RARE DISEASE
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia
Synonyms: CAH
Synonyms: CAH
Synonyms: CAH
Drug discovery
14
drugs
With orphan designations
Overview
Congenital adrenal hyperplasia (CAH) comprises autosomal recessive disorders disrupting adrenal steroidogenesis, most commonly from 21-hydroxylase deficiency [1][6]. Classic CAH manifests with cortisol/aldosterone deficiency and androgen excess, causing ambiguous genitalia in females, adrenal crises, and growth/sexual development abnormalities [1][2][6]. Non-classic CAH presents later with mild hyperandrogenism [7][11]. Diagnosis integrates newborn 17-OHP screening, hormonal profiles, and genetic testing [2][19], while treatment focuses on glucocorticoid/mineralocorticoid replacement and androgen suppression [1][3][8].
Burden
Mortality: ~20% of classic CAH patients die from adrenal crisis complications (average 7-year life loss) [4][9].
Morbidity: Increased fractures (2× baseline risk), cardiometabolic disorders, infertility, and adrenal rest tumors [4][14][18].
Psychosocial: Impaired quality of life, gender identity challenges, and caregiver strain due to chronic management [14][15].
Therapies
Lifelong glucocorticoid (hydrocortisone, prednisone) and mineralocorticoid (fludrocortisone) replacement [1][3][8].
Stress-dose steroids during illness/surgery to prevent adrenal crisis [1][19]; anti-androgens (e.g., spironolactone) for hyperandrogenism [1][13].
Emerging therapies: continuous subcutaneous hydrocortisone pumps, modified-release oral glucocorticoids, and gene therapy trials [8][13][17].
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
1,152 drug discovery papers about Congenital adrenal hyperplasia, with 4 first-in-class and 31 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,152 drug discovery papers about Congenital adrenal hyperplasia, with 4 first-in-class and 31 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Trajectory-based analysis of growth in congenital adrenal hyperplasia: therapeutic implications for final height preservation.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder resulting in a dysfunction of the steroidogenesis pathway and glucocorticoid deficiency. Proper care demands not only preventing acute complications but also optimizing growth and sexual development. This study was set out to analyze final height metrics and the factors affecting them as a long-term outcome measure in CAH patients. This observational retrospective study evaluated almost 3000 visits of 63 CAH patients treated in one center between 1996 and 2025, who reached their near-final height (nFH). The population was divided into the salt-wasting (SW, n = 45) and non-SW groups (n = 18). The main outcome measures were nFH, corrected nFH (c-nFH), and their standard deviation scores (SDSs). They were associated with numerous factors, including glucocorticoid doses, bone age (BA), height velocity (HV), occurrence of puberty, body mass index, and adiposity rebound. c-nFH SDS was compromised in both the SW (- 0.99 ± 0.87) and non-SW patients (- 0.57 ± 0.71) (p = 0.053). HV trajectories pointed to a flattened pubertal growth spurt in both populations. Maximum BA advancement (BAA) and peak ΔBAA were lower in SW than in non-SW patients, while age at peak ΔBAA and age at maximum BAA were comparable between groups. Both longitudinal and cross-sectional regression models showed negative interactions between hydrocortisone doses and height outcomes. We observed that CAH patients tend to have compromised final height, with the SW-CAH population presenting with most compromised growth. Higher hydrocortisone doses were associated with worse outcomes. The analysis of BA and HV trajectories seems to suggest a period demanding intensified care. • CAH and long-term glucocorticoid therapy may impair growth and final height, particularly in salt-wasting forms, with bone age advancement regarded as a major determinant of height outcome. • Higher hydrocortisone exposure has been associated with poorer growth outcomes in CAH patients. • Longitudinal analysis of 2949 visits identified a shared critical period between 6 and 10 years of age characterized by accelerated bone age advancement and altered height velocity trajectories requiring intensified disease control. • Early optimization of androgen suppression and consideration of aromatase inhibitor therapy may improve growth outcomes.
2026-09-19 | Prescription pattern of oral hydrocortisone by Indian healthcare professionals: An online questionnaire-based survey.
Objective. Adrenal insufficiency is predominantly managed by glucocorticoids, from which hydrocortisone is most frequently prescribed. However, limited data are available on prescription patterns among Indian healthcare professionals (HCPs). This study assessed the prescription practices of hydrocortisone among Indian HCPs and evaluated their awareness of tapering protocols and necessity for modified-release formulations of hydrocortisone. Methods. This online questionnaire-based survey involved 300 HCPs across India who prescribe oral hydrocortisone for various endocrinological and non-endocrinological indications. Google Forms were used and survey was carried out over a period of two months. Only fully accomplished responses were included in the analysis and the response rate was calculated. Results. The survey response rate was 84.27%. Among HCPs, 94.7% prescribed oral hydrocortisone with 47.5% using it often and 28.9% very often. Prescription frequency varied from 29.9% (prescribed once weekly) to 25.7% (two or more times weekly). Awareness of approved indications was high (96.8%). Tapering protocols were widely practiced (95.4%) often or very often by 82.7% HCPs. Hydrocortisone was mainly prescribed for primary adrenal insufficiency (77.5%), secondary adrenal insufficiency (63.0%), and congenital adrenal hyperplasia (55.6%). Frequent adverse events included hyperglycemia (43.3%) and weight gain (43.0%). Most HCPs (89.8%) felt need for sustained-release hydrocortisone, particularly for primary adrenal insufficiency (81.7%). Alternatives of hydrocortisone mainly included prednisolone (65.8%), prednisone (37.3%), and dexamethasone (21.8%). Conclusion. Indian HCPs frequently prescribe oral hydrocortisone and are well-versed in tapering protocols. However, frequent adverse events and unmet needs emphasize strong demand for modified-release formulations, particularly for management of adrenal insufficiency.
2026-09-17 | Management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update
Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders characterized by enzyme deficiencies that impair adrenal steroidogenesis, most commonly due to 21-hydroxylase deficiency. The biochemical defects in CAH translate to a spectrum of clinical consequences, which include adrenal insufficiency, genital ambiguity or disordered sex development, infertility, short stature, and an increased risk of metabolic syndrome during adolescence and adulthood. The severity and clinical features of CAH vary depending on the enzymatic defect, residual enzymatic activity, the age of presentation, and genotype. This review comprehensively covers the genetic background, classification, and clinical spectrum of CAH, including classical and non-classical forms. We discuss the importance and implementation of neonatal screening programs for early diagnosis and intervention. Special attention is given to differences in treatment approaches between children and adolescents, highlighting the challenges of optimizing glucocorticoid and mineralocorticoid therapy across developmental stages. Furthermore, we present emerging novel pharmacological agents currently in clinical trials aimed at improving disease management. The review also addresses potential complications associated with CAH, such as metabolic syndrome, cardiovascular risks, and bone health issues. Emphasizing a patient-centered approach, we highlight the critical role of experienced endocrinologists in delivering individualized care to improve long-term outcomes. Our review summarizes the current knowledge, aims to guide clinicians in evidence-based management and highlights ongoing research into innovative therapies for CAH.
2026-09-17 | The association between abdominal muscle mass quantified by computed tomography and osteoporosis in postmenopausal women.
Osteoporosis is a significant health concern among postmenopausal women owing to its association with increased fracturerisk and morbidity. Although traditional risk factors such as hormonal changes, dietary intake, and physical activity have been extensivelyinvestigated, the role of muscle mass, particularly abdominal muscle mass, in bone health remains incompletely understood. This studyaimed to investigate the association between abdominal muscle mass, as measured by computed tomography (CT), and osteoporosis inpostmenopausal Korean women. This retrospective cross-sectional study included 1,723 postmenopausal women who underwent both abdominal CT and dual-energy X-ray absorptiometry (DXA) for bone mineral density (BMD) assessment. Abdominal muscle mass was quantifiedusing total abdominal muscle area (TAMA) at the L3 vertebral level on CT. Osteoporosis was defined as a T-score ≤ -2.5 at the lumbar spine or hip. Multivariable logistic regression analyses were conducted to examine the association between TAMA and osteoporosis, adjustingfor age, body mass index, lifestyle factors, and biochemical markers. Participants in the highest TAMA quartile exhibited significantly higher BMD in both the lumbar spine and hip than those in the lowest quartile (p < 0.05). Higher TAMA was independently associated with a lower risk of osteoporosis (adjusted OR, 0.365up of autosomal recessive disorders characterized by enzyme deficiencies thatimpair adrenal steroidogenesis, most commonly due to 21-hydroxylase deficiency. The biochemical defects in CAH translate to a spectrumof clinical consequences, which include adrenal insufficiency, genital ambiguity or disordered sex development, infertility, short stature,and an increased risk of metabolic syndrome during adolescence and adulthood. The severity and clinical features of CAH vary dependingon the enzymatic defect, residual enzymatic activity, the age of presentation, and genotype. This review comprehensively covers the genetic background, classification, and clinical spectrum of CAH, including classical and non-classical forms. We discuss the importance and implementation of neonatal screening programs for early diagnosis and intervention. Specialattention is given to differences in treatment approaches between children and adolescents, highlighting the challenges of optimizingglucocorticoid and mineralocorticoid therapy across developmental stages. Furthermore, we present emerging novel pharmacologicalagents currently in clinical trials aimed at improving disease management. The review also addresses potential complications associatedwith CAH, such as metabolic syndrome, cardiovascular risks, and bone health issues. Emphasizing a patient-centered approach, wehighlight the critical role of experienced endocrinologists in delinering individualized care to improve long-term outcomes. Our review summarizes the current knowledge, aims to guide clinicians in evidence-based management and highlights ongoing research into innovativetherapies for CAH.
2026-09-03 | Testicular adrenal rests tumours in congenital adrenal hyperplasia: unraveling prevalence, risk factors and new therapeutic horizons in adolescents
Testicular adrenal rest tumours (TARTs) are benign intratesticular lesions occurring in males with classic congenital adrenal hyperplasia (CAH), with a prevalence ranging from 0% to 94% depending on age, disease severity and screening method. Although TARTs are non-malignant, their characteristic location can lead to compression of seminiferous tubules causing infertility. Adolescence represents a critical and particularly vulnerable window for TART development and progression. Besides ACTH chronic stimulation, which remains the main pathogenic driver, several other converging factors can contribute to suboptimal hormonal control and promote adrenal rest cell proliferation during adolescence. The aim of this minireview is to provide a comprehensive and updated overview of TARTs in the adolescent population, focusing on three key areas: prevalence across different CAH aetiologies, risk factors driving development and progression during puberty and emerging therapeutic approaches with potential impact on this complication.
proteins
2026-03-08 | Congenital adrenal hyperplasia-induced central precocious puberty: Importance of early recognition and treatment
One of the commonest causes of peripheral precocious puberty in boys is congenital adrenal hyperplasia (CAH). Hydrocortisone treatment typically prevents peripheral precocity from progressing. However, a small number of patients may develop central precocious puberty while receiving this therapy. In this situation, gonadotropin-releasing hormone analogue (GnRHa) therapy typically arrests subsequent pubertal progression and advancement of bone age. Here, we present a boy with peripheral iso-sexual precocious puberty due to CAH presented at eight years. Since the age of six years, he had a history of the appearance of pubic hair, penile lengthening, offensive behaviour, and gradual darkening of skin. However, his pubertal development and bone age advancement persisted even after conventional treatment with hydrocortisone and fludrocortisone. Conversion to central precocious puberty was subsequently confirmed by clinical and hormonal evaluation. Further, pubertal progression was successfully arrested with a GnRHa in addition to a glucocorticoid and mineralocorticoid regimen. Delayed diagnosis and treatment of CAH may be complicated by true precocious puberty, which can be successfully arrested by treatment with GnRHa along with hydrocortisone and fludrocortisone. [J Assoc Clin Endocrinol Diabetol Bangladesh, July 2026; 5 (2): e87119]
2025-10-29 | A double challenge: Managing precocious puberty in congenital adrenal hyperplasia with gonadotropin releasing hormone agonist
Congenital adrenal hyperplasia is the most common cause of peripheral precocious puberty in boys. Treatment with hydrocortisone usually halts the progression of peripheral precocity. However, being on this treatment, a few cases may be complicated by central precocious puberty. In such cases, treatment with a Gonadotropin-Releasing Hormone agonist (GnRHa) usually prevents further pubertal development and the acceleration of bone age. Here, we present a case of an 8-year-old boy who was diagnosed with peripheral precocious puberty due to congenital adrenal hyperplasia. He had a history of the appearance of pubic hair and phallic enlargement at 6 years of age, aggressive behavior, and hyperpigmentation. Notably, he had bilateral testicular microlithiasis and a varicocele. Despite treatment with hydrocortisone and fludrocortisone, his pubertal progression and advancement of bone age continued. Clinical and hormonal evaluation subsequently confirmed conversion to central precocious puberty. Addition of a GnRHa to his glucocorticoid and mineralocorticoid regimen successfully arrested further pubertal progression. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S48]
2025-02-01 | Has the Era of Individualized Intrauterine Treatment for Congenital Adrenal Hyperplasia Arrived?
Congenital adrenal hyperplasia (CAH) is a common metabolic genetic disease. Early diagnosis and intervention are crucial to improve the prognosis. Noninvasive prenatal diagnosis (NIPD) is an early, safe, and accurate method. This study aimed to evaluate the NIPD of CAH while guiding individualized intrauterine treatment. Twenty families with a 25% risk of having a baby with 21-hydroxylase deficiency (21-OHD) were included. Haplotypes were constructed based on targeted sequencing and family linkage analysis. Relative haplotype dosage (RHDO) combined with Bayes factor was used to infer fetal genotypes. Invasive prenatal diagnosis was performed to verify the reliability of NIPD. For affected-female fetuses, intrauterine treatment was applied until delivery. In 20 families, NIPD successfully identified one female-affected fetus, four male-affected fetuses, nine heterozygotes, and five normal fetuses. The first-pass success rate of NIPD was 90% (18/20), the reporting rate was 95% (19/20), and the accuracy was 100% (19/19). Individualized intrauterine treatment avoided 88.9% (8/9) of unnecessary treatment of unaffected female fetuses. Moreover, no significant virilization was observed in the newborn of CAH16, which underwent intrauterine treatment. NIPD has far-reaching implications for the early treatment and clinical management of pregnancy in families with 21-OHD.
2025-01-26 | Semaglutide and laparoscopic sleeve gastrectomy in an adolescent with congenital adrenal hyperplasia due to 21-hydroxylase: a case report.
Classic congenital adrenal hyperplasia, primarily due to 21-hydroxylase deficiency, leads to impaired cortisol and aldosterone production and excess adrenal androgens. Lifelong glucocorticoid therapy is required, often necessitating supraphysiological doses in youth to manage androgen excess and growth acceleration. These patients experience higher obesity rates, hypertension, and glucose metabolism issues, complicating long-term health management. Despite this, there is limited literature on effective obesity management strategies in congenital adrenal hyperplasia patients, emphasizing the need for comprehensive care approaches. We present the case of an 18-year-old Hispanic male with classic congenital adrenal hyperplasia and class III obesity, who underwent a multimodal obesity treatment plan. Diagnosed shortly after birth, he experienced rapid weight gain starting at the age of 2 years, with his body mass index escalating to 52.5 kg/m2 by age 15. Initial interventions included lifestyle modifications and pharmacotherapy with metformin and topiramate, which were ineffective alone. Subsequently, he was treated with semaglutide, achieving an 11% body mass index reduction. Owing to ongoing metabolic dysregulation, he underwent laparoscopic sleeve gastrectomy at the age of 17 years. The surgery was well tolerated, with careful intraoperative glucocorticoid management. Post-surgery, he experienced significant improvements in body mass index, hunger, and satiety, along with a reduction in emotional overeating. This case highlights the potential of an integrative, multidisciplinary approach to address severe obesity and its associated comorbidities in patients with classic congenital adrenal hyperplasia. The successful outcomes from both pharmacotherapy and bariatric surgery suggest that tailored obesity management strategies can optimize health in this unique population, reinforcing the need for further research into comprehensive obesity care in individuals with congenital adrenal hyperplasia.
2024-01-19 | Gonadotropin-Releasing Hormone Agonist Therapy and Longitudinal Bone Mineral Density in Congenital Adrenal Hyperplasia.
Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty. Gonadotropin-releasing hormone analog (GnRHa) is frequently used and can decrease bone mineral density (BMD). Our aim was to investigate the effect of GnRHa therapy on BMD in a longitudinal study of patients with CAH spanning both childhood and adulthood. Sixty-one patients with classic CAH due to 21-hydroxylase deficiency (20 treated with GnRHa) were followed with dual-energy X-ray absorptiometry (DXA) scans at puberty onset, attainment of adult height, and during early adulthood. Whole body, lumbar spine, femoral neck, total hip, and distal radius BMD z-score at adult height. Longitudinal BMD and adult height were also assessed. Twenty patients received GnRHa for an average of 4.5 ± 2 years. There were no differences in BMD between GnRHa-treated and -untreated groups at adult height for all sites. Overall, the follow-up DXA during early adulthood showed decreases in BMD z-scores for whole body (P = .01), lumbar spine (P < .0001), femoral neck (P = .06), total hip (P = .009), and distal radius (P = .05). GnRHa treatment correlated with improved height outcomes compared to predicted height at puberty onset after adjusting for midparental height (P = .02). Patients in both groups achieved similar adult height. In children with CAH, GnRHa does not compromise BMD. However, BMD decreases with time and during the second and third decades of life is a possible effect of chronic supraphysiologic glucocorticoids. Children with CAH who experience early puberty benefit from GnRHa treatment as evidenced by the positive effect on height.
oligonucleotides
2025-03-26 | Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China.
Long-read sequencing (LRS) provides comprehensive genetic information, but research of LRS applied to congenital adrenal hyperplasia (CAH) newborn screening is limited. This study aimed to evaluate the clinical utility of LRS in genetic diagnosis and second-tier newborn screening. Neonates born between January 2017 and December 2022 in Fujian, China, were recruited for biochemical and LRS-based genetic screening assay. The LRS covers the entire gene regions and exon-intron boundary regions for CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In this retrospective study, 1,774,555 newborns received 17α-OHP screening, yielding a screening positive rate of 0.20%. Of these high-risk neonates, 3411 were successfully recalled for re-evaluation. Finally, 66 neonates were diagnosed with CAH, with a positive predictive value of 28.82%. Based on this data, the overall prevalence of CAH in Fujian was estimated to be 1:26,883. LRS was performed on 57 neonates with 21-hydroxylase deficiency (21-OHD) and 109 variant alleles were identified. The c.293-13C>G variant (31.19%) was the most prevalent in Fujian. Additionally, 647 neonates with suspected positive results were genotyped, and 41 were identified as carriers, with carrier frequencies of 1:18 for CYP21A2, 1:162 for HSD3B2, and 1:324 for CYP17A1 in Xiamen. Therefore, LRS can provide comprehensive genotypes in approximately 1.5 days at a cost of less than $20 USD per sample, and effectively improve screening efficiency, reduce anxiety of parents during newborn screening (NBS), and shorten the time to referral of CAH patients (approximately 10 days). Such a combined screening strategy is worthy to be recommended for NBS programs in the future.
2024-05-03 | Can Incorporating Molecular Testing Improve the Accuracy of Newborn Screening for Congenital Adrenal Hyperplasia?
Single-tier newborn screening (NBS) for congenital adrenal hyperplasia (CAH) using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24 to 48 hours produces a high false-positive rate (FPR). Second-tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multitier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the first-tier 17OHP cutoff to minimize missed cases. We create a Minnesota-specific CYP21A2 pathogenic variants panel; developed a rapid, high-throughput multiplex, allele-specific-primer-extension assay; and performed a 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based 2-tier protocol and a molecular-based multitier NBS protocol, applied post hoc. CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. The Centers for Disease Control and Prevention created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68 659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A 3-tier protocol with a lower first-tier steroid cutoff, second-tier 21-variant CYP21A2 panel, and third-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs, and 3 TPs. Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.
2021-11-08 | Nonsense variant of NR0B1 causes hormone disorders associated with congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. The DAX-1 protein (encoded by NR0B1) is a vertebrate-specific orphan nuclear receptor and is also a transcriptional factor for adrenal and reproductive development. CAH usually causes adrenal insufficiency in infancy and early childhood, leading to hypogonadotropic hypogonadism in adulthood; however, few adult cases have been reported to date. In this study, we examined a Chinese family with one adult patient with CAH, and identified a putative variant of NR0B1 gene via next-generation sequencing (NGS), which was confirmed with Sanger sequencing. A novel nonsense variant (c.265C>T) was identified in the NR0B1 gene, which caused the premature termination of DAX-1 at residue 89 (p.G89*). Furthermore, mutant NR0B1 gene displayed a partial DAX-1 function, which may explain the late pathogenesis in our case. Additionally, qPCR revealed the abnormal expression of four important genes identified from ChIP-seq, which were associated with energy homeostasis and steroidogenesis, and were influenced by the DAX-1 mutant. In addition, hormone disorders can be caused by DAX-1 mutant and partially recovered by siRNA of PPARGC1A. Herein, we identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH. This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient's phenotypic features.
2017-04-12 | Variations in the 3'UTR of the CYP21A2 Gene in Heterozygous Females with Hyperandrogenaemia.
Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the∗52C>T,∗440C>T, and∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the∗12C>T and∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.
2017-01-18 | Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report.
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation. A 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6-9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7-8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins. Compound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.
cell therapies
2026-03-18 | Genotype Description in Patients with Congenital Adrenal Hyperplasia in Bogotá, Colombia
Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzymatic deficiencies in the steroidogenic pathway.Approximately 90% of cases are due to pathogenic variants in the CYP21A2 gene, leading to 21-hydroxylase deficiency (21-OHD).This enzyme is essential for the synthesis of cortisol and aldosterone.Objective: To evaluate an Advanced Regenerative and Immunomodulatory Drainage Protocol (ARDIP) as a treatment strategy in patients presenting with facial tissue necrosis unresponsive to conventional management. Case presentation:We report a case series of seven patients aged between 4 and 9 years who presented with growth acceleration and/or premature pubarche and had a confirmed molecular genetic diagnosis.Results are expressed as mean standard deviation.The mean age was 7.11 2.61 years.Basal 17-alpha-hydroxyprogesterone (17-OHP) levels were 22.9 26.72, increasing to 37.43 22.53 following ACTH stimulation testing.The mean bone age was 9.86 2.86 years, with an average advancement of 2.74 0.86 years compared with chronological age.Molecular genetic studies were performed using sequencing, copy number variant (CNV) and insertion-deletion (InDel) analysis, multiplex ligation-dependent probe amplification (MLPA) of the CYP21A2 gene or clinical exome sequencing.Pathogenic variants were identified in homozygosity, compound heterozygosity (CH) or carrier status (Table 1).Discussion: Approximately 75% of pathogenic variants result from rearrangements between the CYP21A1P pseudogene and the functional CYP21A2 gene, typically manifesting as copy number variants.Around 20-25% are caused by single nucleotide variants, including missense, nonsense, splice-site variants and small insertions and deletions.The remaining 1-2% correspond to de novo variants arising from unequal crossover events during meiosis 1 .
2024-09-27 | Establishment of Star-edited Y1 cells as a novel in vitro functional assay for STAR.
Genetic variants involving steroidogenic acute regulatory protein cause lipoid congenital adrenal hyperplasia, which is characterized by impaired steroidogenesis in the adrenal glands and gonads. Functional assessment of variant STAR proteins is necessary for an accurate genetic diagnosis. Ideally, steroidogenic cells should be used to assess the functionality of STAR proteins, but the presence of endogenous STARs in steroidogenic cells precludes such a method. Here, we generated Star-edited cells from steroidogenic Y1 mouse adrenocortical tumor cells by genome editing. Star-edited Y1 cells exhibited very low but measurable cAMP-dependent pregnenolone production. Furthermore, stimulation of the cAMP pathway for 2 weeks resulted in the formation of lipid droplets in the cytoplasm of Star-edited Y1 cells, which resembled the histology of the adrenal glands of patients with lipoid congenital adrenal hyperplasia. The steroidogenic defect of Star-edited Y1 cells can be restored by transient overexpression of mouse Star. We found that human STAR can also restore defective steroidogenesis in Star-edited Y1 cells, and we were able to construct a novel in vitro system to evaluate human STAR variants. Collectively, we established Star-edited Y1 cells that retain the steroidogenic pathway downstream of the Star protein. Star-edited Y1 cells recapitulate the functional and morphological changes of lipoid congenital adrenal hyperplasia and can be used to evaluate the functionality of human STAR variants.
2024-05-25 | A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia-CYP21A2-R484Q Mutant Mouse.
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
2023-10-01 | SAT275 Generation And Characterization Of A Humanized CYP21A2 Mouse Model For Congenital Adrenal Hyperplasia
Abstract Disclosure: A. Huebner: None. S. Thirumalasetty: None. T. Schubert: None. R. Naumann: None. I. Reichardt: None. M. Rohm: None. D. Landgraf: None. F. Gembardt: None. M.F. Hartmann: None. S.A. Wudy: None. M. Peitzsch: None. N. Reisch: None. K. Koehler, PhD: None. 21-hydroxylase deficiency (21OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene. 21OHD causes a wide array of clinical symptoms that result from gluco- and mineralocorticoid deficiency and adrenal androgen excess. Treatment firstly aims to substitute lacking steroid hormones, and secondly to restore negative feedback towards CRH and pituitary ACTH secretion to diminish adrenal androgen overproduction. In most cases supra-physiological glucocorticoid doses are necessary which may cause short stature, obesity, hypertension, and cardiovascular and metabolic co-morbidity with reduced quality of life. Hence, current steroid substitution regimens have significant limitations, so novel therapeutic strategies are required. In recent years new therapeutic approaches have emerged including new non-glucocorticoid substances interfering with the HPA axis to minimize adrenal androgen production and to lower external glucocorticoid substitution to physiological levels. However, valuable in-vivo models for pre-clinical testing of such drugs are lacking. Here we present the first viable and humanized mouse model in which the mouse gene Cyp21a1 is replaced by the human orthologue CYP21A2 in which the human point mutation R484Q is integrated. Twenty-weeks-old homozygous mice show marked adrenal hyperplasia, enhanced expression of the CYP21A2 gene and a weak increase of Cyp11a1 and Cyp11b2 gene expression. Tandem mass spectrometry measurements of the mice plasma at 20 weeks show decreased corticosterone and 11-deoxycorticosterone levels in the presence of increased ACTH levels in both male and female homozygous animals. Progesterone levels in homozygous mice are significantly higher (p<0.01) than in wildtype mice. We also observed increased aldosterone levels in female mutants whereas blood pressure does not differ between wildtype and mutant mice strains. Histologically, mutants exhibit adrenocortical hyperplasia. While mutant male mice are fertile with normal appearing testes, females are infertile, remain in the diestrus phase and present with a reduced number of ovarian follicles. In parallel, a second mouse strain bearing the I173N mutation was developed. This mutation is frequent in human patients causing simple virilizing or rarely salt wasting CAH. Homozygous mice require dexamethasone treatment during pregnancy and until weaning but are viable without treatment afterwards. Preliminary results show adrenal hyperplasia and alteration in steroidogenic gene expression and steroid profiles. In conclusion, we demonstrate that the humanized mutant CYP21A2 mice may represent an excellent animal CAH model to test novel treatment strategies for CAH patients. We believe that this model(s) will facilitate the transition from basic research into clinical application. Presentation: Saturday, June 17, 2023
2023-06-16 | Endocrine profiles and cycle characteristics of infertile 17α-hydroxylase/17,20-lyase Deficiency Patients undergoing assisted Reproduction Treatment: a retrospective cohort study.
17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene variants. Female patients with 17-OHD demonstrate a broad clinical spectrum, including oligomenorrhea or amenorrhea and infertility, often as the sole manifestation. However, no spontaneous pregnancies in affected women have been reported. This retrospective cohort study aimed to explore the endocrine characteristics and assisted reproductive technique (ART) performance in women with 17-OHD. Five women were referred for primary infertility in a university-affiliated hospital over an eight-year period. The endocrine profiles and cycle characteristics during a total of nine cycles of ovarian stimulation and eight cycles of frozen-thawed embryo transfer (FET) were described in details. Three cases had homozygous variants and two cases had compound heterozygous variants, including one novel missense variant (p.Leu433Ser) in the CYP17A1 gene. Despite dual-suppression of progesterone (P) production by glucocorticoid and gonadotropin releasing hormone agonist, gradually increased P level, relatively low estradiol concentrations and thin endometrium were observed, negating fresh embryo transfer. During FET cycles, appropriate treatment resulted in low serum P levels and adequate endometrial thickness, leading to four live births. Our findings demonstrate that continuous elevation of serum P during follicular growth impairs endometrial receptivity, the likely cause of female infertility in 17-OHD. Therefore, female infertility caused by 17-OHD is suggested as an indication for freeze-all strategy, with promising reproductive prognoses following segmented ovarian stimulation and FET treatment.
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2025-12-26 | Exploration of the potential of genomic editing in the treatment of congenital adrenal hyperplasia.
Despite life-saving glucocorticoids, therapeutic options for congenital adrenal hyperplasia (CAH) remain sub-optimal. Adrenal crisis continues to be the highest cause of mortality in individuals with CAH and even with recommended treatment regimens complications from the disease and treatments themselves persist. These patients have limited treatment options and advanced therapeutics could be a solution. Development of genetic therapies have exponentially increased in recent years. The advent of CRISPR/Cas technology has brought previously inconceivable treatment options to reality. Genomic editing could repair the defective 21-hydroxylase gene and provide a cure for 21-hydroxylase deficiency, the most common CAH variant, eliminating the current need for constant patient intervention. There are a number of technologies within reach for CAH, however, delivery of the genomic editing reagents to the elusive adrenocortical progenitor cells remains challenging. Here we discuss the complexity of CAH genetics, which has implications for choice of genomic editing strategy, and potential future strategies for the development of a cure of CAH.
2025-12-05 | Impact of Growth-promoting Therapies on Puberty, Growth, and Final Height in Classical 21-hydroxylase Deficiency.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) poses significant growth challenges, including accelerated bone maturation, precocious puberty, and compromised final height (FH). Data on pubertal growth in large 21-OHD cohorts remain limited. To assess puberty timing, duration, height gain, FH outcomes, and the effects of growth-promoting therapies (GPTs), including GnRH analog, aromatase inhibitors, and cyproterone acetate, in a large cohort with genetically confirmed classical 21-OHD. A multicenter, retrospective, longitudinal analysis of 284 patients (46,XX: 160; 46,XY: 124). Data on puberty, growth, and treatments were collected from clinical records. Growth curves were plotted based on GPT use. Median age at diagnosis was 0.1 years (interquartile range [IQR]: 0.03-1.1), and at last visit, 12.1 years (IQR: 7.0-17.0). Median FH was 154.0 cm (IQR: 147.3-158.2) in 46,XX (menarche at 13.0 years) and 167.0 cm (IQR: 160.0-170.0) in 46,XY. In the total cohort, 63.4% were pubertal/postpubertal, and the ratio of GPTs used alone or in combination was 41.1%. GnRH analogs, cyproterone acetate, and aromatase inhibitors were administered in 21.8% (n = 62), 8.1% (n = 23), and 5.3% (n = 15) of the cohort, respectively. The median FH-MPH difference improved from -6.7 cm to -2.3 cm in boys without and with GPT, respectively, whereas in girls it declined from -3.7 cm to -6.6 cm. Patients with 21-OHD had diminished FH despite early diagnosis. Puberty in classical 21-OHD had an earlier onset, slower tempo, and prolonged duration, especially in girls, in which GPTs are less effective in promoting height. The management of pubertal growth needs a personalized approach in patients with classical 21-OHD.
2025-11-12 | Targeted editing of the 21-hydroxylase locus confers durable therapeutic effect in a murine model of congenital adrenal hyperplasia.
Contemporary treatment for congenital adrenal hyperplasia is lifesaving; however, long-term deleterious effects from the disease and complications from the inadequacy of available treatment remain problematic. Locus-specific correction of the defective 21-hydroxylase gene through genomic editing has the potential to address this unmet need by simultaneously restoring gene function and physiological control. Editing is necessitated by the constant cellular turnover in the adrenal cortex which limits the durability of conventional gene addition strategies using recombinant adeno-associated virus. We have developed a homology-independent targeted integration genomic editing strategy that conferred phenotypic benefit in a mouse model using a dual recombinant adeno-associated virus approach. Reconstitution of 21-hydroxylase expression in the adrenal gland increased corticosteroid production, reduced adrenal gland hyperplasia, and reduced expression of renin and aldosterone synthase with these effects maintained to 15 weeks without diminution. This is beyond the adrenocortical cellular turnover time, providing initial evidence of adrenocortical progenitor cell targeting. Importantly, the editing strategy used is potentially applicable to the majority of causative mutations in classical congenital adrenal hyperplasia. Collectively these data provide strong impetus for addressing the challenges of clinical translation, with development and evaluation of strategies for efficient targeting of human adrenocortical progenitor cells being the most formidable.
2025-10-01 | MON-468 A Novel Anti-ACTH Antibody Lu AG13909 in Clinical Development for Treatment of Classic Congenital Adrenal Hyperplasia: A Phase 1 Open-Label, Multiple-Ascending-Dose Study
Abstract Disclosure: G. Johannsson: AstraZeneca, Novo Nordisk, Pharmanovia, Pfizer, Inc., Takeda, Shire. A. Velusamy: Immunovant, Novo Nordisk, Samsung/Philips/Canon. A. Prete: Diurnal, Spruce, Recordati, Lundbeck. H. Falhammar: None. M.M. Binderup: None. K.G. Larsen: None. M. Folden Flensburg: None. J. Luthman: None. U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. Nonclinical studies demonstrated that Lu AG13909 induces a significant and durable reduction of corticosterone and aldosterone in rats, and of cortisol and aldosterone in cynomolgus monkeys. Here, we present the results of a first-in-human trial investigating the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of Lu AG13909 in adults with classic CAH. Methods: This was a phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (NCT05669950). Eligible participants were men and women, aged ≥18 to ≤70 years, with classic CAH and pre-GC morning 17-hydroxyprogesterone (17-OHP) concentrations >4 times the upper limit of normal. Each participant received up to 6 doses of Lu AG13909 every 28 to 35 days at increasing dose levels, with stable GC therapy and mineralocorticoid replacement if needed. The trial consisted of 2 parts: Part A had a 3+3 design, in which 3 participants were given a certain dose level, and escalation to the next dose level was based on a 28-day safety observation period. Part B explored the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The primary endpoints included adverse events; clinical safety; maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval; and the relative reductions in morning 17-OHP and androstenedione (A4) concentrations from baseline to the day after each Lu AG13909 dose. Results: In total, 11 participants were enrolled (4 men, 7 women), with a mean age of 37 years (range: 21-58 years). At the Baseline Visit the geometric means for the concentrations of morning 17-OHP and A4 were 274 nmol/L (range: 100-1033 nmol/L) and 11.0 nmol/L (range: 3.9-49.5 nmol/L), respectively. Preliminary data (N=11) demonstrated clear pharmacodynamic effects following up to 6 intravenous infusions of Lu AG13909 at increasing doses, with consistent reductions in morning 17-OHP and A4 concentrations observed at all dose levels. No safety concerns were raised. Conclusions: The preliminary results of this phase 1 study show that Lu AG13909 is well-tolerated and can reduce adrenal androgen production, reinforcing continued clinical development of Lu AG13909 as a novel anti-ACTH treatment strategy for classic CAH. Presentation: Monday, July 14, 2025
2025-05-07 | Combination therapy of GnRHa, RhGH and anastrozole to improve final adult height deficit in CAH children with CPP.
To investigate the clinical and genetic characteristics of classic congenital adrenal hyperplasia (CAH) patients. To determine whether gonadotropin-releasing hormone analogs (GnRHa) + recombinant human growth hormone (rhGH) + Anastrozole combined therapy improves the final adult height of CAH patients with central precocious puberty (CPP). We described the clinical and genetic characteristics of 16 classic CAH patients, and performed pathogenic analysis and structural modeling of the newly discovered mutation. By using the method of self-before and after control, we statistically analyzed bone age advancement, predicted adult height (PAH) and other indicators of 7 CAH children with CPP before and after combined treatment to observe its effect on adult height. All patients showed high levels of 17-hydroxyprogesterone, testosterone and adrenocorticotropic hormone. All patients had CYP21A2 gene mutations, and the newly discovered mutation c.79 A > G (p.Ser27Gly) may change the hydrophilicity of the protein and affect its function. Seven CAH patients with CPP were diagnosed at 5.6 (3.5 to 7.3) years. Their target height was 0.18 (-1.2 to 0.78) SD, and the PAH at the start of treatment was - 3.01 (-3.75 to -2.89) SD. The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The PAH at treatment end was - 0.28 (-1.2 to 0.4) SD. The final height was - 0.28 (-1 to 1.04) SD, significantly higher than the initial PAH (P < 0.001) and similar to the target height (P = 0.478). GnRHa + rhGH + Anastrozole therapy can improve the final adult height of CAH patients with CPP. In addition, this study also discovered a new CYP21A2 gene mutation c.79 A > G.
small molecules
2026-09-30 | Trajectory-based analysis of growth in congenital adrenal hyperplasia: therapeutic implications for final height preservation.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder resulting in a dysfunction of the steroidogenesis pathway and glucocorticoid deficiency. Proper care demands not only preventing acute complications but also optimizing growth and sexual development. This study was set out to analyze final height metrics and the factors affecting them as a long-term outcome measure in CAH patients. This observational retrospective study evaluated almost 3000 visits of 63 CAH patients treated in one center between 1996 and 2025, who reached their near-final height (nFH). The population was divided into the salt-wasting (SW, n = 45) and non-SW groups (n = 18). The main outcome measures were nFH, corrected nFH (c-nFH), and their standard deviation scores (SDSs). They were associated with numerous factors, including glucocorticoid doses, bone age (BA), height velocity (HV), occurrence of puberty, body mass index, and adiposity rebound. c-nFH SDS was compromised in both the SW (- 0.99 ± 0.87) and non-SW patients (- 0.57 ± 0.71) (p = 0.053). HV trajectories pointed to a flattened pubertal growth spurt in both populations. Maximum BA advancement (BAA) and peak ΔBAA were lower in SW than in non-SW patients, while age at peak ΔBAA and age at maximum BAA were comparable between groups. Both longitudinal and cross-sectional regression models showed negative interactions between hydrocortisone doses and height outcomes. We observed that CAH patients tend to have compromised final height, with the SW-CAH population presenting with most compromised growth. Higher hydrocortisone doses were associated with worse outcomes. The analysis of BA and HV trajectories seems to suggest a period demanding intensified care. • CAH and long-term glucocorticoid therapy may impair growth and final height, particularly in salt-wasting forms, with bone age advancement regarded as a major determinant of height outcome. • Higher hydrocortisone exposure has been associated with poorer growth outcomes in CAH patients. • Longitudinal analysis of 2949 visits identified a shared critical period between 6 and 10 years of age characterized by accelerated bone age advancement and altered height velocity trajectories requiring intensified disease control. • Early optimization of androgen suppression and consideration of aromatase inhibitor therapy may improve growth outcomes.
2026-09-19 | Prescription pattern of oral hydrocortisone by Indian healthcare professionals: An online questionnaire-based survey.
Objective. Adrenal insufficiency is predominantly managed by glucocorticoids, from which hydrocortisone is most frequently prescribed. However, limited data are available on prescription patterns among Indian healthcare professionals (HCPs). This study assessed the prescription practices of hydrocortisone among Indian HCPs and evaluated their awareness of tapering protocols and necessity for modified-release formulations of hydrocortisone. Methods. This online questionnaire-based survey involved 300 HCPs across India who prescribe oral hydrocortisone for various endocrinological and non-endocrinological indications. Google Forms were used and survey was carried out over a period of two months. Only fully accomplished responses were included in the analysis and the response rate was calculated. Results. The survey response rate was 84.27%. Among HCPs, 94.7% prescribed oral hydrocortisone with 47.5% using it often and 28.9% very often. Prescription frequency varied from 29.9% (prescribed once weekly) to 25.7% (two or more times weekly). Awareness of approved indications was high (96.8%). Tapering protocols were widely practiced (95.4%) often or very often by 82.7% HCPs. Hydrocortisone was mainly prescribed for primary adrenal insufficiency (77.5%), secondary adrenal insufficiency (63.0%), and congenital adrenal hyperplasia (55.6%). Frequent adverse events included hyperglycemia (43.3%) and weight gain (43.0%). Most HCPs (89.8%) felt need for sustained-release hydrocortisone, particularly for primary adrenal insufficiency (81.7%). Alternatives of hydrocortisone mainly included prednisolone (65.8%), prednisone (37.3%), and dexamethasone (21.8%). Conclusion. Indian HCPs frequently prescribe oral hydrocortisone and are well-versed in tapering protocols. However, frequent adverse events and unmet needs emphasize strong demand for modified-release formulations, particularly for management of adrenal insufficiency.
2026-09-17 | Management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update
Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders characterized by enzyme deficiencies that impair adrenal steroidogenesis, most commonly due to 21-hydroxylase deficiency. The biochemical defects in CAH translate to a spectrum of clinical consequences, which include adrenal insufficiency, genital ambiguity or disordered sex development, infertility, short stature, and an increased risk of metabolic syndrome during adolescence and adulthood. The severity and clinical features of CAH vary depending on the enzymatic defect, residual enzymatic activity, the age of presentation, and genotype. This review comprehensively covers the genetic background, classification, and clinical spectrum of CAH, including classical and non-classical forms. We discuss the importance and implementation of neonatal screening programs for early diagnosis and intervention. Special attention is given to differences in treatment approaches between children and adolescents, highlighting the challenges of optimizing glucocorticoid and mineralocorticoid therapy across developmental stages. Furthermore, we present emerging novel pharmacological agents currently in clinical trials aimed at improving disease management. The review also addresses potential complications associated with CAH, such as metabolic syndrome, cardiovascular risks, and bone health issues. Emphasizing a patient-centered approach, we highlight the critical role of experienced endocrinologists in delivering individualized care to improve long-term outcomes. Our review summarizes the current knowledge, aims to guide clinicians in evidence-based management and highlights ongoing research into innovative therapies for CAH.
2026-09-17 | The association between abdominal muscle mass quantified by computed tomography and osteoporosis in postmenopausal women.
Osteoporosis is a significant health concern among postmenopausal women owing to its association with increased fracturerisk and morbidity. Although traditional risk factors such as hormonal changes, dietary intake, and physical activity have been extensivelyinvestigated, the role of muscle mass, particularly abdominal muscle mass, in bone health remains incompletely understood. This studyaimed to investigate the association between abdominal muscle mass, as measured by computed tomography (CT), and osteoporosis inpostmenopausal Korean women. This retrospective cross-sectional study included 1,723 postmenopausal women who underwent both abdominal CT and dual-energy X-ray absorptiometry (DXA) for bone mineral density (BMD) assessment. Abdominal muscle mass was quantifiedusing total abdominal muscle area (TAMA) at the L3 vertebral level on CT. Osteoporosis was defined as a T-score ≤ -2.5 at the lumbar spine or hip. Multivariable logistic regression analyses were conducted to examine the association between TAMA and osteoporosis, adjustingfor age, body mass index, lifestyle factors, and biochemical markers. Participants in the highest TAMA quartile exhibited significantly higher BMD in both the lumbar spine and hip than those in the lowest quartile (p < 0.05). Higher TAMA was independently associated with a lower risk of osteoporosis (adjusted OR, 0.365up of autosomal recessive disorders characterized by enzyme deficiencies thatimpair adrenal steroidogenesis, most commonly due to 21-hydroxylase deficiency. The biochemical defects in CAH translate to a spectrumof clinical consequences, which include adrenal insufficiency, genital ambiguity or disordered sex development, infertility, short stature,and an increased risk of metabolic syndrome during adolescence and adulthood. The severity and clinical features of CAH vary dependingon the enzymatic defect, residual enzymatic activity, the age of presentation, and genotype. This review comprehensively covers the genetic background, classification, and clinical spectrum of CAH, including classical and non-classical forms. We discuss the importance and implementation of neonatal screening programs for early diagnosis and intervention. Specialattention is given to differences in treatment approaches between children and adolescents, highlighting the challenges of optimizingglucocorticoid and mineralocorticoid therapy across developmental stages. Furthermore, we present emerging novel pharmacologicalagents currently in clinical trials aimed at improving disease management. The review also addresses potential complications associatedwith CAH, such as metabolic syndrome, cardiovascular risks, and bone health issues. Emphasizing a patient-centered approach, wehighlight the critical role of experienced endocrinologists in delinering individualized care to improve long-term outcomes. Our review summarizes the current knowledge, aims to guide clinicians in evidence-based management and highlights ongoing research into innovativetherapies for CAH.
2026-09-03 | Testicular adrenal rests tumours in congenital adrenal hyperplasia: unraveling prevalence, risk factors and new therapeutic horizons in adolescents
Testicular adrenal rest tumours (TARTs) are benign intratesticular lesions occurring in males with classic congenital adrenal hyperplasia (CAH), with a prevalence ranging from 0% to 94% depending on age, disease severity and screening method. Although TARTs are non-malignant, their characteristic location can lead to compression of seminiferous tubules causing infertility. Adolescence represents a critical and particularly vulnerable window for TART development and progression. Besides ACTH chronic stimulation, which remains the main pathogenic driver, several other converging factors can contribute to suboptimal hormonal control and promote adrenal rest cell proliferation during adolescence. The aim of this minireview is to provide a comprehensive and updated overview of TARTs in the adolescent population, focusing on three key areas: prevalence across different CAH aetiologies, risk factors driving development and progression during puberty and emerging therapeutic approaches with potential impact on this complication.
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2026-03-08 | Congenital adrenal hyperplasia-induced central precocious puberty: Importance of early recognition and treatment
One of the commonest causes of peripheral precocious puberty in boys is congenital adrenal hyperplasia (CAH). Hydrocortisone treatment typically prevents peripheral precocity from progressing. However, a small number of patients may develop central precocious puberty while receiving this therapy. In this situation, gonadotropin-releasing hormone analogue (GnRHa) therapy typically arrests subsequent pubertal progression and advancement of bone age. Here, we present a boy with peripheral iso-sexual precocious puberty due to CAH presented at eight years. Since the age of six years, he had a history of the appearance of pubic hair, penile lengthening, offensive behaviour, and gradual darkening of skin. However, his pubertal development and bone age advancement persisted even after conventional treatment with hydrocortisone and fludrocortisone. Conversion to central precocious puberty was subsequently confirmed by clinical and hormonal evaluation. Further, pubertal progression was successfully arrested with a GnRHa in addition to a glucocorticoid and mineralocorticoid regimen. Delayed diagnosis and treatment of CAH may be complicated by true precocious puberty, which can be successfully arrested by treatment with GnRHa along with hydrocortisone and fludrocortisone. [J Assoc Clin Endocrinol Diabetol Bangladesh, July 2026; 5 (2): e87119]
2025-10-29 | A double challenge: Managing precocious puberty in congenital adrenal hyperplasia with gonadotropin releasing hormone agonist
Congenital adrenal hyperplasia is the most common cause of peripheral precocious puberty in boys. Treatment with hydrocortisone usually halts the progression of peripheral precocity. However, being on this treatment, a few cases may be complicated by central precocious puberty. In such cases, treatment with a Gonadotropin-Releasing Hormone agonist (GnRHa) usually prevents further pubertal development and the acceleration of bone age. Here, we present a case of an 8-year-old boy who was diagnosed with peripheral precocious puberty due to congenital adrenal hyperplasia. He had a history of the appearance of pubic hair and phallic enlargement at 6 years of age, aggressive behavior, and hyperpigmentation. Notably, he had bilateral testicular microlithiasis and a varicocele. Despite treatment with hydrocortisone and fludrocortisone, his pubertal progression and advancement of bone age continued. Clinical and hormonal evaluation subsequently confirmed conversion to central precocious puberty. Addition of a GnRHa to his glucocorticoid and mineralocorticoid regimen successfully arrested further pubertal progression. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S48]
2025-02-01 | Has the Era of Individualized Intrauterine Treatment for Congenital Adrenal Hyperplasia Arrived?
Congenital adrenal hyperplasia (CAH) is a common metabolic genetic disease. Early diagnosis and intervention are crucial to improve the prognosis. Noninvasive prenatal diagnosis (NIPD) is an early, safe, and accurate method. This study aimed to evaluate the NIPD of CAH while guiding individualized intrauterine treatment. Twenty families with a 25% risk of having a baby with 21-hydroxylase deficiency (21-OHD) were included. Haplotypes were constructed based on targeted sequencing and family linkage analysis. Relative haplotype dosage (RHDO) combined with Bayes factor was used to infer fetal genotypes. Invasive prenatal diagnosis was performed to verify the reliability of NIPD. For affected-female fetuses, intrauterine treatment was applied until delivery. In 20 families, NIPD successfully identified one female-affected fetus, four male-affected fetuses, nine heterozygotes, and five normal fetuses. The first-pass success rate of NIPD was 90% (18/20), the reporting rate was 95% (19/20), and the accuracy was 100% (19/19). Individualized intrauterine treatment avoided 88.9% (8/9) of unnecessary treatment of unaffected female fetuses. Moreover, no significant virilization was observed in the newborn of CAH16, which underwent intrauterine treatment. NIPD has far-reaching implications for the early treatment and clinical management of pregnancy in families with 21-OHD.
2025-01-26 | Semaglutide and laparoscopic sleeve gastrectomy in an adolescent with congenital adrenal hyperplasia due to 21-hydroxylase: a case report.
Classic congenital adrenal hyperplasia, primarily due to 21-hydroxylase deficiency, leads to impaired cortisol and aldosterone production and excess adrenal androgens. Lifelong glucocorticoid therapy is required, often necessitating supraphysiological doses in youth to manage androgen excess and growth acceleration. These patients experience higher obesity rates, hypertension, and glucose metabolism issues, complicating long-term health management. Despite this, there is limited literature on effective obesity management strategies in congenital adrenal hyperplasia patients, emphasizing the need for comprehensive care approaches. We present the case of an 18-year-old Hispanic male with classic congenital adrenal hyperplasia and class III obesity, who underwent a multimodal obesity treatment plan. Diagnosed shortly after birth, he experienced rapid weight gain starting at the age of 2 years, with his body mass index escalating to 52.5 kg/m2 by age 15. Initial interventions included lifestyle modifications and pharmacotherapy with metformin and topiramate, which were ineffective alone. Subsequently, he was treated with semaglutide, achieving an 11% body mass index reduction. Owing to ongoing metabolic dysregulation, he underwent laparoscopic sleeve gastrectomy at the age of 17 years. The surgery was well tolerated, with careful intraoperative glucocorticoid management. Post-surgery, he experienced significant improvements in body mass index, hunger, and satiety, along with a reduction in emotional overeating. This case highlights the potential of an integrative, multidisciplinary approach to address severe obesity and its associated comorbidities in patients with classic congenital adrenal hyperplasia. The successful outcomes from both pharmacotherapy and bariatric surgery suggest that tailored obesity management strategies can optimize health in this unique population, reinforcing the need for further research into comprehensive obesity care in individuals with congenital adrenal hyperplasia.
2024-01-19 | Gonadotropin-Releasing Hormone Agonist Therapy and Longitudinal Bone Mineral Density in Congenital Adrenal Hyperplasia.
Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty. Gonadotropin-releasing hormone analog (GnRHa) is frequently used and can decrease bone mineral density (BMD). Our aim was to investigate the effect of GnRHa therapy on BMD in a longitudinal study of patients with CAH spanning both childhood and adulthood. Sixty-one patients with classic CAH due to 21-hydroxylase deficiency (20 treated with GnRHa) were followed with dual-energy X-ray absorptiometry (DXA) scans at puberty onset, attainment of adult height, and during early adulthood. Whole body, lumbar spine, femoral neck, total hip, and distal radius BMD z-score at adult height. Longitudinal BMD and adult height were also assessed. Twenty patients received GnRHa for an average of 4.5 ± 2 years. There were no differences in BMD between GnRHa-treated and -untreated groups at adult height for all sites. Overall, the follow-up DXA during early adulthood showed decreases in BMD z-scores for whole body (P = .01), lumbar spine (P < .0001), femoral neck (P = .06), total hip (P = .009), and distal radius (P = .05). GnRHa treatment correlated with improved height outcomes compared to predicted height at puberty onset after adjusting for midparental height (P = .02). Patients in both groups achieved similar adult height. In children with CAH, GnRHa does not compromise BMD. However, BMD decreases with time and during the second and third decades of life is a possible effect of chronic supraphysiologic glucocorticoids. Children with CAH who experience early puberty benefit from GnRHa treatment as evidenced by the positive effect on height.
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2025-03-26 | Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China.
Long-read sequencing (LRS) provides comprehensive genetic information, but research of LRS applied to congenital adrenal hyperplasia (CAH) newborn screening is limited. This study aimed to evaluate the clinical utility of LRS in genetic diagnosis and second-tier newborn screening. Neonates born between January 2017 and December 2022 in Fujian, China, were recruited for biochemical and LRS-based genetic screening assay. The LRS covers the entire gene regions and exon-intron boundary regions for CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In this retrospective study, 1,774,555 newborns received 17α-OHP screening, yielding a screening positive rate of 0.20%. Of these high-risk neonates, 3411 were successfully recalled for re-evaluation. Finally, 66 neonates were diagnosed with CAH, with a positive predictive value of 28.82%. Based on this data, the overall prevalence of CAH in Fujian was estimated to be 1:26,883. LRS was performed on 57 neonates with 21-hydroxylase deficiency (21-OHD) and 109 variant alleles were identified. The c.293-13C>G variant (31.19%) was the most prevalent in Fujian. Additionally, 647 neonates with suspected positive results were genotyped, and 41 were identified as carriers, with carrier frequencies of 1:18 for CYP21A2, 1:162 for HSD3B2, and 1:324 for CYP17A1 in Xiamen. Therefore, LRS can provide comprehensive genotypes in approximately 1.5 days at a cost of less than $20 USD per sample, and effectively improve screening efficiency, reduce anxiety of parents during newborn screening (NBS), and shorten the time to referral of CAH patients (approximately 10 days). Such a combined screening strategy is worthy to be recommended for NBS programs in the future.
2024-05-03 | Can Incorporating Molecular Testing Improve the Accuracy of Newborn Screening for Congenital Adrenal Hyperplasia?
Single-tier newborn screening (NBS) for congenital adrenal hyperplasia (CAH) using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24 to 48 hours produces a high false-positive rate (FPR). Second-tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multitier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the first-tier 17OHP cutoff to minimize missed cases. We create a Minnesota-specific CYP21A2 pathogenic variants panel; developed a rapid, high-throughput multiplex, allele-specific-primer-extension assay; and performed a 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based 2-tier protocol and a molecular-based multitier NBS protocol, applied post hoc. CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. The Centers for Disease Control and Prevention created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68 659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A 3-tier protocol with a lower first-tier steroid cutoff, second-tier 21-variant CYP21A2 panel, and third-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs, and 3 TPs. Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.
2021-11-08 | Nonsense variant of NR0B1 causes hormone disorders associated with congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. The DAX-1 protein (encoded by NR0B1) is a vertebrate-specific orphan nuclear receptor and is also a transcriptional factor for adrenal and reproductive development. CAH usually causes adrenal insufficiency in infancy and early childhood, leading to hypogonadotropic hypogonadism in adulthood; however, few adult cases have been reported to date. In this study, we examined a Chinese family with one adult patient with CAH, and identified a putative variant of NR0B1 gene via next-generation sequencing (NGS), which was confirmed with Sanger sequencing. A novel nonsense variant (c.265C>T) was identified in the NR0B1 gene, which caused the premature termination of DAX-1 at residue 89 (p.G89*). Furthermore, mutant NR0B1 gene displayed a partial DAX-1 function, which may explain the late pathogenesis in our case. Additionally, qPCR revealed the abnormal expression of four important genes identified from ChIP-seq, which were associated with energy homeostasis and steroidogenesis, and were influenced by the DAX-1 mutant. In addition, hormone disorders can be caused by DAX-1 mutant and partially recovered by siRNA of PPARGC1A. Herein, we identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH. This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient's phenotypic features.
2017-04-12 | Variations in the 3'UTR of the CYP21A2 Gene in Heterozygous Females with Hyperandrogenaemia.
Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the∗52C>T,∗440C>T, and∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the∗12C>T and∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.
2017-01-18 | Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report.
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation. A 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6-9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7-8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins. Compound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.
cell therapies
2026-03-18 | Genotype Description in Patients with Congenital Adrenal Hyperplasia in Bogotá, Colombia
Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzymatic deficiencies in the steroidogenic pathway.Approximately 90% of cases are due to pathogenic variants in the CYP21A2 gene, leading to 21-hydroxylase deficiency (21-OHD).This enzyme is essential for the synthesis of cortisol and aldosterone.Objective: To evaluate an Advanced Regenerative and Immunomodulatory Drainage Protocol (ARDIP) as a treatment strategy in patients presenting with facial tissue necrosis unresponsive to conventional management. Case presentation:We report a case series of seven patients aged between 4 and 9 years who presented with growth acceleration and/or premature pubarche and had a confirmed molecular genetic diagnosis.Results are expressed as mean standard deviation.The mean age was 7.11 2.61 years.Basal 17-alpha-hydroxyprogesterone (17-OHP) levels were 22.9 26.72, increasing to 37.43 22.53 following ACTH stimulation testing.The mean bone age was 9.86 2.86 years, with an average advancement of 2.74 0.86 years compared with chronological age.Molecular genetic studies were performed using sequencing, copy number variant (CNV) and insertion-deletion (InDel) analysis, multiplex ligation-dependent probe amplification (MLPA) of the CYP21A2 gene or clinical exome sequencing.Pathogenic variants were identified in homozygosity, compound heterozygosity (CH) or carrier status (Table 1).Discussion: Approximately 75% of pathogenic variants result from rearrangements between the CYP21A1P pseudogene and the functional CYP21A2 gene, typically manifesting as copy number variants.Around 20-25% are caused by single nucleotide variants, including missense, nonsense, splice-site variants and small insertions and deletions.The remaining 1-2% correspond to de novo variants arising from unequal crossover events during meiosis 1 .
2024-09-27 | Establishment of Star-edited Y1 cells as a novel in vitro functional assay for STAR.
Genetic variants involving steroidogenic acute regulatory protein cause lipoid congenital adrenal hyperplasia, which is characterized by impaired steroidogenesis in the adrenal glands and gonads. Functional assessment of variant STAR proteins is necessary for an accurate genetic diagnosis. Ideally, steroidogenic cells should be used to assess the functionality of STAR proteins, but the presence of endogenous STARs in steroidogenic cells precludes such a method. Here, we generated Star-edited cells from steroidogenic Y1 mouse adrenocortical tumor cells by genome editing. Star-edited Y1 cells exhibited very low but measurable cAMP-dependent pregnenolone production. Furthermore, stimulation of the cAMP pathway for 2 weeks resulted in the formation of lipid droplets in the cytoplasm of Star-edited Y1 cells, which resembled the histology of the adrenal glands of patients with lipoid congenital adrenal hyperplasia. The steroidogenic defect of Star-edited Y1 cells can be restored by transient overexpression of mouse Star. We found that human STAR can also restore defective steroidogenesis in Star-edited Y1 cells, and we were able to construct a novel in vitro system to evaluate human STAR variants. Collectively, we established Star-edited Y1 cells that retain the steroidogenic pathway downstream of the Star protein. Star-edited Y1 cells recapitulate the functional and morphological changes of lipoid congenital adrenal hyperplasia and can be used to evaluate the functionality of human STAR variants.
2024-05-25 | A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia-CYP21A2-R484Q Mutant Mouse.
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
2023-10-01 | SAT275 Generation And Characterization Of A Humanized CYP21A2 Mouse Model For Congenital Adrenal Hyperplasia
Abstract Disclosure: A. Huebner: None. S. Thirumalasetty: None. T. Schubert: None. R. Naumann: None. I. Reichardt: None. M. Rohm: None. D. Landgraf: None. F. Gembardt: None. M.F. Hartmann: None. S.A. Wudy: None. M. Peitzsch: None. N. Reisch: None. K. Koehler, PhD: None. 21-hydroxylase deficiency (21OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene. 21OHD causes a wide array of clinical symptoms that result from gluco- and mineralocorticoid deficiency and adrenal androgen excess. Treatment firstly aims to substitute lacking steroid hormones, and secondly to restore negative feedback towards CRH and pituitary ACTH secretion to diminish adrenal androgen overproduction. In most cases supra-physiological glucocorticoid doses are necessary which may cause short stature, obesity, hypertension, and cardiovascular and metabolic co-morbidity with reduced quality of life. Hence, current steroid substitution regimens have significant limitations, so novel therapeutic strategies are required. In recent years new therapeutic approaches have emerged including new non-glucocorticoid substances interfering with the HPA axis to minimize adrenal androgen production and to lower external glucocorticoid substitution to physiological levels. However, valuable in-vivo models for pre-clinical testing of such drugs are lacking. Here we present the first viable and humanized mouse model in which the mouse gene Cyp21a1 is replaced by the human orthologue CYP21A2 in which the human point mutation R484Q is integrated. Twenty-weeks-old homozygous mice show marked adrenal hyperplasia, enhanced expression of the CYP21A2 gene and a weak increase of Cyp11a1 and Cyp11b2 gene expression. Tandem mass spectrometry measurements of the mice plasma at 20 weeks show decreased corticosterone and 11-deoxycorticosterone levels in the presence of increased ACTH levels in both male and female homozygous animals. Progesterone levels in homozygous mice are significantly higher (p<0.01) than in wildtype mice. We also observed increased aldosterone levels in female mutants whereas blood pressure does not differ between wildtype and mutant mice strains. Histologically, mutants exhibit adrenocortical hyperplasia. While mutant male mice are fertile with normal appearing testes, females are infertile, remain in the diestrus phase and present with a reduced number of ovarian follicles. In parallel, a second mouse strain bearing the I173N mutation was developed. This mutation is frequent in human patients causing simple virilizing or rarely salt wasting CAH. Homozygous mice require dexamethasone treatment during pregnancy and until weaning but are viable without treatment afterwards. Preliminary results show adrenal hyperplasia and alteration in steroidogenic gene expression and steroid profiles. In conclusion, we demonstrate that the humanized mutant CYP21A2 mice may represent an excellent animal CAH model to test novel treatment strategies for CAH patients. We believe that this model(s) will facilitate the transition from basic research into clinical application. Presentation: Saturday, June 17, 2023
2023-06-16 | Endocrine profiles and cycle characteristics of infertile 17α-hydroxylase/17,20-lyase Deficiency Patients undergoing assisted Reproduction Treatment: a retrospective cohort study.
17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene variants. Female patients with 17-OHD demonstrate a broad clinical spectrum, including oligomenorrhea or amenorrhea and infertility, often as the sole manifestation. However, no spontaneous pregnancies in affected women have been reported. This retrospective cohort study aimed to explore the endocrine characteristics and assisted reproductive technique (ART) performance in women with 17-OHD. Five women were referred for primary infertility in a university-affiliated hospital over an eight-year period. The endocrine profiles and cycle characteristics during a total of nine cycles of ovarian stimulation and eight cycles of frozen-thawed embryo transfer (FET) were described in details. Three cases had homozygous variants and two cases had compound heterozygous variants, including one novel missense variant (p.Leu433Ser) in the CYP17A1 gene. Despite dual-suppression of progesterone (P) production by glucocorticoid and gonadotropin releasing hormone agonist, gradually increased P level, relatively low estradiol concentrations and thin endometrium were observed, negating fresh embryo transfer. During FET cycles, appropriate treatment resulted in low serum P levels and adequate endometrial thickness, leading to four live births. Our findings demonstrate that continuous elevation of serum P during follicular growth impairs endometrial receptivity, the likely cause of female infertility in 17-OHD. Therefore, female infertility caused by 17-OHD is suggested as an indication for freeze-all strategy, with promising reproductive prognoses following segmented ovarian stimulation and FET treatment.
other
2025-12-26 | Exploration of the potential of genomic editing in the treatment of congenital adrenal hyperplasia.
Despite life-saving glucocorticoids, therapeutic options for congenital adrenal hyperplasia (CAH) remain sub-optimal. Adrenal crisis continues to be the highest cause of mortality in individuals with CAH and even with recommended treatment regimens complications from the disease and treatments themselves persist. These patients have limited treatment options and advanced therapeutics could be a solution. Development of genetic therapies have exponentially increased in recent years. The advent of CRISPR/Cas technology has brought previously inconceivable treatment options to reality. Genomic editing could repair the defective 21-hydroxylase gene and provide a cure for 21-hydroxylase deficiency, the most common CAH variant, eliminating the current need for constant patient intervention. There are a number of technologies within reach for CAH, however, delivery of the genomic editing reagents to the elusive adrenocortical progenitor cells remains challenging. Here we discuss the complexity of CAH genetics, which has implications for choice of genomic editing strategy, and potential future strategies for the development of a cure of CAH.
2025-12-05 | Impact of Growth-promoting Therapies on Puberty, Growth, and Final Height in Classical 21-hydroxylase Deficiency.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) poses significant growth challenges, including accelerated bone maturation, precocious puberty, and compromised final height (FH). Data on pubertal growth in large 21-OHD cohorts remain limited. To assess puberty timing, duration, height gain, FH outcomes, and the effects of growth-promoting therapies (GPTs), including GnRH analog, aromatase inhibitors, and cyproterone acetate, in a large cohort with genetically confirmed classical 21-OHD. A multicenter, retrospective, longitudinal analysis of 284 patients (46,XX: 160; 46,XY: 124). Data on puberty, growth, and treatments were collected from clinical records. Growth curves were plotted based on GPT use. Median age at diagnosis was 0.1 years (interquartile range [IQR]: 0.03-1.1), and at last visit, 12.1 years (IQR: 7.0-17.0). Median FH was 154.0 cm (IQR: 147.3-158.2) in 46,XX (menarche at 13.0 years) and 167.0 cm (IQR: 160.0-170.0) in 46,XY. In the total cohort, 63.4% were pubertal/postpubertal, and the ratio of GPTs used alone or in combination was 41.1%. GnRH analogs, cyproterone acetate, and aromatase inhibitors were administered in 21.8% (n = 62), 8.1% (n = 23), and 5.3% (n = 15) of the cohort, respectively. The median FH-MPH difference improved from -6.7 cm to -2.3 cm in boys without and with GPT, respectively, whereas in girls it declined from -3.7 cm to -6.6 cm. Patients with 21-OHD had diminished FH despite early diagnosis. Puberty in classical 21-OHD had an earlier onset, slower tempo, and prolonged duration, especially in girls, in which GPTs are less effective in promoting height. The management of pubertal growth needs a personalized approach in patients with classical 21-OHD.
2025-11-12 | Targeted editing of the 21-hydroxylase locus confers durable therapeutic effect in a murine model of congenital adrenal hyperplasia.
Contemporary treatment for congenital adrenal hyperplasia is lifesaving; however, long-term deleterious effects from the disease and complications from the inadequacy of available treatment remain problematic. Locus-specific correction of the defective 21-hydroxylase gene through genomic editing has the potential to address this unmet need by simultaneously restoring gene function and physiological control. Editing is necessitated by the constant cellular turnover in the adrenal cortex which limits the durability of conventional gene addition strategies using recombinant adeno-associated virus. We have developed a homology-independent targeted integration genomic editing strategy that conferred phenotypic benefit in a mouse model using a dual recombinant adeno-associated virus approach. Reconstitution of 21-hydroxylase expression in the adrenal gland increased corticosteroid production, reduced adrenal gland hyperplasia, and reduced expression of renin and aldosterone synthase with these effects maintained to 15 weeks without diminution. This is beyond the adrenocortical cellular turnover time, providing initial evidence of adrenocortical progenitor cell targeting. Importantly, the editing strategy used is potentially applicable to the majority of causative mutations in classical congenital adrenal hyperplasia. Collectively these data provide strong impetus for addressing the challenges of clinical translation, with development and evaluation of strategies for efficient targeting of human adrenocortical progenitor cells being the most formidable.
2025-10-01 | MON-468 A Novel Anti-ACTH Antibody Lu AG13909 in Clinical Development for Treatment of Classic Congenital Adrenal Hyperplasia: A Phase 1 Open-Label, Multiple-Ascending-Dose Study
Abstract Disclosure: G. Johannsson: AstraZeneca, Novo Nordisk, Pharmanovia, Pfizer, Inc., Takeda, Shire. A. Velusamy: Immunovant, Novo Nordisk, Samsung/Philips/Canon. A. Prete: Diurnal, Spruce, Recordati, Lundbeck. H. Falhammar: None. M.M. Binderup: None. K.G. Larsen: None. M. Folden Flensburg: None. J. Luthman: None. U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. Nonclinical studies demonstrated that Lu AG13909 induces a significant and durable reduction of corticosterone and aldosterone in rats, and of cortisol and aldosterone in cynomolgus monkeys. Here, we present the results of a first-in-human trial investigating the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of Lu AG13909 in adults with classic CAH. Methods: This was a phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (NCT05669950). Eligible participants were men and women, aged ≥18 to ≤70 years, with classic CAH and pre-GC morning 17-hydroxyprogesterone (17-OHP) concentrations >4 times the upper limit of normal. Each participant received up to 6 doses of Lu AG13909 every 28 to 35 days at increasing dose levels, with stable GC therapy and mineralocorticoid replacement if needed. The trial consisted of 2 parts: Part A had a 3+3 design, in which 3 participants were given a certain dose level, and escalation to the next dose level was based on a 28-day safety observation period. Part B explored the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The primary endpoints included adverse events; clinical safety; maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval; and the relative reductions in morning 17-OHP and androstenedione (A4) concentrations from baseline to the day after each Lu AG13909 dose. Results: In total, 11 participants were enrolled (4 men, 7 women), with a mean age of 37 years (range: 21-58 years). At the Baseline Visit the geometric means for the concentrations of morning 17-OHP and A4 were 274 nmol/L (range: 100-1033 nmol/L) and 11.0 nmol/L (range: 3.9-49.5 nmol/L), respectively. Preliminary data (N=11) demonstrated clear pharmacodynamic effects following up to 6 intravenous infusions of Lu AG13909 at increasing doses, with consistent reductions in morning 17-OHP and A4 concentrations observed at all dose levels. No safety concerns were raised. Conclusions: The preliminary results of this phase 1 study show that Lu AG13909 is well-tolerated and can reduce adrenal androgen production, reinforcing continued clinical development of Lu AG13909 as a novel anti-ACTH treatment strategy for classic CAH. Presentation: Monday, July 14, 2025
2025-05-07 | Combination therapy of GnRHa, RhGH and anastrozole to improve final adult height deficit in CAH children with CPP.
To investigate the clinical and genetic characteristics of classic congenital adrenal hyperplasia (CAH) patients. To determine whether gonadotropin-releasing hormone analogs (GnRHa) + recombinant human growth hormone (rhGH) + Anastrozole combined therapy improves the final adult height of CAH patients with central precocious puberty (CPP). We described the clinical and genetic characteristics of 16 classic CAH patients, and performed pathogenic analysis and structural modeling of the newly discovered mutation. By using the method of self-before and after control, we statistically analyzed bone age advancement, predicted adult height (PAH) and other indicators of 7 CAH children with CPP before and after combined treatment to observe its effect on adult height. All patients showed high levels of 17-hydroxyprogesterone, testosterone and adrenocorticotropic hormone. All patients had CYP21A2 gene mutations, and the newly discovered mutation c.79 A > G (p.Ser27Gly) may change the hydrophilicity of the protein and affect its function. Seven CAH patients with CPP were diagnosed at 5.6 (3.5 to 7.3) years. Their target height was 0.18 (-1.2 to 0.78) SD, and the PAH at the start of treatment was - 3.01 (-3.75 to -2.89) SD. The ages at which CAH patients with CPP started to be treated with GnRHa, rhGH and Anastrozole were 5.8 (5.5 to 8.7), 7.1 (5.5 to 9.8), 8.7 (7.6 to 10.7) years old, and discontinued them at 8.8 (7.5 to 10.2), 10.4 (9.0 to 12.7), 11.0 (9.7 to 12.7) years old, respectively. The PAH at treatment end was - 0.28 (-1.2 to 0.4) SD. The final height was - 0.28 (-1 to 1.04) SD, significantly higher than the initial PAH (P < 0.001) and similar to the target height (P = 0.478). GnRHa + rhGH + Anastrozole therapy can improve the final adult height of CAH patients with CPP. In addition, this study also discovered a new CYP21A2 gene mutation c.79 A > G.
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Drug Discovery Landscape
14 orphan drug designations for Congenital adrenal hyperplasia, including 1 approved therapy.
14 orphan drug designations for Congenital adrenal hyperplasia, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
atumelnant | small molecules | FDA | Crinetics Pharmaceuticals, Inc. | |
Humanised IgG1 monoclonal antibody against adrenocorticotropic hormone | antibodies | EMA | H. Lundbeck A/S | |
humanized anti-adrenocorticotropic hormone immunoglobulin gamma subclass 1 monoclonal antibody (anti-ACTH IgG1 mAb) | antibodies | FDA | H. Lundbeck A/S | |
4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine | small molecules | EMA | Neurocrine Therapeutics Ltd | |
crinecerfont [Crenessity] | small molecules | FDA | Approved | Neurocrine Biosciences, Inc. |
Adeno-associated viral vector expressing human 21-hydroxylase | gene therapies | EMA | Pharma Gateway AB | |
N-[2,6-bis(1-methylethyl)phenyl]-N'-[[1-[4-(dimethylamino)phenyl]cyclopentyl]methyl]urea, hydrochloride salt | small molecules | EMA | Millendo Therapeutics S.A.S. | |
Pyrazolo[1,5-a]pyrimidine, 3-[4-chloro-2-(4-morpholinyl)-5-thiazolyl]-7-(1-ethylpropyl)-2,5-dimethyl-pyrazolo[1,3-a]pyrimidine | small molecules | EMA | Regintel Limited | |
corticotropin-releasing factor receptor-1 antagonist containing an unfused thiazole ring | small molecules | FDA | Spruce Biosciences | |
nevanimibe HCL | small molecules | FDA | Millendo Therapeutics, Inc. | |
Verucerfont [NBI-77860] | small molecules | EMA | Neurocrine Therapeutics Limited | |
hydrocortisone modified release capsules | small molecules | FDA | Diurnal Limited | |
2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5- | small molecules | FDA | Neurocrine Biosciences, Inc. | |
Hydrocortisone [Efmody] | small molecules | EMA | Immedica Netherlands B.V. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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