the centers. Among 223 cases 181 (81.16%) patients had 21-hydroxylase deficiency (21OHD), 27 (12.10%) had 11-beta-hydroxylase deficiency (110HD), 13 (5.82%) had 17-hydroxylase deficiency (17OHD) and 2 (0.89%) had 3-beta-hydroxysteroid-dehydrogenase deficiency. 21OHD was the most prevalent CAH form in our national series. There were 102 (56.4%) classical and 79 (43.6%) non-classical 210HD cases in our cohort. The age of the patients was 24.9 ± 6.1 (minimum-maximum: 17-44) for classical CAH patients and 30.2 ± 11.2 (minimum-maximum: 17-67). More patients in the nonclassical CAH group were married and had children. Reconstructive genital surgery was performed in 54 (78.3%) of classical CAH females and 42 (77.8%) of them had no children. Thirty-two (50.8%) NCAH cases had homogenous and 31 (49.2%) had heterogeneous CYP21A2 gene mutations. V281L pathological variation was the most prevalent mutation, it was detected in 35 (55.6%) of 21OHD NCAH patients. Our findings are compatible with the current literature except for the higher frequency of 110HD and 17OHD, which may be attributed to unidentified genetic causes. A new classification for CAH cases rather than classical and non-classical may be helpful as the disease exhibits a large clinical and biochemical continuum. Affected cases should be informed of the possible complications they may face. The study concludes that a better understanding of the clinical characteristics of patients with CAH can improve the management of the disorder in daily practice.

Alkindi Sprinkle for Pediatric Patients With Primary Adrenocortical Insufficiency: A Narrative Review.

Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.

A Rare Case of Co-occurrence of Multiple Endocrine Neoplasia Syndrome and Congenital Adrenal Hyperplasia

Multiple endocrine neoplasia type 1 (MEN1) and congenital adrenal hyperplasia (CAH) are rare monogenic hereditary endocrinopathies with a prevalence of 1–9 cases per 100,000 and 9–15 cases per 100,000, respectively. MEN1 is characterized by the development of multiple endocrine and nonendocrine organ tumors, including parathyroid, pituitary, and duodenopancreatic neuroendocrine tumors (NETs), which constitute the classical triad of the disease. CAH is associated with genetic defects in enzymes and transport proteins involved in the synthesis of adrenal cortical steroid hormones. Overall, cases of the combination of two hereditary diseases in one patient are extremely rare. In this article, we describe a clinical case of the combination of MEN-1 with all three classical components and CAH, which, taking into account the low prevalence of both diseases, represents scientific interest. To date, only one similar case has been described in the literature. In addition, the paper discusses the pathogenetically determined combination of CAH and Ehlers-Danlos syndrome, known as the CAH-X syndrome.

Neural Correlates of Obesity and Inflammation in Children and Adolescents with Congenital Adrenal Hyperplasia.

Patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. 27 CAH (12.6±3.4y, 16 females) and 35 controls (13.0±2.8y, 20 females) had MRI of gray matter regions of interest [prefrontal cortex (PFC), amygdala, hippocampus] and white matter microstructure [fornix, stria terminalis (ST)]. Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal [β = -0.56, (-0.96, -0.15)] and superior frontal [β = -0.58 (-0.92, -0.25)] subregion volumes, increased orientation dispersion index in the fornix [β = 0.56 (0.01, 1.10)] and ST [β = 0.85 (0.34, 1.36)], and decreased fractional anisotropy in the fornix [β = -0.91 (-1.42, -0.42)] and ST [β = -0.83 (-1.34, -0.33)] (all p's <0.05) indicating axonal disorganization, reduced myelin content, and/or higher microglial density within the affected white matter tracts. For the full cohort, SF was correlated with MCP-1 (r=-0.41), visceral adipose tissue (r=-0.25), and waist-to-height ratio (r=-0.27, all p's <0.05); ST was correlated with MCP-1 (r=0.31) and TNF-α (r= 0.29, all p's <0.05); however, after adjusting for CAH status, almost all correlations were attenuated for significance. Relationships among key brain structures, body composition and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.

Konjenital Adrenal Hiperplazili Hastalarda Final Boyun Değerlendirilmesi

Purpose : Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that occurs as a result of deficiency of any of the enzymes required for the synthesis of glucocorticoid, mineralocorticoid and sex steroid from cholesterol in the adrenal cortex .In this study, we aimed to evaluate the final height in patients with CAH due to 21-hydroxylase and 11 Beta hydroxylase deficiency and to investigate the factors affecting it.&#x0D; Material-method: The anthropometric, clinical and laboratory findings of the patients who were diagnosed with CAH in the Pediatric Endocrinology Clinic were evaluated retrospectively. A total of 39 patients with CAH who had regular controls, who did not have precocious puberty and no additional disease during their follow-up, and who reached the final height were included in the study.&#x0D; Results: The final height was 158.2±5.46 cm in female cases and 168.8±11.67 cm in male cases with classic simple virilizing CAD due to 21 hydroxylase deficiency, and it was 152.2±5.94 cm in salt-wasting female cases and 156.5±6.2 cm in salt-wasting male cases. It was found to be 155.9±7.59 cm in non-classic female cases and 157 cm in 1 non-classic male case. The final height of all classic type CAH cases is SD - 1.41±1.45 SD, and it was calculated as -0.81±1.12 (-2,30 - 0,80) in cases with simple virilizing type classic CAH and -1.79±1.53 (-3.70 - 0.70) in cases with salt-wasting type classic CAD. In non-classic CAH cases, final height SD was calculated as -1.65±1.69 SD. When patients with salt-wasting CAH and simple virilizing CAH were compared in terms of final height SD and genetically adjusted height SD, the final heights of patients with simple virilizing CAH were significantly longer (p

Quantitative Characterization of Ectopic Adrenal Gene Expression in Fetal Testes in 21-Hydroxylase Deficient Mice.

Testicular adrenal rest tumors (TART) are a frequent and fertility impairing long-term complication in males with classic congenital adrenal hyperplasia. Due to lack of clear experimental data on their origin, they are hypothesized to be derived from ectopic adrenocortical cells within testicular tissue mainly growing upon stimulation by chronically elevated levels of adrenocorticotropin (ACTH). Alternatively, a more totipotent embryological origin has been discussed as the potential source of these tumors. The aim of this study was to quantify alterations of ectopic expression of adrenocortical genes (CYP11B1, CYP11B2, CYP21, MC2R) and the Leydig cell specific marker (INSL3) in testicular tissue of fetal 21-hydroxylase deficient (21OHD) mice. Timed-pregnancy studies were performed using H-2aw18 (aw18)-mice. Testes and adrenals of E15.5 and E18.5 mouse fetuses were used for real-time PCR and immunohistochemistry. Gene expression levels were analyzed for genotype-dependent alterations and compared with immunohistochemistry. While enzymes of steroidogenesis showed a significant increased expression in adrenals of 21OHD mice at both E15.5 and E18.5 compared to wild-type (WT) mice, expression levels were unaltered in testes of 21OHD mice. When compared to WT adrenals a significant increase of INSL3 expression in adrenals of 21OHD mice at E15.5 and E18.5 was detected. Cells with adrenocortical properties in mice fetal testis differ from in situ adrenocortical cells in gene expression and growth at E15.5 and E18.5. These findings suggest that the different local regulation and different local niche in adrenals and testes influence growth of aberrant adrenal cells.

Sexual dimorphism in anxiety is programmed in-utero by sex-steroids: Proof of concept using a disease-model and stress responses to COVID pandemic

Sex differences in the psychological impact of the COVID-19 pandemic have been consistently reported, showing disproportionally high rates of anxiety/distress in women relative to men. The mechanisms underlying this sexual dimorphism remain unclear. The present study queries the potential protective role of early hyperandrogenism on brain development. A natural model of sex-steroids abnormality, classic congenital adrenal hyperplasia (CAH), was used to test this question. CAH is characterized by adrenal androgen overproduction in utero (prenatal) through the neonatal critical developmental period. An online survey collected information on subjective responses to the COVID-19 pandemic. Matched on demographic variables, 60 adults carrying a diagnosis of classic CAH and 240 adults from the general population (non-CAH) were compared on levels of anxiety/distress in the first year of the COVID-19 pandemic (May 2020-April 2021). Structural Equation Modeling was used to test the modulation by CAH status of Sex effects on anxiety/distress. Results revealed lower levels of anxiety/distress in the female CAH group compared to the other 3 groups (male CAH, female non-CAH, and male non-CAH). This finding suggests that pre-neonatal hyperandrogenism might impact the development of neural circuits underlying anxiety processes, in a way that enhances resilience to chronic stress.

Is there reversal of virilisation after commencing medical replacement therapy for 46XX classical congenital adrenal hyperplasia (CAH)?

Is there reversal of virilisation after commencing medical replacement therapy for 46XX classical congenital adrenal hyperplasia (CAH)?

Origins of the lower vagina and the role of androgens from 20 years' experience with genitoplasty for 46XX classical congenital adrenal hyperplasia (CAH)

Origins of the lower vagina and the role of androgens from 20 years' experience with genitoplasty for 46XX classical congenital adrenal hyperplasia (CAH)

SAT288 Development Of CAH-specific Patient Reported Outcome (PRO) Instrument To Assess Health-related Quality Of Life (HRQoL)

Abstract Disclosure: M.E. Flokas: None. L. Yang: None. K. Middleton: None. R.W. Persky: None. S. Kollender: None. M. Parker: None. D.P. Merke: Grant Recipient; Self; Diurnal, received unrelated research funds through the National Institutes of Health Cooperative Research and Development Agreement., D.P.M. received unrelated research funds from Neurocrine Biosciences through the National Institutes of Health Cooperative Research and Development Agreement. Objectives: Measuring health-related quality of life (HRQoL) is a crucial and often required process of evaluating health care outcomes. The aim of our study is to develop a disease-specific patient reported outcome (PRO) instrument to evaluate the HRQoL of patients &amp;gt;16 years old with classic congenital adrenal hyperplasia (CAH). Methods: Following the FDA guidelines for developing PRO instruments, we developed a conceptual framework for the instrument. The process involved interviewing a representative sample of the CAH population and along with expert feedback and review of the literature. We are assessing the instruments’ validity and reliability with the assistance of patient participation. Internal consistency of the instrument is being evaluated using Cronbach’s alpha. We are also assessing the validity by comparing the scores of our instrument with scores from widely used instruments for HRQoL namely, Short Form Health Survey-36 (SF-36), AddiQol, Tuebingen CD-25 and Female Sexual Functioning Index. Furthermore, we collected data regarding the clinical outcomes, symptoms and patient characteristics to investigate the correlation between patient-reported and provider- observed outcomes. Results: Twelve patients with CAH, aged between 16 to 68 years old were interviewed and provided insight on the CAH - related health outcomes that were most relevant to them. A preliminary instrument was developed and subjected to validity testing in the form of cognitive interviewing. The edited instrument consisting of 73 questions covering 9 preliminary domains (General Health, Adrenal Insufficiency, Glucocorticoid Excess, Androgen Excess, Physical Functioning, Sexual Functioning and Fertility, Mental Health and Cognition, Social Functioning and CAH Management). Sixty-nine participants aged 16 to 75 years old participated in validating our preliminary instrument. Forty- six participants (67%) had salt-wasting CAH while 23 (33%) had simple virilizing CAH. Fifty-one percent of participants identified as male, 46% female, while 3% as other gender. Preliminary results show mostly acceptable (&amp;gt;0.7) Cronbach’s alpha, showing reliability in most domains. Further data analysis is underway. Conclusion: This is the first PRO instrument to capture the HRQoL outcomes in the CAH population. In addition to its anticipated use in the clinical setting, the instrument could be used to assess the efficacy of novel treatments in development. The final instrument is currently under development. Presentation: Saturday, June 17, 2023

THU207 11-oxygenated Androgens Are Strongly Associated With Treatment Quality In Children With Congenital Adrenal Hyperplasia Due To 21-Hydroxylase Deficiency

Abstract Disclosure: O. Abawi: None. T. Du Toit: None. G. Sommer: None. C.D. Vögel: None. M. Groessl: None. U. Halbsguth: None. S.E. Hannema: None. C. de Bruin: None. E. Charmandari: None. E.L. van den Akker: None. C.E. Flueck: None. Introduction: Treatment of children with Congenital Adrenal Hyperplasia (CAH) aims at balancing steroid replacement, hyperandrogenism and hypercortisolism. Optimal treatment and its assessment however remain a conundrum. Currently, specialists integrate clinical and conventional laboratory parameters such as 17-hydroxyprogesterone (17OHP) and androstenedione (A4). In recent years, 11-oxygenated androgens (11oxyAs) have been proposed as promising biomarkers, but their merit in treatment monitoring is not yet established. Aim: To investigate potential biomarkers of treatment quality in children with CAH by comprehensive serum steroid profiling. Methods: This prospective, observational cohort study was conducted at 4 academic pediatric endocrinology outpatient clinics and included children with genetically confirmed 21-hydroxylase deficiency. At 2 consecutive visits (mean 4.1 ± 0.7 months apart), a targeted and untargeted panel of conventional adrenal and additional peripheral steroids was analysed in serum using liquid chromatography-mass spectrometry. This included 11β-hydroxy (11OH)-androstenedione (11OHA4), 11keto-A4 (11KA4), 11OH-testosterone (11OHT), and 11keto-T (11KT). At each visit, the pediatric endocrinologist classified patients as undertreated, optimally treated or overtreated based on detailed clinical and endocrinologic evaluation, including serum 17OHP and A4 profiling. Mixed-effects logistic regression analyses on log-steroid concentrations adjusted for age, sex, BMI-z, pubertal status, CAH subtype (classic vs non-classic) and random effects for unique patients were performed to investigate odds ratios (OR) of being undertreated vs optimally treated. False discovery rate adjusted P&amp;lt;0.05 was considered significant. Results: We included 138 visits (86 [62%] optimal treatment, 52 [38%] undertreatment) from 72 patients, of whom 31 (43%) girls, 59 (82%) had classic CAH, and 31 (43%) were prepubertal. Mean age at first visit was 10.6 ± 5.2 years, mean BMI-z was 0.6 ± 1.1. Ten out of 17 conventional steroids, including 17OHP and 21-deoxycortisol but not A4, were associated with undertreatment. All 11oxyAs were associated with undertreatment: 11OHA4 (OR 3.64, SE 1.42, P=0.008), 11OHT (OR 2.91, SE 1.09, P=0.012), 11KT (OR 2.77, SE 1.00, P=0.01), and 11KA4 (OR 2.64, SE 0.84, P=0.009). The strongest association with undertreatment was found for the sum of 11oxyAs (OR 4.04, SE 1.70, P=0.008). Discussion: We show that 11oxyAs have the strongest association with undertreatment in children with CAH. This study supports the inclusion of 11oxyAs in the biochemical work-up of CAH to improve treatment monitoring and underscores the importance of analysing unconventional steroids in CAH by comprehensive steroid profiling. Following on, our steroid profiling can now be extended to characterise other forms of CAH and cases of suspected overtreatment. Presentation: Thursday, June 15, 2023

THU208 Predicting Treatment Quality Assessment Of Children With Congenital Adrenal Hyperplasia Using 24h Urine Metabolomics Profiling And A Machine Learning-assisted Approach

Abstract Disclosure: O. Abawi: None. G. Sommer: None. M. Groessl: None. U. Halbsguth: None. S.E. Hannema: None. C. de Bruin: None. E. Charmandari: None. E.L. van den Akker: None. A.B. Leichtle: None. C.E. Flueck: None. Introduction: Current treatment monitoring of children with congenital adrenal hyperplasia (CAH) relies on specialist’s interpretation of clinical and biochemical parameters, but remains dissatisfactory. Comprehensive 24h urine steroid profiling provides detailed insight into adrenal steroid pathways, but its merit in routine treatment monitoring of CAH is not yet established. Aim: To investigate whether 24h urine steroid profiling can predict treatment quality assessment in children with CAH using machine learning (ML). Methods: This prospective observational cohort study included children with genetically confirmed 21-hydroxylase deficiency. Children collected 24h urine at 2 outpatient clinic visits (mean 4.1 ± 0.7 months apart). Using gas chromatography-mass spectrometry, 40 adrenal steroids and metabolites from the classic, backdoor and 11-oxygenated pathways were analysed. Patients were classified as undertreated, optimally treated or overtreated by the pediatric endocrinologist based on detailed clinical and endocrinological evaluation including serum 17-hydroxyprogesterone and androstenedione. We used sparse partial least-squares discriminant analysis (sPLS-DA) to investigate optimal prediction of treatment quality assessment. This ML method computes components (combinations of all input variables) and selects the most discriminative parameters to classify samples (in our case optimally treated vs undertreated) by maximizing between-class variance. We computed area under the ROC-curve (AUC) of two sPLS-DA models: 1. using only 24h urine metabolites; 2. adding also clinical variables age, sex, pubertal status, CAH subtype (classic vs non-classic), medication (hydrocortisone [HC] vs prednisolone), daily HC-equivalent dose, Δbone age minus chronological age, ΔBMI-z, and Δheight-z. Results: We included 112 visits (68 [61%] optimally treated, 44 [39%] undertreated) of 59 patients: 27 (46%) girls, 46 (78%) classic CAH, 19 (32%) prepubertal. Mean age at first visit was 11.9 ± 4.0 years and mean BMI SDS 0.6 ± 1.1. SPLS-DA using 24h urine metabolites showed clear clustering of optimally treated patients on two components, while undertreated patients were more heterogenous (AUC 0.88; 95% CI 0.81-0.94). The model selected pregnanetriol and hydroxypregnanolon contributing to excluding undertreatment and 7 metabolites contributing to excluding optimal treatment: estradiol, cortison, tetrahydroaldosterone, androstenetriol, etiocholanolone, androstenediol, and α-dihydrocortison. Addition of clinical variables did not improve classification (AUC 0.90, 95% CI 0.84-0.96, P=0.59). Discussion: Using ML on 24h urine steroid profiling predicted treatment quality assessment in children with CAH even in absence of clinical data, suggesting that comprehensive 24h urine steroid profiling could improve treatment monitoring in children with CAH. Presentation: Thursday, June 15, 2023

SAT380 Clinical, Metabolic And Hormonal Profile In Women Carrying Cyp21a2 Mutations

Abstract Disclosure: S. Livadas: None. D.G. Goulis: None. E. Belardinelli: None. E. Armeni: None. B. Solmi: None. S. veneti: None. I. Lambrinoudaki: None. C. Cecchetti: None. D.P. Macut: None. A. Gambineri: None. Background: Heterozygote (HET) CYP21A2 gene mutations are present in 5-10% of the general Mediterranean population. Despite that homozygotes suffer from classical or non-classical congenital adrenal hyperplasia (NC-CAH), a survival advantage has been suggested for heterozygote carriers. The aim of this study was to describe the clinical, metabolic and hormonal profile in reproductive age women with CYP21A2 HET. Methods: Data from 56 HET women were compared with 105 controls, 64 untreated women with NC-CAH and 63 women with polycystic ovary syndrome (PCOS) of similar age and body mass index. Results: The prevalence of hirsutism (54 vs. 8%) and acne (44 vs. 4%) was higher in HET than controls. The degree of menstrual irregularities was similar between HET and NC-CAH and worse than controls. The lipid profile was better in HET than PCOS (Cholesterol 170.2±37.1 vs. 187. 7±39.3 mg/dl, HDL 61.4±26.1 vs. 46.8±8.6 mg/dl), but similar to NC-CAH. Testosterone (0.78±0.45 vs. 0.50±0.25 ng/dl), SHBG (38.2±20.1 vs. 56.2±31.4 nmol/l), FAI (9.56±3.45 vs. 5.37±1.24) and DHEAS concentrations (2.62±1.31 vs. 1.27±0.94 nmol/l) were similar to HET, NC-CAH and PCOS and significantly higher than controls as well as insulin (13.88±7.96 vs. 7.51±2.82 IU/l) and HOMA-IR (2.95±1.60 vs. 1.65±0.67). Δ4- androstenedione (5.97±2.88 vs. 8.80±3.45 ng/ml) and 17(OH)-progesterone (4.32±2.02 vs. 13.75±8.34 ng/ml) concentrations were lower in HET than in NC-CAH, but higher than PCOS and controls. Finally, ovarian PCO morphology prevalence was similar in HET than NC-CAH and PCOS. Conclusions: HET display a favorable lipidemic profile, but a similar degree of hyperandrogenic signs, menstrual disturbances, insulin resistance, hyperandrogenemia and ovarian morphology than women with PCOS or NC-CAH. Therefore, these women, when identified, should be followed-up. Presentation Date: Saturday, June 17, 2023

FRI254 Unconventional Pre-operative Management Of Congenital Adrenal Hyperplasia

Abstract Disclosure: M.A. Ortiz-Rivera: None. L.N. Madera Marin: None. A. Rosado-Burgos: None. L. El Musa Penna: None. W. Medina-Torres: None. L.R. Sepulveda-Garcia: None. L.A. Gonzalez-Rodriguez: None. M. Ramirez-Vick: None. M. Alvarado-Santiago: None. A.J. Grana Santini: None. M. Feliciano-Emmanuelli: None. Management of classic salt-wasting congenital adrenal hyperplasia [CAH] warrants suppression of the hypothalamic-pituitary-adrenal axis through glucocorticoid and mineralocorticoid supplementation. Preferred glucocorticoid replacement is generally hydrocortisone [HC] 3 times daily but caring for these patients often involves unconventional choices of glucocorticoid preparation regimens tailored to meet patient needs. A 41-year-old female with history of long-standing poorly controlled classic salt-wasting CAH associated to secondary amenorrhea and hypothyroidism, presenting with bilateral myelolipomas was consulted to our service for pre-op optimization. She underwent evaluation by Urology due to worsening right-sided back pain for which an abdominal-pelvic CT was performed showing large bilateral adrenal gland lesions (left mass measuring 11.5 x 10.3 x 10.6 cm and right mass measuring 8.1 x 10.4 x 7.7 cm) consistent with adrenal myelolipomas. Endocrine surgeon favored adrenalectomy due to mass effect brought about by massive adrenal growth secondary to inadequate therapeutic regime. Patient had been lost to follow-up after transitioning from pediatric to adult Endocrinology and was managed by her primary care physician who kept her on an unmodified therapeutic regime. During a pharmacy shortage of HC, she was switched from HC 25 mg TID to 5 mg daily. Furthermore, use of fludrocortisone 0.1 mg daily had been inadvertently halted in the past year. There had been progressive skin hyperpigmentation since the age of 20, significant hirsutism and salt cravings which made her add soy sauce to meals. At the age of 12 a vaginoplasty was performed, with menstrual periods ceasing at age 15. Physical examination was remarkable for grave voice, broad shoulders, bronze skin and coarse terminal hairs on chin, upper lip, sides of face and upper back. Hormonal workup revealed a direct renin &amp;gt; 300 pg/mL (nl 3.6 – 81.6), ACTH 463 pg/mL (nl 0.00 – 46.00), androstenedione &amp;gt; 10 ng/mL (nl 0.6 – 3.10), total testosterone [TT] 419 ng/dL (nl 13 – 53) and 17-hydroxyprogesterone [17-OHprog] &amp;gt; 20 ng/mL (nl 0.20 – 2.6). Frequent increases in medication dosing, up to HC 20mg TID and fludrocortisone 0.1mcg BID, did not attain adequate hormonal control. Dexamethasone 0.25 mg was then added at bedtime and the patient was finally able to achieve restoration of menses, resolution of salt cravings and hormonal profile control with decreases in renin to 23.02 pg/mL, androstenedione to &amp;lt; 0.30 ng/mL, TT to 11 ng/dL and 17-OHprog to 3.15 ng/mL. Alternative treatment strategies are sometimes warranted to achieve control of CAH. In this patient with prominent androgen excess and amenorrhea who failed to meet goals on high doses of hydrocortisone and fludrocortisone, combination therapy with a small dose of long-acting glucocorticoid at bedtime achieved the desired goal. Presentation: Friday, June 16, 2023

The impact of neonatal 17-hydroxyprogesterone cutoff determination in a public newborn screening program for congenital adrenal hyperplasia in Southern Brazil: 3 years' experience.

Congenital adrenal hyperplasia (CAH) occurs due to enzyme defects in adrenal steroidogenesis. The 21-hydroxylase deficiency accounts for 90-95% of cases, triggering accumulation of 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening allows adequate treatment and reduced mortality. The purpose of the study was to determine 17-OHP cutoffs for the diagnosis of CAH in a public newborn screening program in Southern Brazil. A retrospective, descriptive, cross-sectional study was conducted to analyze 17-OHP levels in dried blood samples collected on filter paper of 317,745 newborns screened at a public newborn screening center from May 2014 to April 2017. Neonatal 17-OHP was measured in DBS samples using a time-resolved fluoroimmunoassay (GSP® kit 3305-0010; PerkinElmer). Different cutoffs were determined and stratified by birth weight. The incidence of CAH was 1:15,887 live births in the state of Rio Grande do Sul, with 20 cases of classical CAH diagnosed during the study period. Most newborns (80.73%) were white, and the prematurity rate was 9.8% in the study population. The combination of different percentiles, 98.5th for birth weight 2001-2500 g and 99.8th for the other birth weight groups, decreased false-positive results and increased specificity compared with current reference values to identify classical CAH cases. The local 17-OHP cutoffs determined were higher than those currently used by this screening program for all birth weight groups. The calculation of reference values from local population data and the combination of percentiles proved to be a valuable tool for proper diagnosis of CAH and reduction in the number of false positives.