Management Of Congenital Adrenal Hyperplasia Research Articles

Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

Current Update on the Management and Treatment of Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) comprises a set of inherited conditions marked by enzymatic deficiencies within the adrenal steroidogenesis pathway, resulting in compromised cortisol synthesis and, in certain instances, heightened androgen production. Congenital adrenal hyperplasia (CAH) arises from autosomal recessive genetic mutations affecting enzymes crucial for the adrenal glands’ biochemical synthesis of glucocorticoids, mineralocorticoids, or sex steroids from cholesterol. The majority of these conditions result in either excessive or deficient production of sex steroids, potentially influencing the development of primary or secondary sex characteristics in affected infants, children, or adults. The management and treatment of CAH are geared towards optimizing hormonal equilibrium, averting adrenal crises, and addressing associated comorbidities. This review presents an updated survey of contemporary approaches to CAH management, encompassing glucocorticoid and mineralocorticoid replacement therapies, along with strategies to alleviate androgen excess. Furthermore, it is required that we look into emerging treatments, including novel pharmaceutical interventions and advancements in genetic and reproductive technologies. The complexities and possibilities inherent in the comprehensive care of individuals with CAH, involving collaboration among endocrinologists, geneticists, and reproductive specialists, are also examined. This review presents an updated survey of contemporary approaches to CAH management, encompassing glucocorticoid and mineralocorticoid replacement therapies, along with strategies to alleviate androgen excess. By scrutinizing recent advancements, this abstract provides valuable insights into the dynamic landscape of CAH management, emphasizing the imperative for sustained research efforts to augment the well-being of affected individuals.

New Tools for the Clinical Management of Congenital Adrenal Hyperplasia

New Tools for the Clinical Management of Congenital Adrenal Hyperplasia

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

SAT304 Improved Biochemical Control With Dose Reduction In Chronic Glucocorticoid Therapy: A Phase III Extension Study Of Chronocort (Efmody) In The Treatment Of Congenital Adrenal Hyperplasia (CAH)

Abstract Disclosure: R.J. Ross: Employee; Self; Diurnal, A Neurocrine Biosciences Company. D.P. Merke: None. A. Mallappa: None. W. Arlt: None. A. Brac de la Perriere: None. A.L. Hirschberg: None. A. Juul: None. J.D. Newell-Price: None. C.G. Perry: None. A. Prete: None. A. Rees: None. N. Reisch: None. M. Stikkelbroeck: None. P.A. Touraine: None. N. Aslam: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences company. H. Coope: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences company. J. Porter: Employee; Self; Diurnal Ltd, a Neurocrine Biosciences Company. Background: Management of congenital adrenal hyperplasia (CAH) involves replacing cortisol deficiency and controlling raised adrenal androgens. Guidelines recommend a target daily hydrocortisone dose of ≤25mg to replace adrenal insufficiency; however, cohort studies show doses &amp;gt;25mg are used to control androgens in CAH patients. Modified-release hydrocortisone (MRHC) capsules, (Efmody, UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy1. This post-hoc analysis examines total glucocorticoid daily dose and 9am 17-hydroxyprogesterone (17-OHP) levels in MRHC treated patients after 24 months in an ongoing MRHC single-arm extension study. Methods: All patients (n=71) that completed 24 months in the extension study at the time of the interim data cut were reviewed. Patients were recruited predominantly from the 6-month randomised phase III study comparing MRHC to standard glucocorticoid with blind titration of MRHC doses. In this extension phase the dose was titrated by the investigator on the 17-OHP and androstenedione levels at 4, 12, 24 weeks and 6 monthly. Androgen control was defined as 17-OHP &amp;lt;36 nmol/L (&amp;lt;1190 ng/dL). After 24 months, 64 of the patients had 9am 17-OHP data. A Wilcoxon-signed ranks test was performed to assess the change in total MRHC daily dose from baseline to 24 months. A Fisher’s exact test was performed to determine if the number of patients that achieved androgen control on a hydrocortisone (HC) dose ≤25 mg showed a statistically significant increase. Results: The median daily HC dose at baseline was 30mg (Inter-quartile range (IQR) 25-40) and at 24 months had reduced to 20mg (IQR 15-25), p&amp;lt;0.0001.Quadrant analysis revealed the following data: Baseline: &amp;gt 36nmol/L 17-OHP &amp; &amp;lt 25mg/day 9/71 (13%). &amp;gt 36nmol/L 17-OHP &amp; &amp;gt 25mg/day18/71 (25%). &amp;lt 36nmol/L 17-OHP &amp; &amp;lt 25mg/day 22/71 (31%). &amp;lt 36nmol/L 17-OHP &amp; &amp;gt 25mg/day 22/71 (31%). 24 months: &amp;gt 36nmol/L 17-OHP &amp; &amp;lt 25mg/day 16/64 (25%). &amp;gt 36nmol/L 17-OHP &amp; &amp;gt 25mg/day 2/64 (3%). &amp;lt 36nmol/L 17-OHP &amp; &amp;lt 25mg/day 31/64 (48%). &amp;lt 36nmol/L 17-OHP &amp; &amp;gt 25mg/day 15/64 (23%). 48% of subjects achieved androgen control based on 9am 17-OHP level at a HC dose ≤ 25 mg following 24 months of MRHC treatment compared with 31% at baseline (31% vs 48%, p= 0.03 by Fisher’s exact test). Conclusions: After 24 months of MRHC treatment the median daily HC dose was reduced from a median of 30mg to 20mg and the number of patients achieving androgen control based on 9am 17-OHP while receiving HC ≤25mg/day increased significantly.

Biomarkers in congenital adrenal hyperplasia.

Monitoring of hormone replacement therapy represents a major challenge in the management of congenital adrenal hyperplasia (CAH). In the absence of clear guidance and standardised monitoring strategies, there is no consensus among clinicians regarding the relevance of various biochemical markers used in practice, leading to wide variability in their application and interpretation. In this review, we summarise the published evidence on biochemical monitoring of CAH. We discuss temporal variations of the most commonly measured biomarkers throughout the day, the interrelationship between different biomarkers, as well as their relationship with different glucocorticoid and mineralocorticoid treatment regimens and clinical outcomes. Our review highlights significant heterogeneity across studies in both aims and methodology. However, we identified key messages for the management of patients with CAH. The approach to hormone replacement therapy should be individualised, based on the individual hormonal profile throughout the day in relation to medication. There are limitations to using 17-hydroxyprogesterone, androstenedione and testosterone, and the role of additional biomarkers such 11-oxygenated androgens which are more disease specific should be further established. Noninvasive monitoring via salivary and urinary steroid measurements is becoming increasingly available and should be considered, especially in the management of children with CAH. Additionally, this review indicates the need for large scale longitudinal studies analysing the interrelation between different monitoring strategies used in clinical practice and health outcomes in children and adults with CAH.

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.

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

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.

Therapeutic advances for the management of congenital adrenal hyperplasia

Over 150 years ago Luigi DeCrecchio first described what we now know as congenital adrenal hyperplasia (CAH). It took another 100 years for Dr. Lawson Wilkins and colleagues to develop effective cortisone treatment. CAH has been treated in much the same way since, but the advent of new pharmacotherapies seeks to revitalize the treatment of this complex disorder (Mallappa & Merke, 2022).

Why do parents recommend clitoral surgery? Parental perception of the necessity, benefit, and cost of early childhood clitoral surgery for congenital adrenal hyperplasia (CAH).

Historically, medical management of Congenital Adrenal Hyperplasia (CAH) in girls typically involved feminising surgery, which meant reducing the size and/or visibility of the enlarged clitoris. This practice may have become less routine but remains a common response to genital differences associated with CAH. Parents typically give permission for the child to undergo surgery in early childhood and recommend other parents facing a similar situation do the same. The current report is based on a qualitative content analysis of interviews with sixteen parents whose daughters with CAH had undergone one of two forms of clitoral surgery. We observed that: (i) some parents were initially unconcerned about their child's genital presentation; (ii) in general, clitoral surgery was considered as a readily available and natural response to the child's bodily difference; (iii) the parents acknowledged that there would be some risk but anticipated various benefits; and (iv) there was an absence of ethical considerations when the parents evaluated the various effects of surgery afterwards. We conclude from our analysis that parents of girls with CAH may not receive psychologically and ethically informed counselling to encourage critical reflections prior to authorizing genital surgery.

Challenges of Management of Congenital Adrenal Hyperplasia in Developing Countries

Challenges of Management of Congenital Adrenal Hyperplasia in Developing Countries

Newborn Screening in Pediatric Endocrine Disorders

Two endocrine disorders, congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH), when untreated, can have devastating, irreversible and fatal outcomes. Permanent cognitive impairment, growth failure and dysmorphic appearance are seen in congenital hypothyroidism (CH) and early infant death in males with salt wasting CAH (as most females are discovered by presence of atypical genital appearance, while males appeared normal). Newborn screening (NBS) for CH was developed with broader engagement of centers, and was more rapidly adopted throughout the US and other large or developed countries, while NBS for CAH was pioneered by relatively few and was not fully adopted in the US until the initiation of Universal Expanded Newborn Screening Panel in 2005. Advances in genetic understanding of CH and CAH continue with NBS. Cost–benefit analysis, showing CH NBS as more successful than CAH NBS, may not fully recognize the cost of a life saved with CAH NBS. Early treatment of CH is much simpler with taking a pill a day unlike CAH requiring multiple medication doses, and possibly surgery apart from enteral and parenteral stress doses during adrenal crisis. CAH management outcomes with gender identity matters in persons with atypical genital appearance and androgen effects are still being studied.

11-Oxygenated Androgens Useful in the Setting of Discrepant Conventional Biomarkers in 21-Hydroxylase Deficiency.

Serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) are the conventional biomarkers used to assess disease control in patients with 21-hydroxylase deficiency (21OHD). However, discrepancy between the two is not uncommon, limiting interpretation. To evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4. Retrospective analysis of 2738 laboratory assessments obtained as part of Natural History Study of congenital adrenal hyperplasia (CAH) at the National Institutes Health Clinical Center. Patients with discrepant 17OHP and A4 and available sera were selected. A 15-steroid mass-spectrometry panel was performed in sera from patients with 21OHD and age- and sex-matched controls. Patients were categorized in "good" or "poor" control based on clinical assessment (bone age advancement, signs and symptoms of precocious puberty, menstrual irregularity, hirsutism, or hypogonadotrophic hypogonadism). Discrepant 17OHP and A4 was found in 469 (17%) laboratory assessments. Of these, 403 (86%) had elevated 17OHP with A4 in reference range. Of 46 patients with available sera, 30 (65%) were in good control. Median fold elevation relative to controls was higher in patients with poor versus good control for 11-hydroxytestosterone (median [interquartile range], 2.82 [1.25-5.43] vs 0.91 [0.49- 2.07], P = .003), and 11-ketotestosterone (3.57 [2.11-7.41] vs 1.76 [1.24-4.00], P = .047). Fold elevation of 11-hydroxytestosterone between 3.48 (sensitivity 97%, specificity 47%) and 3.88 (sensitivity 100%, specificity 40%) provided the best discrimination between poor vs good control. 11-Oxyandrogens, especially 11-hydroxytestosterone, may be useful in the management of CAH when conventional biomarkers are inconclusive.

FAMILY EDUCATION STRATEGIES IN CARING FOR CHILDREN WITH CONGENITAL ADRENAL HYPERPLASIA (CAH): A LITERATURE REVIEW

Families having children with congenital adrenal hyperplasia (CAH) may have low knowledge and awareness in some aspects of CAH management. Information and education regarding caring for children with CAH is essential for families so that they can provide proper care and treatment to their children. This study aims to describe the strategy of family education about caring for children with CAH from the existing literature. A literature review was performed by investigating relevant studies from online databases of Google Scholar, Science Direct, PubMed, and BioMed Central. Keywords of “education” and “children” and “congenital adrenal hyperplasia” and “family or parents” were used in searching the data. The results of the review showed various strategies that can be applied to provide education to families, especially parents. These strategies include providing detailed care instructions about adrenal crisis management, encouraging families/ parents to use positive and useful coping strategies, increasing knowledge and awareness on the use of medical alert IDs, providing Psychosocial Education Program (PEP), increasing nurses’ knowledge and comfort in providing education to families, and suggestions for improving the provision of family education. The provision of education to families or parents having children with CAH should consider some individual aspects such as emotional states, health literacy, learning styles, the amount of information, and knowledge assessment of each family/parent.

Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India.

Accurate diagnosis is required for management of Congenital adrenal hyperplasia (CAH). The conventional method for detection of mutations in the CYP21A2 gene is targeted capillary sequencing which is labor intensive and has limited multiplexing capability. Next generation sequencing (NGS) provides data with high sequence coverage and depth. Our objective was to develop an accurate NGS-based assay to characterize the mutation spectrum in CYP21A2 gene in Indian patients suspected to have 21-OH CAH. Cases with 21-OH CAH from 12 endocrine units across India were studied. DNA was extracted from proband's and parent's(subset) blood. Locus-specific long-range PCR and gel electrophoresis of amplicons was followed by NGS where no visible 30 kb homozygous/whole gene deletion was observed. Orthogonal confirmation was performed by capillary sequencing (ABI 3500) and Multiplex Ligation-dependent Probe Amplification (MLPA, MRC-Holland). PCR products were purified and individual libraries were pooled and sequenced (Illumina). Of the 310 CAH cases, biallelic mutations (pathogenic/ likely pathogenic variants involving both CYP21A2 gene copies) were detected in 256 (82.6%), heterozygous mutations in 13 (4.2 %), and none in 41 (13.2%). Most common mutation was c.293-13A/C>G (29.03%), followed by 30 kb deletion (18.24%). Thirty samples tested orthogonally (by capillary sequencing or MLPA) showed 100% concordance with NGS assay. Nine novel variants were identified. We have developed and validated a comprehensive NGS-based assay for detection of variants in CYP21A2 gene in patients with 21-OH CAH. We describe CYP21A2 mutation spectrum and novel variants in a large cohort of Indian patients with CAH.

Behavioral assessment of females with congenital adrenal hyperplasia.

Patients with congenital adrenal hyperplasia (CAH) have an increased risk of psychological/psychiatric symptoms and disorders. This study aimed to assess the behavior of girls with CAH and its independent risk variables. This cross-sectional study included 55 girls with CAH due to 21-hydroxylase deficiency (mean age 12.64 ± 1.52years; salt-wasting (SW) form = 20, simple virilizing (SV) form = 35). Psychiatric interviewing and the Strength and Difficulties Questionnaire (SDQ) (parent-reporting questionnaires) were used to assess behavior. Compared to controls (n = 60), patients had a high total SDQ score (P = 0.001) and emotional, conduct, and hyperactivity-inattention symptoms, peer relationship problems (P = 0.001 for all), and prosocial behavior (p = 0.01) subscale scores, indicating externalizing and internalizing behavioral problems. Severe emotional symptoms and poor disease control were found with SW compared to the SV form. Multiple linear regression showed that bone age (BA) (β = 0.331, t = 3.608; P = 0.001) and 17-OHP (β = 0.408, t = 4.220; P = 0.001), testosterone (β = 0.348, t = 3.220; P = 0.001), and androstenedione (β = 0.238, t = 2.487; P = 0.015) levels were independently associated with behavioral problems. Females with CAH had frequent and severe behavioral symptoms. Excess androgenization, which was in part due to suboptimal steroid therapy, was the cause of the behavioral problems. Therefore, early optimization of CAH management should be stressed to prevent psychological consequences.

SUN-037 Discordant Serum 17-hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-oxygenated Androgens Useful?

Background 21-hydroxylase-deficiency (21OHD) accounts for more than 95% of CAH cases. Serum 17-hydroxyprogesteron (17OHP) and androstenedione (A4) are traditional biomarkers for monitoring therapy. While generally there is good linear correlation between 17OHP and A4, physicians are likely to encounter scenarios where 17OHP is within “acceptable range” while A4 is elevated and vice versa. Mildly elevated 17OHP is considered acceptable, as normalization of 17OHP is likely to result in overtreatment. 11-ketotestosterone (11KT) is a potent agonist of the androgen receptor with androgenic activity equivalent to testosterone. We hypothesized that patients with high 17OHP would be more likely than those with high A4 to be in good disease control. We speculated that A4 would correlate more strongly with 11-oxygenated C19 steroids (11oxyandrogens) than 17OHP and that patients in poor clinical control would have higher median fold-elevation of 11oxyandrogens, especially 11-KT, compared to controls. Methods We performed retrospective analysis of patients seen at NIH from 2006 to 2019 and identified discordant 17OHP and A4 (17-OHP ≥1200 ng/dL with A4 normal for age/sex or tanner stage and vice-versa). Good or poor clinical control was based on abnormal growth, precocious puberty, irregular menses, hypogonadotrophic hypogonadism and A4/T. Quantitation of 15 steroids in stored peripheral sera was performed by LC-MS/ MS and compared to age- and sex-matched controls. Data between groups were compared using t-tests or non-parametric Wilcoxon rank sum tests. Correlation analyses utilized the Pearson and Spearman’s rho. Results We identified 122 of 789 (15%) discordant laboratory assessments among adults [84 with high 17OHP (69%)] and 347 of 1,949 (18%) among children [319 with high 17OHP (92%)]. Of these, 50 patients with available serum samples were identified (44 with high 17OHP). Twenty-five patients (50%) appeared to have good disease control. There was no difference in the frequency of patients in good or poor control between patients with high 17OHP or those with high A4 (p=0.7). Median fold elevation of 11KT relative to controls was higher in patients in poor control (2.87 fold, IQR 1.87-5.42, range 0.31-10.69) but with wide ranges and substantial overlap compared to those in good control (1.71 fold, IQR 1.06-2.92, range 0.35-16.59, p=0.068). 17OHP correlated with 21-deoxycortisol (rs=0.67, p<.001) while A4 correlated strongly with 11oxyandrogens (rs range 0.42-0.71, p<.003 for all). However, we did not find any substantial difference in the level of 11oxyandrogens between patients with high 17OHP and those with high A4. Conclusion: Discordance between 17OHP and A4 is common in the management of CAH and patients with elevation of either of these biomarkers are equally likely to have poor disease control. Limited evidence suggests a role for 11KT, as a discriminator for disease control.

Abstract #810984: Discordant Serum 17-Hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-Oxygenated-Androgens Useful?

Abstract #810984: Discordant Serum 17-Hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-Oxygenated-Androgens Useful?

Beyond changing diapers: stress and decision-making among parents of girls with congenital adrenal hyperplasia seeking consultation about feminizing genital restoration surgery

The impact of having a child with atypical genitalia due to a life-threating chronic medical condition like congenital adrenal hyperplasia (CAH) is poorly understood. The aim of the study was to determine parental stress and impact of CAH on parental decisions, including decisions regarding female genital restoration surgery (FGRS). The authors surveyed consecutive parents of girls with CAH ≤3 yearspresenting at a tertiary referral center for FGRS consultation (2016-2019). The survey was developed by three families of daughters with CAH and six clinicians. Nine potentially stressful past experiences were rated on a 6-point Likert scale ('not at all' to 'extremely' stressful). Overall parental stress and strain (broader negative consequences) were reported using validated instruments (Perceived Stress Scale and Caregiver Strain Questionnaire Short Form, respectively). Impact of CAH on past decisions about childcare, social interactions, and who changes diapers were also assessed. Non-parametric tests were used for analysis. Twenty-nine parents (median age: 32years) of 22 consecutive children participated (Prader 3/4/5: 59.1%/36.4%/4.5%). After the study, 20 girls (90.9%) underwent FGRS at a median age of 8 months. The most stressful experiences werehaving an adrenal crisis ('very much' stressful), waiting for the CAH diagnosis, and making sense of the diagnosis (both 'quite a bit') (Figure1). Remaining issues were 'somewhat' stressful. Deciding whether to proceed with FGRS was ranked as the least stressful issue. Overall parental stress was similar to overall stress previously reported by spousal caregivers of stroke or heart failure survivors (P≥0.15). Overall parental strain was similar to parents of adolescents receiving mental health counseling (P=0.77). Congenital adrenal hyperplasia impacted decisions about babysitting, daycare, who changed diapers, and choosing a pediatrician (P≤0.02), but did not impact parental social interactions (P≥0.11). Diapers were typically changed by parents (100.0%) and grandmothers (50.0%). Parents anticipated that some individuals currently not allowed to change diapers would be allowed after FGRS: grandfathers (+18.2%), aunts/uncles (+27.3-32.8%), cousins (+18.2%), and family friends (+45.5%). The authors present the first assessment of parental stress with respect to different aspects of care of a daughter with CAH. Larger studies are required to determine if the parental stress associated with these experiences varies over time and how these stressors rank relative to each other through the child's development. Parents experience multiple stressors after having a daughter with CAH. Parental stress surrounding a decision about FGRS appears less severe than events pertaining to the diagnosis and medical management of CAH. Congenital adrenal hyperplasia impacts multiple parental decisions.