Classic Classic Congenital Adrenal Hyperplasia Research Articles

Adult Height Following Prepubertal Treatment With Antiandrogen, Aromatase Inhibitor, and Reduced Hydrocortisone in CAH.

Height outcome in patients with classic congenital adrenal hyperplasia (CAH) is suboptimal due to glucocorticoid and androgen excess. In an open, randomized, controlled trial, children with classic CAH were randomized to receive a combination regimen of antiandrogen, aromatase inhibitor, reduced hydrocortisone, and fludrocortisone prior to puberty or standard therapy (hydrocortisone, fludrocortisone). Females continued on antiandrogen during puberty. The primary endpoint was adult height. Of 62 children randomized, 45 completed the study. Adult height SDS did not differ between the investigational and control groups (-0.34 [0.93] vs -0.60 [0.89], respectively), mean difference 0.26 [95% CI -0.29, 0.82], P = .35), irrespective of midparental height, but was greater than the predicted adult height pretreatment in both groups (P < .001). Growth rate and rate of bone maturation were reduced in the investigational group prior to puberty, despite lower hydrocortisone dose (7.6 [1.5] vs 15.0 [3.6] mg/m2/day, P < .001), and improvement in predicted adult height appeared greater at pubertal onset (P = .049) compared to standard therapy. Antiandrogen treatment during puberty in girls allowed for lower-dose glucocorticoid, and improved height outcome (adult minus midparental height: -0.7 [4.6] vs -5.6 [5.2] cm, mean difference 4.9 [95% CI 0.09, 9.7], P = .046). Those who received GnRHa had lower growth rate (P = .023) and longer years of unchanged bone age (P = .017), regardless of treatment. Prepubertal antiandrogen, aromatase inhibitor combination with reduced hydrocortisone improves short-term predicted height for children with CAH but does not result in taller adult stature than those treated with standard therapy, and is not recommended. Females may benefit from antiandrogen treatment during puberty.

12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol

Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone &amp;gt;4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024

9296 A Novel LC-MS/MS Salivary Fludrocortisone Method With Potential for Monitoring in Adrenal Insufficiency Patients

Abstract Disclosure: M. Dolan: None. D. Marshall: None. J. Hawley: None. N. Reisch: None. B.G. Keevil: None. Fludrocortisone (FC) is a fluorinated exogenous mineralocorticoid used to treat conditions associated with adrenal insufficiency including Addison’s disease and classic congenital adrenal hyperplasia (CAH). The mineralocorticoid action of FC allows the drug to compensate for aldosterone deficiency, thus helping to maintain blood pressure and other homeostatic mechanisms. Optimising FC replacement is vital as under-replacement can cause dizziness and hypotension, whereas over-replacement can lead to cardiometabolic disturbances. Treatment in classic CAH patients, who are typically diagnosed as new-borns, is even more complex as the requirement for mineralocorticoid replacement decreases with age. Endocrine Society guidelines recommend that FC monitoring should involve the clinical assessment of symptoms, which can be non-specific, and regular blood pressure measurements. Plasma renin activity (PRA) should be measured if clinical changes occur, aiming towards the upper end of the reference range. The utility of PRA is debated due to methodological issues and the inherent variability of the analyte itself, which may not always represent FC replacement status. Therefore, investigation into alternative biochemical markers of FC replacement is required. Here we aimed to facilitate this by developing an LC-MS/MS method for the measurement of salivary FC. Method: A salivary FC LC-MS/MS assay has been developed and validated for use according to FDA and EMA guidelines. Passive drool samples from 10 clinical trial patients with classic CAH were collected on two separate occasions at select time points throughout the day (0800, 1200, 1600, 2000 and 2300h). In most patients the 0800h sample was taken pre-FC dose. Once in the laboratory the patient samples were extracted and analysed using the FC method to produce a FC concentration day curve. Results: The method analysis time was 2.1 minutes, with a mean recovery of 102% and limit of quantification of 5 pmol/L (2.1 pg/mL). No analytical interference was identified. Analysis of patient samples using the method showed the presence of FC allowing the production of day curves. In most patients, the pre-dose sample contained no FC, with the subsequent samples showing a peak FC concentration corresponding to the Cmax. After this the FC concentration gradually tapered off throughout the remainder of the day. Conclusions: We have developed a novel assay for the measurement of salivary FC, which may allow the calculation of the area under the curve. As an optimal FC dose has yet to be determined this method may facilitate more in-depth pharmacokinetic studies into FC metabolism and blood pressure control. Thereby identifying patients that are fast metabolisers or poor absorbers of the medication, enabling a non-invasive strategy to optimise patient care. Presentation: 6/1/2024

Free cortisol and free 21-deoxycortisol in the clinical evaluation of congenital adrenal hyperplasia.

Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing the cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some untreated classic CAH patients. Develop and validate an LC-MS/MS method for free cortisol and free 21DF to quantify these steroids in untreated patients with classic CAH (n=29), non-classic CAH (NCCAH, n=5), other forms of adrenal insufficiency (AI, n=3), and controls (n=11) before and 60 minutes after Synacthen® administration. Unstimulated total cortisol concentrations of untreated classic CAH patients (median 109 nmol/L) were lower than in untreated NCCAH patients (249 nmol/L, p=0.010) and controls (202 nmol/L, p=0.016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in 21OHD patients (median 5.32 nmol/L) and undetectable in AI patients and controls (<0.19 nmol/L). After Synacthen® administration, free 21DF concentrations increased in 21OHD patients, while free cortisol concentrations did not change. Free cortisol concentrations in classic CAH patients were similar to those in controls and NCCAH patients, indicating comparable cortisol availability. Additionally, 21OHD patients produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some classic 21OHD patients. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.

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.

Serum steroid profile captures metabolic phenotypes in adults with classic congenital adrenal hyperplasia

ObjectivesAdult patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have an increased risk of metabolic diseases. We aimed to investigate whether liquid chromatography-mass spectrometry (LC-MS)-based serum steroid profiling reveals metabolic phenotypes in adults with classic CAH. Design and methodsThis study prospectively enrolled 63 adult patients with CAH and 38 healthy volunteers. The levels of the 24 steroids were quantified in the morning serum using LC-MS. Unsupervised clustering algorithms were applied to the serum steroid profiles to identify unique patterns associated with metabolic syndrome. ResultsSerum steroid profiles of patients with CAH were clearly delineated from those of healthy controls with a higher degree of interindividual heterogeneity. The unsupervised clustering algorithm divided CAH patients into two clusters based on serum steroid profile. Cluster 2 showed higher serum levels of glucocorticoids and androgens than cluster 1. The prevalence of metabolic syndrome was significantly higher in cluster 2 than in cluster 1 (37.8 % vs. 5.6 %, P = 0.011). Other clinical characteristics, including age, sex, body mass index, CAH subtypes, and glucocorticoid dose, did not differ between the two clusters. The multivariate logistic regression model of selective 15 steroids could discriminate metabolic syndrome in patients with CAH with an area under the receiver operating characteristic curve of 0.832 (95 % confidence interval:0.732–0.933). ConclusionsSerum steroid profiles can be valuable biomarkers for estimating metabolic risk in adult patients with CAH.

Metabotypes of congenital adrenal hyperplasia in infants determined by gas chromatography-mass spectrometry in spot urine

Biochemical monitoring of treatment in infants with classic congenital adrenal hyperplasia (CAH) is not yet well defined. The aim of this study was to perform a cluster analysis of the urinary steroid metabolome for treatment monitoring of infants with classic salt-wasting CAH. We analyzed spot urine samples obtained from 60 young children ≤ 4 years of age (29 females) with classic CAH due to 21-hydroxylase deficiency treated with hydrocortisone and fludrocortisone by targeted gas chromatography-mass spectrometry (GC-MS). Patients were classified into different groups according to their metabolic patterns (metabotypes) using unsupervised k-means clustering algorithms. Three metabotypes could be discovered. Metabotype #1 (N = 15 (25%)) showed high concentrations of androgen and 17-hydroxyprogesterone (17OHP) precursor steroids, metabotype #2 (N = 28 (47%)) revealed balanced metabolic control, and metabotype #3 (N = 17; 28%) demonstrated severe adrenal suppression with low concentrations of androgen and 17OHP precursor steroids. Daily hydrocortisone doses and urinary concentrations of cortisol and cortisone metabolites did not differ between all three metabotypes. Metabotype #2 had highest daily dose of fludrocortisone (p = 0.006). Receiver operating characteristic curve analysis showed that 11-ketopregnanetriol (area under the curve [AUC] 0.967) and pregnanetriol (AUC 0.936) were most suitable of separating metabotype #1 from #2. For separation between metabotypes #2 vs. #3, the 11-oxygenated androgen metabolite 11-hydroxyandrosterone (AUC 0.983) and the ratio of 11-hydroxyandrosterone to tetrahydrocortisone (AUC 0.970) were most suitable. In conclusion, GC-MS-based urinary steroid metabotyping is a new method to help monitor the treatment of infants with CAH. This method allows classification of under-, over- and adequately treated young children.

Testicular Adrenal Rest Tumor

A 17-year-old boy with a history of classic congenital adrenal hyperplasia (CAH) secondary to 21-α hydroxylase deficiency on treatment with hydrocortisone and fludrocortisone presented to the endocrinology clinic with bilateral painful testicular masses. Previous urologic evaluation revealed no evidence of hydrocele or epididymitis. Semen analysis showed azoospermia. Physical examination demonstrated Tanner stage V and normal phallus; the left testicle measured approximately 8 cm, and the right testicle measured 7 cm in largest diameter (Fig. 1 and 2). Laboratory evaluation showed the following: (1) alfa-fetoprotein level, 1.4 (reference range, 0.0-10.0) ng/mL; (2) human chorionic gonadotropin level, <0.1 (reference range, 0.0-1.0) mU/mL; (3) total testosterone level, 541 (reference range, 250-1100) ng/dL; (4) follicle-stimulating hormone level, 11.4 (reference range, 1.5-12.4) mU/mL; (5) luteinizing hormone level, 1.7 (reference range, 1.7-11) mU/mL; (6) adrenocorticotropic hormone level, 86 (reference range, 6-50) pg/mL; and (7) inhibin A level, <1 (reference range, <21) pg/mL.Fig. 2The left testicle measuring approximately 8 cm in largest diameter.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Scrotal ultrasound revealed markedly enlarged testes (60 mL and 70 mL) with hyperemia and no discrete masses, findings consistent with testicular adrenal rest tumor (TART) (Fig. 3). Partial orchiectomy confirmed the diagnosis. TARTs are firm bilateral painful masses originating near the rete testes developed in men with poorly controlled classic 21-α hydroxylase deficiency under the influence of chronically elevated adrenocorticotropic hormone levels. In recent studies, an overall prevalence of 40% (14%-89%) has been reported in patients with classic CAH.1Engels M. Span P.N. van Herwaarden A.E. Sweep F.C.G.J. Stikkelbroeck N.M.M.L. Claahsen-van der Grinten H.L. Testicular adrenal rest tumors: current insights on prevalence, characteristics, origin, and treatment.Endocr Rev. 2019; 40: 973-987Crossref PubMed Scopus (53) Google Scholar Ultrasonography is the most sensitive method of diagnosis. This condition is the most common cause of infertility in male patients with CAH. Although surgery can relieve the pain associated with the mass, it does not lead to increased testosterone production and improved fertility. Intensified glucocorticoid therapy is sometimes, but not always, effective in decreasing TART size and restoring fertility.2Claahsen-van der Grinten H.L. Otten B.J. Stikkelbroeck M.M. Sweep F.C. Hermus A.R. Testicular adrenal rest tumours in congenital adrenal hyperplasia.Best Pract Res Clin Endocrinol Metab. 2009; 23: 209-220Crossref PubMed Scopus (111) Google Scholar Routine physical examination along with annual ultrasound screening is recommended for early detection of the disease. The importance of good medication compliance was discussed with the patient, and the dosage of glucocorticoids was increased. The plan was to proceed with microdissection of testicular sperm extraction with cryopreservation in case fertility is not achieved by medical approach. The authors have no multiplicity of interest to disclose.

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.

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.

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

EE126 Cost Drivers in Patients with Classic Congenital Adrenal Hyperplasia (CAH)

Classic CAH is a rare condition characterized by cortisol deficiency and androgen excess, typically requiring treatment with supraphysiologic doses of glucocorticoids. This study evaluated the costs and identified key cost drivers for classic CAH in the United States (US).

PCR114 The Adjunctive Therapy Preferences of Adults with Classic Congenital Adrenal Hyperplasia: A Discrete Choice Experiment

Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic doses of glucocorticoids to replace missing cortisol and reduce adrenal androgens. Current treatments aim to control androgen-driven symptoms/impacts but can result in glucocorticoid-related side effects/complications. This study aimed to understand the preferences of adults with classic CAH for the benefits of a potential new adjunctive therapy that could provide better androgen control with lower glucocorticoid doses via an online discrete choice experiment (DCE).

Characterization of the CYP21A2 Gene Mutations in Children with Classic Congenital Adrenal Hyperplasia.

To characterize the CYP21A2 gene mutations in children with classic congenital adrenal hyperplasia (CAH). A prospective, cross-sectional study was conducted on 24 children with classic CAH. Molecular characterization of the CYP21A2 gene was carried out by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or clinical exome sequencing. Another 21 previously mutation-proven CAH patients were also included and a combined result was drawn. Out of 45 children, pathogenic variants in the CYP21A2 gene were identified in 43 patients (95.5%). Homozygous, probable compound heterozygous, and heterozygous variants were seen in 69%, 22%, and 18% of patients, respectively. The most common variant was c.293-13C/A>G(33%), followed by deletion/duplication (24%), and c.955C>T (p.Gln319Ter) (21%), similar to previous Indian studies. Allelic frequencies of c.332_339del and c.518T>A(p.Ile173Asn) were 9% and 4%, respectively. Less common variants were c.923dupT(p.Leu308PhefsTer6), c.92C>T(p.Pro31Leu), c.1069C>T(p.Arg357Trp), c.1267G>C(p.Gly423Arg), and c.710_719delins(p.Ile237_Met240delinsAsnGluGluLys). A good genotype-phenotype correlation was observed; only p.Pro31Leu and p.Ile173Asn variants showed discordance. The diagnostic yield of Sanger sequencing alone, Sanger sequencing with MLPA, and clinical exome alone was 85%, 100%, and 100%, respectively. All children, except two, diagnosed clinically as classic CAH, showed pathogenic variants in the CYP21A2 gene; the most common variant was c.293-13 C/A>G. The results suggest a broad mutation spectrum in the authors' single-center cohort of children with CAH. Clinical exome sequencing is the preferred stand-alone method for molecular diagnosis of CAH.

Hyponatremia, Metabolic Acidosis, and Abnormal Newborn Screen in a Preterm Neonate.

A 2,250-g male neonate is born at 34 weeks of gestation via spontaneous vaginal delivery to a 30-year-old gravida 1, para 0 woman after presentation to a community hospital with uterine contractions and spontaneous rupture of membranes. The mother receives 1 dose of ampicillin, 1 dose of betamethasone, and magnesium before delivery. At delivery, the neonate is vigorous and crying. His Apgar scores are 8 and 9 at 1 and 5 minutes after birth, respectively, with no abnormalities noted on physical examination. In the first couple of hours after birth, he develops persistent oxygen desaturations and is started on continuous positive airway pressure.He is admitted to the NICU for prematurity and low birthweight. Admission examination demonstrates nondysmorphic features, no respiratory distress with good air exchange, regular heart rate and rhythm without murmur, soft and flat abdomen, patent anus, normal external male genitalia, unremarkable neurologic findings, and pink skin color.Chest radiography shows mild diffuse ground-glass reticular densities. He is placed on a stock solution of parenteral nutrition via a peripheral intravenous catheter. Antibiotics are started because of the mother’s unknown group B Streptococcus status and preterm labor. Initial surveillance of electrolytes demonstrates sodium, potassium, calcium, phosphorus, and glucose levels within normal limits. On day 4 after birth, the neonate continues on nasal canula for tachypnea, receiving parenteral nutrition, and advancing gavage feeds of maternal breast milk or formula. A capillary blood gas measurement shows mild metabolic acidosis, with a pH of 7.28, Pco2 32 mm Hg (4.26 kPa), and bicarbonate 19 mEq/L (19 mmol/L).On day 6 after birth, repeat surveillance of electrolytes shows a sodium concentration of 126 mEq/L (126 mmol/L) and potassium of 6.7 mEq/L (6.7 mmol/L). Glucose concentration is 53 mg/dL (2.94 mmol/L). Blood gas continues to show mild metabolic acidosis with a pH of 7.27, Pco2 31 mm Hg (4.12 kPa), and bicarbonate 19 mEq/L (19 mmol/L). Results of the state newborn screening demonstrate an elevated 17-hydroxyprogesterone (17-OHP) of 221 nmol/L (normal <80 nmol/L) on dried blood spot testing, or 14,586 ng/dL (normal <5,280 ng/dL) as serum equivalent. A confirmatory serum 17-OHP level is sent that same day. The pediatric endocrinology service is consulted for the concerning laboratory results.The neonate is transferred to a tertiary care pediatric hospital for further management. He is started on hydrocortisone and fludrocortisone replacements along with sodium chloride supplementation. Repeat serum 17-OHP before treatment is greater than 50,000 ng/dL, and the actual diagnosis of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is made.The neonate continues to appear well with normal vital signs, including blood pressure. He is breathing room air, receiving full enteral feeds, and working on oral feeds with the occupational therapist. Parenteral nutrition has been discontinued.The differential diagnosis for hyponatremia and hyperkalemia in a neonate includes CAH, pseudohypoaldosteronism, inappropriate parenteral nutrition composition, and exogenous diuretic use.CAH is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway and is the most common cause of primary adrenal insufficiency in children. The classic form of CAH affects 1 in 15,000 neonates and is commonly identified through newborn screening, (1) with screening mandated across the United States since 2008. (2) Most cases of CAH are caused by 21-OHD, which is marked by an elevated serum 17-OHP. In the steroidogenic pathway, 17-OHP is the precursor in the enzymatic reaction that is catalyzed by 21-OHD, and is the primary analyte tested in newborn screening for CAH. If treatment is not initiated early, neonates may present in acute salt-wasting adrenal crisis with vomiting, hypotension, and severe dehydration, electrolyte abnormalities, and hypoglycemia. (1)(3)(4)(5) Female neonates with classic CAH also present with virilization of external genitalia at birth.False-positive newborn screening results for CAH are common in preterm neonates, related to the fact that healthy preterm neonates have higher overall levels of 17-OHP compared with term neonates. (6) Thus, many screening programs have established reference ranges that are based on weight and gestational age.For neonates with classic CAH, therapy should be initiated soon after birth to reduce the potentially life-threatening sequelae of CAH. Classic CAH is treated with steroid hormone replacements including hydrocortisone (to replace cortisol) and fludrocortisone (to replace aldosterone). Supplemental sodium chloride (salt) is also recommended for neonates with classic CAH who could have salt-wasting.

Characteristics of Growth in Children With Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency During Adrenarche and Beyond.

ContextPatients with classic congenital adrenal hyperplasia (CAH) often do not achieve their full growth potential. Adrenarche may accelerate bone maturation and thereby result in decreased growth in CAH.ObjectiveThe study aimed to analyze the impact of growth during adrenarche on final height of adequately treated classic CAH patients.MethodsThis retrospective, multicenter study (4 academic pediatric endocrinology centers) included 41 patients with classical CAH, born 1990-2012. We assessed skeletal maturation (bone age), growth velocity, and (projected) adult height outcomes, and analyzed potential influencing factors, such as sex, genotype, and glucocorticoid therapy.ResultsPatients with classic CAH were shorter than peers (−0.4 SDS ± 0.8 SD) and their parents (corrected final height −0.6 SDS ± 1.0 SD). Analysis of growth during adrenarche revealed 2 different growth patterns: patients with accelerating bone age (49%), and patients with nonaccelerating bone age relative to chronological age (BA-CA). Patients with accelerating BA-CA were taller than the normal population during adrenarche years (P = 0.001) and were predicted to achieve lower adult height SDS (−0.9 SDS [95% CI, −1.3; −0.5]) than nonaccelerating patients when assessed during adrenarche (0.2 SDS [95% CI, −0.3; 0.8]). Final adult height was similarly reduced in both accelerating and nonaccelerating BA-CA groups (−0.4 SDS [95% CI, −0.9; 0.1] vs −0.3 SDS [95% CI, [−0.8; 0.1]).ConclusionPatients with and without significant bone age advancement, and thus differing height prediction during adrenarche, showed similar (predicted) final height when reassessed during pubertal years. Bone age alone should not be used during adrenarche as clinical marker for metabolic control in CAH treatment.

Urinary GC-MS steroid metabotyping in treated children with congenital adrenal hyperplasia

Abstract Background Treatment of children with classic congenital adrenal hyperplasia (CAH) is a difficult balance between hypercortisolism and hyperandrogenism. Biochemical monitoring of treatment is not well defined. Objective Cluster analysis of the urinary steroid metabolome obtained by targeted gas chromatography–mass spectrometry (GC–MS) for treatment monitoring of children with CAH. Methods We evaluated 24-h urinary steroid metabolome analyses of 109 prepubertal children aged 7.0 ± 1.6 years with classic CAH due to 21-hydroxylase deficiency treated with hydrocortisone and fludrocortisone. 24-h urinary steroid metabolite excretions were transformed into CAH-specific z-scores. Subjects were divided into groups (metabotypes) by k-means clustering algorithm. Urinary steroid metabolome and clinical data of patients of each metabotype were analyzed. Results Four unique metabotypes were generated. Metabotype 1 (N = 21 (19%)) revealed adequate metabolic control with low cortisol metabolites (mean: −0.57z) and suppressed androgen and 17α-hydroxyprogesterone (17OHP) metabolites (−0.79z). Metabotype 2 (N = 23 (21%)) showed overtreatment consisting of a constellation of elevated urinary cortisol metabolites (0.62z) and low metabolites of androgens and 17OHP (−0.75z). Metabotype 3 (N = 32 (29%)) demonstrated undertreated patients with low cortisol metabolites (−0.69z) and elevated metabolites of androgens and 17OHP (0.50z). Metabotype 4 (N = 33 (30%)) presented patients with treatment failure reflected by unsuppressed androgen- and 17OHP metabolites (0.71z) despite elevated urinary cortisol metabolites (0.39z). Conclusion Metabotyping, which means grouping metabolically similar individuals, helps to monitor treatment of children with CAH using GC–MS urinary steroid metabolome analysis. This method allows classification in adequately-, over-, or undertreated children as well as identification of patients with treatment failure.

Second-tier Testing for 21-Hydroxylase Deficiency in the Netherlands: A Newborn Screening Pilot Study.

Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives. We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study. Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis. A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days). Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time.

11-oxygenated androgens and their relation to hypothalamus-pituitary-gonadal-axis disturbances in adults with congenital adrenal hyperplasia

ContextHypothalamus-pituitary-gonadal (HPG)-axis disturbances are a common phenomenon in patients with classic congenital adrenal hyperplasia (CAH). 11-oxygenated androgens have been suggested to play a role in this context. DesignCross-sectional single center study including 89 patients (N = 42 men, N = 55 women) with classic CAH. Main Outcome MeasuresDifferences in steroid markers in men with hypogonadism and women with secondary amenorrhea with a special focus on 11-ketotestosterone (11KT) and 11β-hydroxyandrostenedione (11OHA4). ResultsHypogonadotropic hypogonadism was present in 23 % of men and 61 % of those women currently not on contraceptives suffered from irregular menstrual cycles or amenorrhea. Testicular adrenal rest tumor (TART) was documented in 28 % of men. 11KT (3.5x) and 11OHA4 (5.7x) among other adrenal steroids were significantly elevated in men with hypogonadism and in women with amenorrhea in comparison to those with a regular cycle (11KT: 5.2x; 11OHA4: 3.7x). 11-oxygenated androgens were not higher in men with TART than in those without. There was a negative association of 11KT and 11OHA4 with FSH but not with LH in men. As expected, all steroids were strongly correlated with each other and cases of disproportionally elevated 11-oxygenated androgens that could explain for HPG-disturbances or TART in otherwise controlled patients were rare and also found in eugonadal individuals. ConclusionsIn CAH, 11-oxygenated androgens are elevated in women with menstrual disturbances and in men with hypogonadotropic hypogonadism. Due to the close correlation of 11-oxygenated androgens with other adrenal steroids it remains to be shown if their measurement is superior to conventional markers of androgen control.

Real-World Evidence of Clinical Outcomes in Patients With Assumed Classic Congenital Adrenal Hyperplasia in the United States

Background: Classic congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, usually due to a deficiency in the 21-hydroxylase enzyme, that results in impaired cortisol synthesis and excess androgen production. Patients with classic CAH experience both disease-related features from excess androgens and treatment-related complications from the chronic, supraphysiologic use of glucocorticoids (GCs) often required for androgen control. This study was conducted to evaluate the demographics and clinical characteristics of adult and pediatric patients in the United States (US) with assumed classic CAH based on International Classification of Diseases (ICD) codes, GC prescriptions, and medical claims. Methods: Analyses were based on longitudinal patient-level data from the Decision Resources Group Real World Evidence repository, which links medical claims, prescription claims, and electronic health records from >300 million US patients. Data were analyzed for patients aged ≥18 years (adult) and <18 years (pediatric) with assumed classic CAH based on ICD 9/10 codes associated with “adrenogenital disorders” and whose proportion of days covered with a GC in 2018–2019 was >75%. These patients were matched 1:3 with a control cohort based on age, gender, geographic region, and insurance type. Both assumed CAH and control cohorts had continuous coverage with at least 1 medical claim and 1 pharmacy claim in each year, 2018–2019. Results: Of 1,111 patients with assumed classic CAH, 778 were ≥18 years old (65% female; mean age [±SD], 43±17 years) and 333 were <18 years old (51% female; mean age [±SD], 11±4.7 years). Both adult and pediatric patients with assumed classic CAH were more likely than matched controls (adult N=2334; pediatric N=999) to experience events that could be related to chronic GC use, including infection (adult: 49.9% vs 37.3% [control]; pediatric: 49.5% vs 40.0%), weight gain (adult: 5.9% vs 2.5%; pediatric: 9.0% vs 2.6%), and moon face (adult: 44.0% vs 0.1%; pediatric: 37.8% vs 0.1%); all P<0.01 vs control. Adult patients were more likely than matched controls to experience acne (6.0% vs 3.6%), hirsutism (8.1% [47/508] vs 5.5% [84/1524]), and infertility (1.7% vs 0.4%); all P<0.01. Pediatric patients were more likely to experience pubertal development issues (10.5% vs 1.8%), acne (8.4% vs 5.1%), and advanced bone age (1.2% vs 0.1%); all P<0.05. Conclusions: Compared to matched controls, both adult and pediatric patients with assumed classic CAH had significantly more disease-related comorbidities and potential GC treatment-related conditions, indicating the challenges with current GC treatments. This study was limited by the assumed nature of classic CAH due to lack of a specific ICD code, but the combination of chronic GC use (>75% days) with the diagnosis code most likely used in these patients (adrenogenital disorder) supports the validity of this analysis.