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Primary adrenal insufficiency (PAI) is a rare medical condition, characterized by a deficiency in adrenal hormones. Although rare, PAI is a life-threatening disease requiring prompt recognition and treatment. However, symptoms of PAI are often non-specific and diagnosis can be challenging, causing frequent diagnostic delays. In adults, autoimmunity is the most common cause of PAI in industrialized countries, whereas in children, the most frequent etiology is represented by congenital defects of steroidogenesis and, in particular, by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. A few recent case series from different countries have reported that autoimmunity is the second most common etiology of PAI in the pediatric age group. However, data on autoimmune PAI in children are still scant and the exact epidemiology, clinical manifestations, and long-term outcomes of this condition have yet to be defined. The scope of this review is to summarize the current knowledge on the etiology, presentation, and treatment of autoimmune PAI in childhood and to increase physicians' awareness of the signs that should raise an early suspicion of this condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer NI declared a shared affiliation with the authors to the handling editor at the time of review. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Capalbo, Esposito, Gaeta, Lorello, Vasaturo, Di Mase and Salerno.)

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1 , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY ; copy number variants in NR2F2 , NR0B1 , SOX3 , SOX9 , SOX10 , and FGF9 , and sequence variants in NR5A1 , NR2F2 , RSPO1 , SOX9 , WNT2B , WNT4 , and WT1 . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2024 Yavas Abalı and Guran.)

Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids, mineralocorticoids and androgens. These may be associated with other hormone deficiencies. Adrenal insufficiency may be primary, affecting the adrenal gland's ability to produce cortisol directly; secondary, affecting the pituitary gland's ability to produce adrenocorticotrophic hormone (ACTH); or tertiary, affecting corticotrophin-releasing hormone (CRH) production at the level of the hypothalamus. Congenital causes of adrenal insufficiency include the subtypes of Congenital Adrenal Hyperplasia, Adrenal Hypoplasia, genetic causes of Isolated ACTH deficiency or Combined Pituitary Hormone Deficiencies, usually caused by mutations in essential transcription factors. The most commonly inherited primary cause of adrenal insufficiency is Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency; with the classical form affecting 1 in 10,000 to 15,000 cases per year. Acquired causes of adrenal insufficiency can be subtyped into autoimmune (Addison's Disease), traumatic (including haemorrhage or infarction), infective (e.g. Tuberculosis), infiltrative (e.g. neuroblastoma) and iatrogenic. Iatrogenic acquired causes include the use of prolonged exogenous steroids and post-surgical causes, such as the excision of a hypothalamic-pituitary tumour or adrenalectomy. Clinical features of adrenal insufficiency vary with age and with aetiology. They are often non-specific and may sometimes become apparent only in times of illness. Features range from those related to hypoglycaemia such as drowsiness, collapse, jitteriness, hypothermia and seizures. Features may also include signs of hypotension such as significant electrolyte imbalances and shock. Recognition of hypoglycaemia as a symptom of adrenal insufficiency is important to prevent treatable causes of sudden deaths. Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress. Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia. In this review, we summarise the pathogenesis of hypoglycaemia in the context of adrenal insufficiency. We further explore the clinical features of hypoglycaemia based on different age groups and the burden of the disease, focusing on hypoglycaemic-related events in the various aetiologies of adrenal insufficiency. Finally, we sum up strategies from published literature for improved recognition and early prevention of hypoglycaemia in adrenal insufficiency, such as the use of continuous glucose monitoring or modifying glucocorticoid replacement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Baranowski, Sakremath, Saraff and Mohamed.)

Introduction: 11β-Hydroxylase deficiency (11β-OHD, OMIM#202010) is the second most common form of congenital adrenal hyperplasia (CAH) caused by pathogenic variants in the CYP11B1 gene. Both single nucleotide variations (SNV)/small insertion and deletion and genomic rearrangements of CYP11B1 are important causes of 11β-OHD. Among these variant types, pathogenic CYP11B2 / CYP11B1 chimeras only contribute to a minority of cases. Heterozygote cases (chimera combined with SNV) are very rare, and genetic analysis of these cases can be challenging., Case Presentation: We presented a suspected 11β-OHD female patient with incomplete virilization, adrenal hyperplasia, and hypokalemia hypertension. Whole exome sequencing (WES) revealed that the patient carried both a chimeric CYP11B2/CYP11B1 and a novel missense variant, NM_000497.4: c.203T>G, p.Val68Gly (chr8:143961027) in CYP11B1 , which were confirmed by CNVplex and Sanger sequencing, respectively. The patient's manifestations and genetic findings confirmed the diagnosis of 11β-OHD, and oral dexamethasone was administered as a subsequent treatment., Conclusion: This report showed a rare CYP11B2 / CYP11B1 chimera combined with a novel missense variant in a 11β-OHD female patient. The result expands variant spectrum of CYP11B1 and suggests that both chimera and CYP11B1 variant screening should be performed simultaneously in suspected cases of 11β-OHD. To our knowledge, this is the first report about CYP11B2 / CYP11B1 chimera detected by WES analysis. WES combined with CNV analysis is an efficient method in the genetic diagnosis of this rare and complex disorder., Competing Interests: LQ, FZ, and HQ were employed by Dian Diagnostics Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zhang, Xu, Qiu, Zhou, Li and Qin.)

Newborn screening for congenital adrenal hyperplasia using 17-hydroxyprogesterone by immunoassay remains controversial despite screening been available for almost 40 years. Screening is confounded by poor immunoassay specificity, fetal adrenal physiology, stress, and illness which can result in a large number of false positive screening tests. Screening programmes apply higher screening thresholds based on co-variates such as birthweight or gestational age but the false positive rate using immunoassay remains high. Mass spectrometry was first applied to newborn screening for congenital adrenal hyperplasia over 15 years ago. Elevated 17-hydroxprogesterone by immunoassay can be retested with a specific liquid chromatography tandem mass spectrometry assay that may include additional steroid markers. Laboratories register with quality assurance programme providers to ensure accurate steroid measurements. This has led to improvements in screening but there are additional costs and added laboratory workload. The search for novel steroid markers may inform further improvements to screening. Studies have shown that 11-oxygenated androgens are elevated in untreated patients and that the adrenal steroidogenesis backdoor pathway is more active in babies with congenital adrenal hyperplasia. There is continual interest in 21-deoxycortisol, a specific marker of 21-hydroxylase deficiency. The measurement of androgenic steroids and their precursors by liquid chromatography tandem mass spectrometry in bloodspots may inform improvements for screening, diagnosis, and treatment monitoring. In this review, we describe how liquid chromatography tandem mass spectrometry has improved newborn screening for congenital adrenal hyperplasia and explore how future developments may inform further improvements to screening and diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Hora, Heather, Webster, Albert and Hofman.)

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang and Tian.)

Objective: The study aimed to identify the pathogenic status of p.Gln319Ter (NM_000500.7: c.955C>T) variant when inherited in a single CYP21A2 gene (bimodular RCCX haplotype) and to discriminate between a non-causing congenital adrenal hyperplasia (CAH) allele when inherited in a duplicated and functional CYP21A2 gene context (trimodular RCCX haplotype)., Methods: 38 females and 8 males with hyperandrogenemia, previously screened by sequencing and identified as carriers for the pathogenic p.Gln319Ter, were herein tested by multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR Copy number Variation (CNV) assay., Results: Both MLPA and real-time PCR CNV analyses confirmed a bimodular and pathogenic RCCX haplotype with a single CYP21A2 in 19/46 (41.30%) p.Gln319Ter carriers and who in parallel all shared elevated 17-OHP levels. The remaining 27 individuals that also carried the p.Gln319Ter exhibited low 17-OHP levels as a result of their carriership of a duplicated CYP21A2 with a trimodular RCCX haplotype. Interestingly, all of these individuals also carried in linkage disequilibrium with p.Gln319Ter two single nucleotide polymorphisms, the c.293-79G>A ( rs114414746 ) in intron 2 and the c.*12C>T ( rs150697472 ) in the 3'-UTR. Therefore, these variants can be used to distinguish between pathogenic and non-pathogenic genomic contexts of the c.955T (p.Gln319) in the genetic diagnosis of congenital adrenal hyperplasia (CAH)., Conclusion: The employed methodologies identified a considerable number of individuals with non-pathogenic p.Gln319Ter from the individuals that typically carry the pathogenic p.Gln319Ter in a single CYP21A2 . Therefore, it is extremely important the detection of such haplotypes for the prenatal diagnosis, treatment and genetic counseling in patients with CAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fanis, Skordis, Toumba, Picolos, Tanteles, Neocleous and Phylactou.)

Objective: To analyze the mutational spectrum, clinical characteristics, genotype-phenotype correlations, testicular adrenal rests tumor prevalence, and role of neonatal screening in congenital adrenal hyperplasia (CAH) patients from Slovakia and Slovenia., Design and Methods: Data were obtained from 104 patients with CAH registered in Slovak and Slovenian databases. Low-resolution genotyping was performed to detect the most common point mutations. To detect deletions, conversions, point mutations, or other sequence changes in the CYP21A2 gene, high-resolution genotyping was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C)., Results: 64% of the individuals had the salt-wasting form (SW-CAH), 15% the simple virilizing form (SV-CAH), and 21% the non-classic (NC-CAH). CYP21A2 gene deletion/conversion and c.293-13A/C>G pathogenic variant accounted together for 55.5% of the affected alleles. In SV-CAH p.Ile172Asn was the most common pathogenic variant (28.13%), while in NC-CAH p.Val282Leu (33.33%), CYP21A2 gene deletion/conversion (21.43%), c.293-13A/C>G (14.29%), Pro30Leu (11.90%). The frequency of alleles with multiple pathogenic variants was higher in Slovenian patients (15.83% of all alleles). Severe genotypes (0 and A) correlated well with the expected phenotype (SW in 94.74% and 97.3%), while less severe genotypes (B and C) correlated weaklier (SV in 50% and NC in 70.8%). The median age of SW-CAH patients at the time of diagnosis was 6 days in Slovakia vs. 28.5 days in Slovenia (p=0.01). Most of the Slovak patients in the cohort were detected by NBS. (24 out of 29). TARTs were identified in 7 out of 24 male patients, of whom all (100%) had SW-CAH and all had poor hormonal control. The median age at the diagnosis of TARTs was 13 years., Conclusion: The study confirmed the importance of neonatal screening, especially in the speed of diagnosis of severe forms of CAH. The prediction of the 21-OH deficiency phenotype was reasonably good in the case of severe pathogenic variants, but less reliable in the case of milder pathogenic variants, which is consistent compared to data from other populations. Screening for TARTs should be realized in all male patients with CAH, since there is possible remission when identified early., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saho, Dolzan, Zerjav Tansek, Pastorakova, Petrovic, Knapkova, Trebusak Podkrajsek, Suput Omladic, Bertok, Avbelj Stefanija, Kotnik, Battelino, Pribilincova and Groselj.)

Introduction: 21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations., Methods: A total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands., Results: Dramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively., Conclusion: Both gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Zhang, Peng, Wang, Li, Wang, Zhang, Huang, Xu, Zhang, Liu, Wang, Lan and Jiang.)

Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Suresh, Jaber, Mercado Munoz and Sarafoglou.)

21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia. In most developed countries, newborn screening enables diagnosis of 21-OHD in asymptomatic patients during the neonatal period. In addition, recent advances in genetic testing have facilitated diagnosing 21-OHD, particularly in patients with equivocal clinical information. On the other hand, many challenges related to treatment remain. The goals of glucocorticoid therapy for childhood 21-OHD are to maintain growth and maturation as in healthy children by compensating for cortisol deficiency and suppressing excess adrenal androgen production. It is not easy to calibrate the glucocorticoid dosage accurately for patients with 21-OHD. Auxological data, such as height, body weight, and bone age, are considered the gold standard for monitoring of 21-OHD, particularly in prepuberty. However, these data require months to a year to evaluate. Theoretically, biochemical monitoring using steroid metabolites allows a much shorter monitoring period (hours to days). However, there are many unsolved problems in the clinical setting. For example, many steroid metabolites are affected by the circadian rhythm and timing of medication. There is still a paucity of evidence for the utility of biochemical monitoring. In the present review, we have attempted to clarify the knowns and unknowns about treatment parameters in 21-OHD during childhood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Itonaga and Hasegawa.)

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA., Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH., Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed., Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA., Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nakhleh, Saiegh, Shehadeh, Weintrob, Sheikh-Ahmad, Supino-Rosin, Alboim, Gendelman and Zloczower.)

Background: Differences of sex development (DSD) are congenital conditions linked to atypical development of chromosomal, gonadal, or anatomical sex., Objective: The aim of this study was to demonstrate our experiences at the Diabetes Endocrine and Metabolism Pediatric Unit (DEMPU), Faculty of Medicine, Cairo University in the field of DSD by focusing on the clinical presentation, laboratory profile, classification, and etiological diagnosis of these conditions. In addition, the present study intended to delineate the importance of serum anti-Müllerian hormone (AMH) and inhibin B in detecting the presence of functioning testicular tissue., Methods: This cohort study included 451 infants and children with various clinical presentations of DSD. The study performed a retrospective analysis on medical records of established DSD cases to evaluate the clinical importance of AMH and inhibin B. In addition, newly diagnosed patients were prospectively analyzed., Results: Three hundred thirty-six (74.5%) patients were 46,XY DSD, 98 (21.7%) were 46,XX DSD, 14 patients had other karyotypes and 3 had missing karyotypes. Among the 46XY DSD patients, the most common cause was partial androgen insensitivity. In contrast, congenital adrenal hyperplasia constituted the most common diagnosis in 46,XX DSD cases. The cut off value of serum AMH was 14.5 ng/ml with 100% sensitivity and 55.1% specificity., Conclusion: Partial androgen insensitivity was the most important cause of 46,XY DSD in Egyptian children, and congenital adrenal hyperplasia was the most common cause of 46,XX DSD. AMH was valuable in detecting functioning testicular tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abdelghaffar, AbdelMoneam, Hassanein, Radwan and Mira.)

Introduction: Complete 17α-hydroxylase deficiency (17OHD) is relatively common, with typical juvenile female genitalia, severe hypertension, hypokalemia, and the absence of sexual development, but partial (or non-classical) 17OHD (p17OHD) is extremely rare. The p17OHD patients can present with a broad spectrum of symptoms in 46,XX karyotype including various degree of spontaneous breast development after puberty, recurrent ovarian cysts, oligomenorrhea and infertility depending on specific gene mutations and other influencing factors., Methods: This paper is a retrospective analysis of p17OHD cases from 1997 to 2021 in a Chinese tertiary hospital. Eight patients were recruited from unrelated families according to clinical data. Genotypes of patients were determined by sequencing the CYP17A1 genes. Clinical characteristics were summarized based on manifestations, hormone profiles, and responses to treatments., Results: All seven post-pubertal patients had abnormal menses. All patients had enlarged multilocular ovaries, and six (6/8) had a history of ovarian cystectomy prior to a definite diagnosis of p17OHD. All eight patients' sex hormone levels were in accord to hypogonadism with mildly elevated follicle-stimulating hormone levels, and oral contraceptives effectively suppressed the ovarian cysts. Of the four patients who underwent plasma renin activity tests, all showed results below the reference range. Fourteen alleles with a CYP17A1 mutation were found. Exon 6 was the most frequent mutation site (5/14), and four out of these five mutations were c.985_987delTACinsAA, being the most common one. In Case 2, c.1220dupA was a newly reported mutation of CYP17A1 ., Conclusions: 46,XX p17OHD patients were born with highly fragile ovarian reserve due to diverse mutations of CYP17A1. However, their multi-ovarian cysts can be managed conservatively for fertility preservation. This study focuses on p17OHD in 46,XX by locating the complex genetic causes in novel mutations, summarizing the puzzling spectrum of clinical manifestations, and illustrating the significance of fertility preservation in these scarce cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yao, Luo, Wang, Tian, Deng and Tian.)

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Adriaansen, Schröder, Span, Sweep, van Herwaarden and Claahsen-van der Grinten.)

Background: Undiagnosed congenital adrenal hyperplasia (CAH) can cause adrenal incidentalomas, but the frequency is unclear., Objectives: This study aimed to investigate the prevalence of CAH in a population with adrenal incidentalomas and report the clinical characterization., Material and Methods: This was a prospective study performed at a regional hospital from 2016 to 2021. Patients with adrenal incidentalomas were investigated with an adrenocorticotropic hormone (ACTH)-stimulation test in addition to hormonal workup. Serum cortisol and 17-hydroxyprogesterone (17OHP) were analyzed. Individuals with a basal or stimulated 17OHP ≥30 nmol/L were classified as suspicious non-classic CAH, and a CYP21A2 -gene analysis was performed in these subjects., Results: In total, 320 individuals with adrenal incidentalomas were referred to the center, and of these individuals, an ACTH-stimulation test was performed in 222 (median age, 67 (24-87) years; 58.6% women; and 11.7% with bilateral lesions). None of the individuals presented a basal 17OHP ≥30 nmol/L, but there were 8 (3.6%) who did after ACTH stimulation. Four of these subjects (50%) presented bilateral lesions, and the tumor size was larger compared to that of the individuals with a stimulated 17OHP <30 nmol/L (median, 38 (19-66) vs. 19 (11-85) mm, p=0.001). A CYP21A2 variation (p.Val282Leu) was detected in one of the eight subjects with a stimulated 17OHP ≥30 nmol/L, i.e., the patient was a heterozygotic carrier. None of the eight subjects presented with cortisol insufficiency or clinical signs of hyperandrogenism., Conclusions: The prevalence of non-classic CAH in an adrenal incidentaloma cohort was 3.6% based on stimulated 17OHP and 0% based on gene analysis. CAH should be considered in AI management in selected cases and confirmed by genetic analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Sahlander, Bensing and Falhammar.)

Objective: To raise awareness of Cytochrome P450 Oxidoreductase Deficiency (PORD, a rare form of congenital adrenal hyperplasia (CAH), through a case of pregnant woman with virilization symptoms., Case Description: A 30-year-old Chinese woman was referred to hospital after 7 years of presenting signs of virilization, including voice deepening, acromegaly, hirsutism, clitoromegaly, and acne. These symptoms appeared since her third gestation. Her second birth died 9 hours after birth and had signs of clitoris hypertrophy. Her third born was a son who presented with flat nose, radius and humerus bone malformation, and small penis at birth. Panel of POR-related genetic tests revealed that the patient carried c.1370 G>A (p.R457H), which is a POR heterozygous gene, while her husband carried a POR heterozygous gene as well, c.1379 C>A (p.S460Y). Two heterozygous mutations of the POR were found in her son: c.1370 G>A and c.1379 C>A. In PORD, c.1370 G>A (p.R457H) was reported as a susceptible gene, while c.1379 C>A (p.S460Y) has not been reported as responsible for the disease so far., Discussion and Literature Review: PORD is a rare form of CAH and caused by POR gene mutations. Most PORD patients are identified and diagnosed in pediatrics department. Internal medicine and obstetrics physicians are unfamiliar with the disease. As clinical manifestations are diverse, PORD could be easy to miss or to be misdiagnosed. Typical clinical manifestation includes adrenal insufficiency-related symptoms, such as bone malformations and sexual development disorders. PORD is diagnosed through genetic testing. Investigations of steroid metabolic products in urine through gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry are also helpful for the diagnosis, but neither of them are widely available in China. In this case, the patient had a history of infertility, and her third child was born with congenital defect and carried a PORD-related gene. In general clinical practice, if a pregnant woman presents with abnormal virilization symptoms, CAH possibilities should be considered, including rare causes such as PORD., Conclusion: PORD is a rare autosomal recessive genetic disease. We summarised the clinical characteristics and genotypes that were previously reported in the Chinese population and identified a novel mutation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Woo, Hai, Wang, Lin, Huang, Peng, Wu, Zhang, Yan and Li.)

Background: Lipoid congenital adrenal hyperplasia (LCAH) is a rare and severe disorder that is caused by mutations in the steroidogenic acute regulatory protein (StAR). Non-classic LCAH is defined as late-onset glucocorticoid deficiency and even complete male external genitalia in 46,XY individuals. However, to date, few cases of non-classic LCAH have been reported., Methods: It was attempted to describe the clinical characteristics of a male child with complete male external genitalia in terms of age of onset, adrenal function, and biochemical indicators. Previously reported cases were also reviewed to investigate the relationship of age of onset with enzymatic activity in non-classic LCAH., Results: The patient with complete male external genitalia was diagnosed with non-classic LCAH, in which the reason for his referral to a local hospital at the of age 1.25 years was progressive skin hyperpigmentation, and plasma adrenocorticotropic hormone (ACTH) level was elevated to higher than 1,250 pg/ml. The compound heterozygous mutations c.772C>T/c.562C>T in STAR gene were identified via genetic testing. The literature review resulted in identification of 47 patients with non-classic LCAH from 36 families. The mutational analysis showed that c.562C>T mutation was prevalent in patients with non-classic LCAH, accounting for 37.2% of the total mutant alleles, which could reflect the founder effect on the non-classic LCAH population. In total, 28 46,XY patients were reported, including 22 (78.5%) cases with complete male external genitalia and six (21.5%) cases with different degrees of hypospadias., Conclusion: The clinical phenotypes of non-classic LCAH are highly variable. Routine physical examination, laboratory measurement, genetic testing, and, importantly, enzymatic activity assay may facilitate the early diagnosis of non-classic LCAH. The age of primary adrenal insufficiency (PAI) onset may not be a diagnostic basis for non-classic LCAH, and enzymatic activity assay determination may be more effective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Zhang, Zhang, Wang, Lv, Wang, Ye, Xiao, Dong, Wang, Sun, Li, Hu, Ning and Ma.)

Background: Treated or untreated non-classic congenital adrenal hyperplasia (NCCAH) diagnosed in childhood could pose an increased risk of obesity and metabolic derangements in adolescence and early adulthood. We aimed to explore the interaction between muscle-to-fat ratio (MFR) and components of metabolic syndrome in pediatric subjects with NCCAH., Methods: This retrospective observational study was conducted in the Tel Aviv Medical Center from January 2018 to January 2022. The study group comprised 75 subjects (26 males) with NCCAH (61 hydrocortisone-treated [21 males] and 14 untreated [5 males]) and 134 healthy sex- and age-matched subjects (41 males) with normal puberty served as controls. Body composition was measured by bioelectrical impedance analysis (BIA) and muscle-to-fat ratio (MFR) z-scores were calculated. Stepwise linear regression models were applied to evaluate explanatory variables for MFR z-scores, blood pressure percentiles, lipid profiles, and glucose metabolism., Results: The median age [interquartile range] was 7.5 years [5.3, 8.8] at NCCAH diagnosis and 12.3 years [8.9, 15.4] at BIA. The median cumulative hydrocortisone dose was 7620 mg/m 2 [2547, 12903]. Subjects with NCCAH had higher mean BMI z-scores and lower median MFR z-scores compared to controls [(0.47 ± 0.97 vs. -0.19 ± 1.04, p <0.001) and (-0.74 [-1.06, -0.14] vs.-0.37 [-0.99, 0.15], p =0.045), respectively]. The linear regression models dependent variables and their explanatory variables were: MFR z-score (R 2 = 0.253, p <0.001) - socioeconomic position index (β=0.348, p =0.003), birthweight z-score (β=-0.258, p =0.013), and duration of hydrocortisone treatment in years (β=0.048, p =0.023); systolic blood pressure percentile (R 2  = 0.166, p <0.001) - MFR z-score (β=-9.75, p <0.001); TG/HDL ratio (R 2  = 0.116, p =0.024) - MFR z-score (β=-0.300, p =0.024). No significant variables were found for glucose., Conclusions: Children and adolescents with NCCAH have a body composition characterized by an imbalance between muscle and fat tissues, which may place them at increased risk for early-onset cardiometabolic derangements. It is reassuring that glucocorticoid therapy aimed to alleviate androgen overproduction does not appear to adversely affect their body composition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ben Simon, Brener, Segev-Becker, Yackobovitch-Gavan, Uretzky, Schachter Davidov, Alaev, Oren, Eyal, Weintrob and Lebenthal.)

Since the introduction of glucocorticoid (GC) replacement therapy, congenital adrenal hyperplasia (CAH) is no longer a fatal disease. The development of neonatal screening programs and the amelioration of GC treatment strategies have improved significantly life expectancy in CAH patients. Thanks to these achievements, CAH patients are now in their adulthood, but an increased incidence of cardiovascular risk factors has been reported compared to general population in this stage of life. The aim of CAH treatment is to both prevent adrenal insufficiency and suppress androgen excess; in this delicate balance, under- as well as overtreatment might be equally harmful to long-term cardiovascular health. This work examines the prevalence of metabolic features and cardiovascular events, their correlation with hormone levels and GC replacement regimen in CAH patients and focuses on precocious markers to early detect patients at higher risk and new potential treatment approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barbot, Mazzeo, Lazzara, Ceccato and Scaroni.)

Background: 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes., Patients and Methods: We report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of HSD3B2 was performed using Sanger sequencing., Results: A 3βHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453&#95;464del or p.(Thr152&#95;Pro155del). Probable 3βHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0-390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1-2) with no posterior fusion of the labia. The EMS for males was 6 (3-9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37-164.3) nmol/L; 501.2(9.4-5441.3) nmol/L, and 139.7 (10.9-1500) nmol/l (NB >90 nmol/L diagnostic of 3βHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three., Conclusions: The prevalence of 3βHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3βHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ladjouze, Donaldson, Plotton, Djenane, Mohammedi, Tardy-Guidollet, Mallet, Boulesnane, Bouzerar, Morel and Roucher-Boulez.)

Objective: 11β-Hydroxylase deficiency (11β-OHD) caused by mutations in the CYP11B1 gene is the second most common form of congenital adrenal hyperplasia. Both point mutations and genomic rearrangements of CYP11B1 are important causes of 11β-OHD. However, the high degree of sequence identity between CYP11B1 and its homologous gene CYP11B2 , presents unique challenges for molecular diagnosis of suspected 11β-OHD. The aim of this study was to detect the point mutation, indel, small deletion of CYP11B1 and chimeric CYP11B2 / CYP11B1 gene in a one-tube test, improving the genetic diagnosis of 11β-OHD., Methods: Optimized custom-designed target sequencing strategy was performed in three patients with suspected 11β-OHD, in which both the coverage depth of paired-end reads and the breakpoint information of split reads from sequencing data were analysed in order to detect genomic rearrangements covering CYP11B1 . Long-range PCR was peformed to validate the speculated CYP11B1 rearrangements with the breakpoint-specifc primers., Results: Using the optimized target sequencing approach, we detected two intragenic/intergenic deletions of CYP11B1 and one chimeric CYP11B2 / CYP11B1 gene from three suspected patients with 11β-OHD besides three pathogenic heterozygous point mutation/indels. Furthermore, we mapped the precise breakpoint of this chimeric CYP11B2 / CYP11B1 gene located on chr8:143994517 (hg19) and confirmed it as a founder rearrangement event in the Chinese population., Conclusions: Our optimized target sequencing approach improved the genetic diagnosis of 11β-OHD., Competing Interests: Author NL was employed by Beijing Mygenostics Co.,Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Yin, Ye, Liu, Liu, Zhang, Chen and Chen.)

Adrenal insufficiency in paediatric patients is mostly due to congenital adrenal hyperplasia (CAH), a severe monogenic disease caused by steroid 21-hydroxylase deficiency (21-OHD, encoded by the CYP21A2 gene) in 95% of cases. CYP21A2 genotyping requires careful analyses that guaranty gene-specific PCR, accurate definition of pseudogene-gene chimeras, gene duplications and allele dropout avoidance. A small panel of well-established disease-causing alterations enables a high diagnostic yield in confirming/discarding the disorder not only in symptomatic patients but also in those asymptomatic with borderline/positive results of 17-hydroxyprogesterone. Unfortunately, the complexity of this locus makes it today reluctant to high throughput techniques of massive sequencing. The strong relationship existing between the molecular alterations and the degree of enzymatic deficiency has allowed genetic studies to demonstrate its usefulness in predicting/classifying the clinical form of the disease. Other aspects of interest regarding molecular studies include its independence of physiological variations and analytical interferences, its usefulness in the diagnosis of simple virilizing forms in males and its inherent contribution to the genetic counseling, an aspect of great importance taking into account the high carrier frequency of CAH in the general population. Genetic testing of CYP21A2 constitutes an irreplaceable tool to detect severe alleles not just in family members of classical forms but also in mild late-onset forms of the disease and couples. It is also helpful in areas such as assisted reproduction and preimplantation diagnosis. Molecular diagnosis of 21-OHD under expert knowledge definitely contributes to a better management of the disease in every step of the clinical course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arriba and Ezquieta.)

Background: Congenital adrenal hyperplasia (CAH) is a group of congenital genetic diseases caused by defective steroidogenesis. Our study aims to systematically analyze the screening results for CAH in Chinese newborns., Methods: Studies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to September, 2020. Meta-analysis was performed after quality assessment and data extraction., Results: After a review of 2 694 articles, we included 41 studies enrolling 7 853 756 newborns. In our study, we found that the incidence of CAH in China was 0.43‱ [95% confidence intervals(CI), (0.39‱, 0.48‱)], or 1/23 024 [95%CI, (1/25 757,1/20 815)]. 27 studies were included for analysis of the screening positive rate, which gave a rate of 0.66% [95%CI, (0.54%, 0.78%)]. As for the recall rate of positive cases, 17 studies were included and showed that the recall rate reached 86.17% [95%CI, (82.70%, 89.64%)]. Among the CAH patients, the ratio of males to females was 1.92:1 (119:62), and the ratio of salt wasting (SW) to simple virilization (SV) type was 3.25:1 (104:32). The average 17-hydroxyprogesterone (17-OHP) value of CAH was 393.40 ± 291.85 nmol/L (Range 33-1 300 nmol/L); there was no significant difference between male and female patients (437.17 ± 297.27 nmol/L v.s. 322.25 ± 293.04 nmol/L, P =0.16), but a significant difference was found between SW and SV patients (483.29 ± 330.07 nmol/L v.s. 73.80 ± 7.83nmol/L, P =0.04)., Conclusion: We systematically analyzed the current situation of neonatal CAH screening in China, which will deepen our understanding for future CAH screening and early diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Huang, Du, Zhang, Zhang, Liang and Luo.)

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p<0.05). Patients treated with dexamethasone or prednisone scored higher on the physical health, psychological health, and social relationships domains, but not on the environmental domain. In conclusion, QoL domain scores appeared to be comparable to healthy reference populations and higher compared to patients with a chronic illness. QoL was not influenced by genotype, but undertreatment and use of dexamethasone or prednisone were associated with higher QoL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Verhees, Engels, Span, Sweep, van Herwaarden, Falhammar, Nordenström, Webb, Richter-Unruh, Bouvattier, Perrière, Arlt, Reisch, Köhler, Rapp, Stikkelbroeck, Roeleveld and Claahsen-van der Grinten.)