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Congenital adrenal hyperplasia is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that lead to impaired cortisol biosynthesis. Depending on the type and severity of steroid block, patients can have various alterations in glucocorticoid, mineralocorticoid, and sex steroid production that require hormone replacement therapy. Presentations vary from neonatal salt wasting and atypical genitalia, to adult presentation of hirsutism and irregular menses. Screening of neonates with elevated 17-hydroxyprogesterone concentrations for classic (severe) 21-hydroxylase deficiency, the most common type of congenital adrenal hyperplasia, is in place in many countries, however cosyntropin stimulation testing might be needed to confirm the diagnosis or establish non-classic (milder) subtypes. Challenges in the treatment of congenital adrenal hyperplasia include avoidance of glucocorticoid overtreatment and control of sex hormone imbalances. Long-term complications include abnormal growth and development, adverse effects on bone and the cardiovascular system, and infertility. Novel treatments aim to reduce glucocorticoid exposure, improve excess hormone control, and mimic physiological hormone patterns.

To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency clinical practice guideline published by the Endocrine Society in 2010. The writing committee presents updated best practice guidelines for the clinical management of congenital adrenal hyperplasia based on published evidence and expert opinion with added considerations for patient safety, quality of life, cost, and utilization.

Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.This Review focuses on challenges and advances in the management and treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. New therapeutic developments are discussed, including novel glucocorticoid therapies, adjunct agents aimed at controlling excess androgens, and cell-based and gene-based therapies.

Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by impaired cortisol production and consequent elevated adrenocorticotropic hormone (ACTH): CAH patients often require lifelong hydrocortisone therapy. Disease severity reflects residual 21‐hydroxylase enzyme activity, crucial for cortisol synthesis. Accurate assessment of residual enzymatic activity is key to developing individualized dosing. This study aimed to estimate enzymatic activity using a previously developed healthy adult ACTH‐cortisol model and to evaluate the potential for individualized therapy. Leveraging ACTH (n = 62) and cortisol (n = 66) concentrations from 51 (20 pediatric, 31 adult) untreated CAH patients, and assuming maximal cortisol production (Emax) = 100% in healthy individuals, residual enzymatic activity was estimated as an Emax scaling factor. To assess proof‐of‐concept feasibility of individualized therapy, simulations of individual untreated 24‐h ACTH and cortisol profiles were performed, and for one patient hydrocortisone dosing regimens (15–25 mg/day in 3 doses, q4h or q6h) were compared to simulated untreated and healthy profiles. The original model failed to capture elevated ACTH in severe CAH and was refined to predict observed data across all patients. Using the refined model, estimated enzymatic activity was higher than in vitro values for adults, while children under 13 years old showed 31.6% of adult enzymatic activity. Shortening dosing intervals had a greater impact on reducing the patient's ACTH overexposure than increasing the daily dose. This model‐based approach captured in vivo endogenous cortisol production and enabled simulation‐based evaluation of individualized therapy in adults. In children, further validation of the ACTH‐cortisol dynamics model and enzymatic activity estimates is needed to evaluate individualized therapy.

ContextSerum 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. ObjectiveTo evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4. MethodsRetrospective 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). ResultsDiscrepant 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. Conclusion11-Oxyandrogens, especially 11-hydroxytestosterone, may be useful in the management of CAH when conventional biomarkers are inconclusive.

Chimeric CYP21A1P/CYP21A2 genes, caused by homologous recombination between CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) and its highly homologous pseudogene CYP21A1P (cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene), are common in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). A comprehensive junction site analysis of chimeric CYP21A1P/CYP21A2 genes is needed for optimizing genetic analysis strategy and determining clinical relevance. We conducted a comprehensive genetic analysis of chimeric CYP21A1P/CYP21A2 genes in a cohort of 202 unrelated 21-OHD patients. Targeted CYP21A2 mutation analysis was performed, and genotyping of chimeric CYP21A1P/CYP21A2 genes was cross-confirmed with Southern blot, RFLP, and multiplex ligation-dependent probe amplification analyses. Junction sites of chimera genes were determined by sequencing the long-PCR products amplified with primers CYP779f and Tena32F. An updated bioinformatics survey of Chi-like sequences was also performed. Of 100 probands with a chimeric allele, 96 had a chimera associated with the severe classic salt-wasting form of CAH, and the remaining 4 carried an uncommon attenuated chimera with junction sites upstream of In2G (c.293-13A/C>G), which is associated with a milder phenotype. In addition to 6 of 7 reported chimeras, we identified a novel classic chimera (CH-8) and a novel attenuated chimera (CH-9). Attenuated chimeras explained prior genotype-phenotype discrepancies in 3 of the patients. Sequencing the CYP779f/Tena32F amplicons accurately differentiated between classic and attenuated chimeras. The bioinformatics survey revealed enrichment of Chi-like sequences within or in the vicinity of intron 2. Junction site analysis can explain some genotype-phenotype discrepancies. Sequencing the well-established CYP779f/Tena32F amplicons is an unequivocal strategy for detecting attenuated chimeric CYP21A1P/CYP21A2 genes, which are clinically relevant.

Abstract Context Patients with congenital adrenal hyperplasia (CAH) are exposed to hyperandrogenism and supraphysiologic glucocorticoids, both of which can increase risk of metabolic morbidity. Objective Our aim was to evaluate cardiovascular and metabolic morbidity risk in a longitudinal study of patients with CAH spanning both childhood and adulthood. Design and Setting Patients with classic CAH followed for a minimum of 5 years during both childhood and adulthood (n = 57) at the National Institutes of Health were included and compared with the US general population using NHANES data. Main outcome measures Obesity, hypertension, insulin resistance, fasting hyperglycemia, and dyslipidemia. Results Compared to the US population, patients with CAH had higher (P < 0.001) prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein (HDL) during childhood and obesity (P = 0.024), hypertension (P<0.001), and insulin resistance (P < 0.001) during adulthood. In our cohort, obesity, hypertension, fasting hyperglycemia, and hypertriglyceridemia began prior to age 10. During childhood, increased mineralocorticoid dose was associated with hypertension (P = 0.0015) and low HDL (P = 0.0021). During adulthood, suppressed androstenedione was associated with hypertension (P = 0.002), and high low-density lipoprotein (P = 0.0039) whereas suppressed testosterone (P = 0.003) was associated with insulin resistance. Elevated 17-hydroxyprogesterone, possibly reflecting poor disease control, was protective against high cholesterol (P = 0.0049) in children. Children whose mothers were obese (maternal obesity) had increased risk of obesity during adulthood (P = 0.0021). Obesity, in turn, contributed to the development of hypertension, insulin resistance, and hypertriglyceridemia in adulthood. Conclusion Patients with CAH develop metabolic morbidity at a young age associated with treatment-related and familial factors. Judicious use of glucocorticoid and mineralocorticoid is warranted.

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments. Graphical Abstract Graphical Abstract