Identifying the First Val281L Mutation Causing Nonclassic Congenital Adrenal Hyperplasia in the Central-East Region of Tunisia.

Nonclassic congenital adrenal hyperplasia (NCAH) is a genetic disorder characterized by mutations in the genes encoding enzymes involved in cortisol production, most commonly the 21-hydroxylase enzyme. Unlike classic congenital adrenal hyperplasia (CAH), NCAH typically presents later in life with milder symptoms. The diagnosis of NCAH can be challenging due to its nonspecific symptoms and variable presentation. Early detection is crucial for timely intervention and management, particularly in families with a history of the condition. We report a case of NCAH in a patient from the Central-East Region of Tunisia, in whom the subsequent genetic testing revealed a Val281Leu (V281L) mutation in the CYP21A2 gene. A 26-year-old female presented with facial hirsutism and irregular menstrual cycles. Physical examination revealed mild hirsutism and laboratory tests showed elevated levels of testosterone and 17-hydroxyprogesterone (17-OHP). A provisional diagnosis of NCAH was made, subsequently confirmed by an adrenocorticotropic hormone (ACTH) stimulation test demonstrating an exaggerated 17-OHP response. Genetic testing revealed heterozygosity for the V281L mutation. Family testing showed the patient's mother to be homozygous and the father heterozygous for the mutation. This report highlights the importance of recognizing subtle symptoms of NCAH for early diagnosis and management. Genetic testing aids in confirming the diagnosis and identifying carriers within families. Treatment with glucocorticoids aims to suppress adrenal androgen production and manage symptoms. Regular follow-up is essential to monitor treatment response and adjust medication as needed. NCAH can present with subtle symptoms, necessitating a high index of suspicion for a proper diagnosis. Genetic testing plays a crucial role in confirming the diagnosis and identifying carriers within families. Early intervention and regular follow-up improve outcomes in affected individuals. This report also underscores the significance of genetic testing in the management of NCAH and highlights the need for increased awareness about this condition among healthcare providers.

Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE: To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease. METHODS: This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed. RESULTS: The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis. CONCLUSIONS: our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.

Ensuring quality in 17OHP mass spectrometry measurement: an international study assessing isomeric steroid interference.

OBJECTIVES: Interference from isomeric steroids is a potential cause of disparity between mass spectrometry-based 17-hydroxyprogesterone (17OHP) results. We aimed to assess the proficiency of mass spectrometry laboratories to report 17OHP in the presence of known isomeric steroids. METHODS: A series of five samples were prepared using a previously demonstrated commutable approach. These samples included a control (spiked to 15.0 nmol/L 17OHP) and four challenge samples further enriched with equimolar concentrations of 17OHP isomers (11α-hydroxyprogesterone, 11ß-hydroxyprogesterone, 16α-hydroxyprogesterone or 21-hydroxyprogesterone). These samples were distributed to 38 participating laboratories that reported serum 17OHP results using mass spectrometry in two external quality assurance programs. The result for each challenge sample was compared to the control sample submitted by each participant. RESULTS: Twenty-six laboratories (68 % of distribution) across three continents returned results. Twenty-five laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS), and one used gas chromatography-tandem mass spectrometry to measure 17OHP. The all-method median of the control sample was 14.3 nmol/L, ranging from 12.4 to 17.6 nmol/L. One laboratory had results that approached the lower limit of tolerance (minus 17.7 % of the control sample), suggesting the isomeric steroid caused an irregular result. CONCLUSIONS: Most participating laboratories demonstrated their ability to reliably measure 17OHP in the presence of the four clinically relevant isomeric steroids. The performance of the 12 (32 %) laboratories that did not engage in this activity remains unclear. We recommend that all laboratories offering LC-MS/MS analysis of 17OHP in serum, plasma, or dried bloodspots determine that the isomeric steroids are appropriately separated.

The impact of neonatal 17-hydroxyprogesterone cutoff determination in a public newborn screening program for congenital adrenal hyperplasia in Southern Brazil: 3 years' experience.

Congenital adrenal hyperplasia (CAH) occurs due to enzyme defects in adrenal steroidogenesis. The 21-hydroxylase deficiency accounts for 90-95% of cases, triggering accumulation of 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening allows adequate treatment and reduced mortality. The purpose of the study was to determine 17-OHP cutoffs for the diagnosis of CAH in a public newborn screening program in Southern Brazil. A retrospective, descriptive, cross-sectional study was conducted to analyze 17-OHP levels in dried blood samples collected on filter paper of 317,745 newborns screened at a public newborn screening center from May 2014 to April 2017. Neonatal 17-OHP was measured in DBS samples using a time-resolved fluoroimmunoassay (GSP® kit 3305-0010; PerkinElmer). Different cutoffs were determined and stratified by birth weight. The incidence of CAH was 1:15,887 live births in the state of Rio Grande do Sul, with 20 cases of classical CAH diagnosed during the study period. Most newborns (80.73%) were white, and the prematurity rate was 9.8% in the study population. The combination of different percentiles, 98.5th for birth weight 2001-2500 g and 99.8th for the other birth weight groups, decreased false-positive results and increased specificity compared with current reference values to identify classical CAH cases. The local 17-OHP cutoffs determined were higher than those currently used by this screening program for all birth weight groups. The calculation of reference values from local population data and the combination of percentiles proved to be a valuable tool for proper diagnosis of CAH and reduction in the number of false positives.

Successful Bilateral Sperm Retrieval in a Hypogonadal Patient with Non-Obstructive Azoospermia Showing Normal Serum 17-Hydroxyprogesterone Levels Suggestive of Normal Intratesticular Testosterone Production: A Case Report.

The impact of hypogonadism on the probability of retrieving testicular sperm from patients with non-obstructive azoospermia (NOA) is still a matter of debate. Conflicting evidence in this field may be justified by the striking differences between serum and intratesticular testosterone (ITT) levels found in men with severe spermatogenic dysfunction, so that normal ITT levels may coexist with low serum testosterone levels. Here we report the case of a patient with NOA with a steadily reduced serum testosterone level irresponsive to hormonal stimulation with human chorionic gonadotropin. Supported by his normal serum 17-hydroxyprogesterone (17 OHP) levels, previously suggested to be marker of ITT levels, microdissection testicular sperm extraction was performed for both testes on two separate occasions, resulting in the retrieval of enough sperm for ICSI. Three ICSI cycles were then performed, one blastocyst was transferred, and five were cryopreserved. This case report suggests that normal serum 17 OHP levels, being suggestive of normal ITT levels, may support the decision to proceed with surgical sperm retrieval in hypogonadal patients with NOA, even for those irresponsive to hormonal treatment.

Clinical analysis of 78 patients with nonclassical 21-hydroxylase deficiency.

PURPOSE: Retrospectively analyze the clinical characteristics of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) as well as the relationship between the gene mutations and endocrine hormones. In addition, the relationship between different basal 17-hydroxyprogesterone (17OHP) levels and patients' glucolipid metabolism, hormone levels, pregnancy, and treatment outcomes were examined. METHODS: Clinical data of 78 females with NC21OHD from January 2012 to July 2022 in the Department of Endocrinology and Metabolism of the Third Affiliated Hospital of Guangzhou Medical University were retrospectively analyzed. Diagnosis was based on the 17OHP level combined with clinical manifestations, imaging, and other endocrine hormones and the cytochrome P450 c21, steroid 21-hydroxylase (CYP21A2) gene. RESULTS: The age at diagnosis of the 78 patients was 29.1 ± 4.2 years; 83.3% (65/78) of the patients had menstrual abnormalities, 70 patients were of childbearing age, and 97.1% (68/70) had a history of infertility with a median time of infertility of 3.6 years. Moreover, 71.8% (56/78) of the patients had polycystic ovaries, 26.9% (21/78) had hyperandrogenemia manifestations on physical examination, 66.7% (52/78) had adrenal hyperplasia, 32.1% (25/78) had combined dyslipidemia, and 41.0% (32/78) had combined insulin resistance. Pathogenic mutations were detected in 78.2% (61/78) of the patients with both CYP21A2 alleles; 14.1% (11/78) of the patients had only one allele and 7.7% (6/78) had no pathogenic mutations. The levels of total testosterone (TT), progesterone (P) (0 min, 30 min), and 17-OHP (0 min, 30 min, 60 min) in the adrenocorticotropic hormone (ACTH) stimulation test varied between the groups. Furthermore, patients with NC21OHD were divided into 17OHP < 2 ng/ml, 2 ng/ml < 17OHP < 10 ng/ml, and 17OHP ≥ 10 ng/ml groups according to their different basal 17OHP levels. The 17OHP ≥ 10 ng/ml group had significantly higher TT, FT4, basal and post-stimulation progesterone, and 17OHP, net value added of 17-hydroxyprogesterone (△17OHP), net value added of 17-hydroxyprogesterone/net value added of cortisol ratio (△17OHP/△F), the incidence of adrenal hyperplasia, and number of gene mutations compared to those of the 17OHP < 2 ng/ml group (P < 0.05). NC21OHD infertile patients who received low-dose glucocorticoids showed a significant increase in pregnancy and live birth rates, and a significant decrease in miscarriage rate (all P < 0.05). CONCLUSION: Comprehensive analysis is important as NCCAH diagnoses may be false positive or false negative based on clinical characteristics, hormone levels, and gene detection. Females with NC21OHD showed varying degrees of fertility decline; thus, low doses of glucocorticoid treatment for infertile females with NC21OHD can improve fertility and fertility outcomes.

A novel fully-automated method to measure steroids in serum by liquid chromatography-tandem mass spectrometry.

Background: Steroids play a key role in numerous physiological processes. Steroid determination is a useful tool to explore various endocrine diseases. Because of its specificity, mass spectrometry is considered to be a reference method for the determination of steroids in serum compared to radioimmunoassay. This technology could progress towards more automation for the optimal organization of clinical laboratories and ultimately for the benefit of patients. Methods: A fully automated ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed and fully validated to determine five steroids in serum. Sample preparation was based on protein precipitation with filtration followed by online solid phase extraction. Chromatographic separation was performed using a biphenyl stationary phase. Results: The method was successfully validated according to European Medicine Agency guidelines. Coefficients of variation did not exceed, respectively, 8.4% and 8.1% for intra- and inter-assay precision. Method comparison with radioimmunoassay showed a proportional bias for all compounds, except for testosterone in men. Comparison with another LC-MS/MS method demonstrated acceptable concordance for all steroids, although a small bias was observed for androstenedione. Conclusion: The novelty of this method is that it has been fully automated. Automation provides benefits in traceability and allows significant savings in cost and time.

Measuring steroids in hair opens up possibilities to identify congenital adrenal hyperplasia in developing countries.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) in developing countries have limited access to appropriate laboratory facilities for diagnosis and follow-up. The aim of this study is to evaluate steroid measurement in hair as a diagnostic tool to identify and monitor CAH in these patients. DESIGN: A method was developed to measure steroids in hair, the stability of steroids in hair was assessed, and the concentration range in healthy volunteers was determined. Hair samples of patients, before and after starting therapy, were transported at ambient temperature to The Netherlands for analysis. PATIENTS: Twenty-two Indonesian CAH patients and 84 healthy volunteers participated. MEASUREMENTS: Cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone in hair were measured by liquid chromatography with tandem mass spectrometry. RESULTS: Steroids in hair could be measured and remained stable (<4.9% deviation) for at least 3 weeks at 4°C and 30°C. In each of the untreated patients, hair concentrations of 17OHP (9.43-1135 pmol/g), androstenedione (36.1-432 pmol/g), and testosterone (2.85-69.2 pmol/g) were all above the upper limit of the corresponding range in healthy volunteers; 5.5 pmol/g, 13 pmol/g, and 1.8 pmol/g, respectively. After starting glucocorticoid treatment, the steroid concentrations in the hair of CAH patients decreased significantly for androstenedione (73%) and testosterone (59%) after 6 months. CONCLUSIONS: CAH could be confirmed in Indonesian patients based on the concentration of 17OHP, androstenedione, and testosterone in hair, and a treatment effect was observed. These findings open up opportunities to diagnose and/or monitor CAH in developing countries with a simple noninvasive technique.

Regional differences in utilization of 17α-hydroxyprogesterone caproate (17-OHP).

OBJECTIVES: To describe regional differences in utilization of 17α-hydroxyprogesterone caproate (17-OHP). METHODS: Retrospective cohort study of a large, US commercial managed care plan claims database with pharmacy coverage from 2008 to 2018. Singleton pregnancies with at least one prior spontaneous preterm birth (sPTB) were included. Regional and state-based differences in 17-OHP use were compared. Data were analyzed using t-tests and Fisher's exact tests. RESULTS: Of the 4,514 individuals with an indication for 17-OHP, 580 (12.8%) were prescribed 17-OHP. Regional and state-based differences in 17-OHP utilization were identified; Northeast 15.7%, Midwest 13.7%, South 12.0%, and West 10.4% (p=0.003). CONCLUSIONS: While significant regional differences in 17-OHP utilization were demonstrated, 17-OHP utilization remained low despite this cohort having insurance through a US commercial managed care plan. Suboptimal utilization demonstrates a disconnect between research and uptake in clinical practice. This underscores a need for implementation science in obstetrics to translate updated recommendations more effectively and efficiently into clinical practice.

Development of an in vitro culture system for immature oocytes of red swamp crayfish (Procambarus clarkii).

The present study assessed general strategies for the isolation and in vitro culture of immature ovary-derived cells (oocytes) in red swamp crayfish (Procambarus clarkii). In phase 1 of this study, the effects of different digestive enzymes on cell retrieval from developing ovarian tissues were examined to facilitate efficient oocyte isolation. Subsequently, the ovary-derived cells/oocytes were cultured under various conditions to evaluate the effects of basal media and supplement concentrations. Collagenase I treatment at 26 ℃ for 25 min was more effective (approx. 95 %) in oocytes isolation from ovarian tissues than other treatments. Furthermore, DMEM media with HEPES (DMEM-H) were more effective than L15 for oocyte culture (72.4 % survival rate), while oocyte survival improved to 90.6 % using a 10 % fetal bovine serum supplement. In phase 2, the top-performing media were used in immature oocyte culture to assess 17α-Hydroxyprogesterone (17-OHP) induction in vitro. An up-regulated expression of maturity-related genes, i.e., cyclin B, cdc2, ef1α, after 12 h of incubation was evident in qPCR results, demonstrating that the exogenous hormone 17-OHP could induce P. clarkii oocyte maturation in vitro. These results may provide a basis for developing an in vitro system for P. clarkii germline cell culture, which may ultimately lead to the genetic improvement of this species.

A rare case report about a congenital adrenal hyperplasia by 21-hydroxylase lock in its pure virilizing form discovered in adolescence.

Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disease. The diagnosis of the classic virilizing form must be made at birth. Case presentation: We report the case of a 16-year-old female patient, who consulted for primary amenorrhea and absence of breast development, in whom the clinical examination found a male morphotype, signs of virilization with a peniform hypertrophy of the clitoris. Pelvic ultrasound confirmed the presence of the uterus and ovaries. A syacthen test on 17 hydroxy-progesterone was performed confirming the diagnosis of congenital adrenal hyperplasia by partial 21-hydroxylase deficiency. The treatment was based on hydrocortisone and spironolactone with a decrease in hairiness and a breast development after 3 months. Discussion: The principal aim of the management at adolescent age is to block hyperandrogenism and to prevent or manage the complications of classic form and its treatment. The treatment must be completed by a feminization surgery which constitutes a great challenge given the necessity of participation of a gynecologist and a pediatric surgeon experienced in the surgery of anomalies of sexual development. Conclusion: This rare case of anomaly of sexual development discovered at an adolescent age with all the obstacles and difficulties of its management allows to put the point on the necessity of a good clinical examination at birth and the early management of any anomaly of sexual development.

Progesterone activates GPR126 to promote breast cancer development via the Gi pathway.

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.

17 Alpha-hydroxyprogesterone caproate use in a rural state.

BACKGROUND: 17 alpha-hydroxyprogesterone caproate (17OHP) is used to reduce the recurrent risk of preterm delivery in women with a history of preterm delivery. Meis et al. conducted a double-blind placebo controlled trial to evaluate the effectiveness of 17OHP and observed a significant reduction in the risk of recurrent preterm delivery. The FDA granted 17OHP a conditional approval on 2011. A second study observed that 17OHP did not decrease the risk of a recurrent preterm delivery. Criticism of the second study derived from a dissimilarity of the study population. OBJECTIVE: Our investigation examined the effectiveness of 17OHP in women with a prior preterm delivery in a rural US state with a patient population similar to the original Meis trial. STUDY DESIGN: 17OHP became largely unavailable (due to cost and local pharmacies no longer compounding 17 OHP) and the University of Arkansas for Medical Sciences, Department of Health, and Arkansas Medicaid co-operated to make 17OHP available to women with a prior PTB in our state. This study was a retrospective review of the 17OHP that was offered to women with a prior preterm delivery. For our retrospective review, logistic regression was used on cases of prior preterm delivery between January 2014 and December of 2018 to examine the relationship between 17OHP injections and preterm delivery. RESULTS: A total of 268 women were analyzed for this review. They were divided into three groups: 0 injections, 1-10 injections, and > 10 injections. We found no relationship between 17OHP injections with preterm delivery. CONCLUSION: Although our patient population was similar to that of the original Meis trial, our results were more similar to the second study by Blackwell.

17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses

Objective: Standard dose synacthen stimulation test (SDSST) is a gold standard screening test for evaluating adrenal gland function. Despite studies using SDSST to identify heterozygosity in CYP21A2, the reliability of the test for this purpose is still controversial. Therefore, the meta-analyses were performed to determine the differences in 17-hydroxyprogesterone (17-OHP) responses to standard dose (0.25 mg) SDSST in the diagnosis of CYP21A2 heterozygous individuals, with or without clinical signs of androgen excess disorders. Methods: PubMed and MEDLINE databases were searched. A total of 1215 subjects (heterozygous carriers n=669, mutation-free controls n=546) were included in the meta-analyses. Results: Basal 17-OHP median/mean levels were 4.156 (3.05-10.5)/5.241 (±2.59) nmol/L and 3.90 (2.20-9.74)/4.67 (±2.62) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Stimulated 17-OHP median/mean levels were 17.29 (14.22-37.2)/19.51 (±7.63) nmol/L and 9.27 (7.32-15.9)/10.77 (±3.48) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Basal 17-OHP median/mean levels were 3.21 (2.64-4.78)/3.33 (±0.84) nmol/L and 3.12 (1.82-3.6)/2.83 (±0.71) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. Stimulated 17-OHP median/mean levels were 14.16 (12.73-16.37)/14.16 (±1.37) nmol/L and 6.26 (4.9-8.23)/6.48 (±1.2) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. The cut-off levels for stimulated 17-OHP were 10.48 nmol/L and 13.48 nmol/L for asymptomatic heterozygous and symptomatic heterozygous, respectively. Conclusion: The meta-analyses support the idea that stimulated 17-OHP level has potential for use in identifying CYP21A2 carriers. Besides, considering differences in the basal and stimulated 17-OHP levels in symptomatic heterozygous individuals compared to those who were asymptomatic heterozygous could increase the accuracy of the test.

A Gigantic Uterine Leiomyoma and Big Bilateral Adrenal Myelolipomas as a Result of Untreated Congenital Adrenal Hyperplasia.

INTRODUCTION: Patients with congenital adrenal hyperplasia (CAH) can present early with salt wasting, adrenal insufficiency, and hyperandrogenism. Late consequences as a result of untreated CAH are now rarely seen. We present a patient with a massive uterine leiomyoma and bilateral adrenal myelolipomas due to longstanding treatment noncompliance. CASE REPORT: A female patient with CAH was treated with glucocorticoids until the age of 29 years when they stopped with the intention of identifying as a male. The patient then presented with abdominal pain and distension. Computed tomography images of the abdomen and pelvis revealed a 31 × 35 × 31-cm abdominal mass, a 5.9× 2.4-cm right adrenal mass, and an 11.8 × 8.8-cm left adrenal mass. The patient underwent total hysterectomy and bilateral adrenalectomy. Pathology of the abdominal mass was consistent with uterine leiomyoma, and bilateral adrenal masses were consistent with adrenal myelolipomas. DISCUSSION: The goal of CAH therapy is to provide adequate replacement while reducing adrenocorticotropic hormone and adrenal androgens levels. Due to the conversion of androgens to estrogens, untreated females with CAH have elevated androgen and estrogen levels. High levels of these hormones can stimulate the growth of estrogen-dependent organs as exemplified by our patient. Chronic adrenocorticotropic hormone stimulation can not only cause adrenal hyperplasia but has also been associated with the development of adrenal myelolipomas. CONCLUSION: This case demonstrates the significance of CAH treatment compliance as there are several serious sequela outside of the expected adrenal insufficiency and virilization. Even when the desired effect is virilization, other means of hormonal therapy should be considered.

Analysis of the Screening Results for Congenital Adrenal Hyperplasia Involving 7.85 Million Newborns in China: A Systematic Review and Meta-Analysis.

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.

Programa cubano de pesquisa neonatal de la hiperplasia suprarrenal congénita: una realidad. 2005-2014 / Cuban neonatal screening program for congenital adrenal hyperplasia: a reality. 2005­2014

Introducción: la hiperplasia suprarrenal congénita (HSC) es el desorden adrenal más común en la infancia y la causa más frecuente de ambigüedad sexual. La forma clásica, que representa los casos más severos de este déficit, se asocia en un 75 % con pérdida de sal. Por otra parte, en los recién nacidos (RN) del sexo femenino se pueden presentar grados severos de virilización de genitales. Objetivo: presentar los resultados (durante diez años), del Programa Cubano de Pesquisa Neonatal (PN) de la HSC, soportado en un procedimiento inmunoenzimático desarrollado en Cuba. Resultados: en el período de enero 2005 a diciembre 2014, se han estudiado 1 140 882 RN y se detectaron 56 niños con HSC, para una incidencia de 1:20 373 RN. La cobertura del programa se ha incrementado hasta llegar en el año 2013 al 99.34 % de todos los RN cubanos. Conclusiones: la existencia del Programa Cubano de PN de HSC, ha permitido estimar la incidencia e incrementar el conocimiento de esta enfermedad. La PN ha posibilitado el diagnóstico precoz en la variedad perdedora de sal, contribuyendo a la disminución de la mortalidad infantil. El Programa ha favorecido a pacientes con formas virilizantes de la enfermedad, mediante la asignación correcta del sexo

Introduction: Congenital Adrenal Hyperplasia (HSC) is the most common adrenal disorder in childhood and the most frequent cause of sexual ambiguity. The classic form, which represents the most severe causes of this deficit, is associated in 75 % with loss of salt. On the other hand, in the NB of the female sex that present severe degrees of virilization of the genitals. Objective: To present result of the application for ten years of the Cuban Neonatal Research Program of the HSC, supported by an inmmunoenzymatic procedure developed in Cuba. Result: In the period from January 2005 to December 2014, using the UMELISA 17 OH PROGESTERONA NEONATAL, 1 140882 RN were detected, for an incidence of 1:20373 RN. The coverage of the program has been increasing until2013 reaching 99.34 % of all Cuban RN. Conclusion: The existence of the Cuban HSC PN Program, has allowed estimating the incidence and increase knowledge of this disease in our country. PN has made possible the early diagnosis of patients with the salt losing variety, contributing to decrease in infant mortality nationwide. The Program has favored patients with virilizing form of the disease, through the correct assignment of sex

Adrenal Tumor Mimicking Non-Classic Congenital Adrenal Hyperplasia.

Elevated 17-hydroxyprogesterone may be caused by congenital adrenal hyperplasia, ovarian or adrenal tumors. A positive cosyntropin stimulation test result for 17-hydroxyprogesterone may be found in functional or non-functional tumors and be related to tumor size. Here, we present a case of a 36-year-old woman with a 4-year history of infertility. Laboratory test results revealed elevated progesterone and 17-hydroxyprogesterone, with normal luteinizing hormone, follicle-stimulating hormone, estrogen, testosterone, and anti-Mullerian hormone levels. The 250-µg cosyntropin stimulation test revealed a 17-hydroxyprogesterone level of 11.3 ng/ml (34.3 nmol/L) and 31.8 ng/ml (96.2 nmol/L) at 0 and 60 min, respectively. Non-classic congenital adrenal hyperplasia was diagnosed initially; however, genetic testing revealed no 21-hydroxylase deficiency. She received dexamethasone but progesterone and 17-hydroxyprogesterone levels remained high. Abdominal computed tomography found a 4.5 × 4.8-cm left adrenal tumor. Subsequent pathological report was compatible with an adrenal cortical adenoma. Progesterone and 17-hydroxyprogesterone levels returned to the normal range postoperatively and the 250-µg cosyntropin stimulation test of 17-hydroxyprogesterone showed a normal response. When biochemically diagnosed NCCAH demonstrate no typical features and show poor response to steroid, the patient should undergo gene mutation analysis and receive adrenal or ovarian imaging. For women suffering from infertility, adrenalectomy of 17-OHP secreting adrenal tumor may improve fertility outcome.

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. AIMS: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7). CONCLUSION: Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.

Urinary steroid profiling in diagnostic evaluation of an unusual adrenal mass.

SUMMARY: Adrenal oncocytomas are rare tumours, with only approximately 160 cases reported in the literature. We report the use of urinary steroid profiling as part of their diagnostic evaluation and prognostication. A 45-year-old woman presented with clinical features of hyperandrogenism. Serum biochemistry confirmed androgen excess and computed tomography (CT) demonstrated a 3.2 cm adrenal tumour with density 39 HU pre-contrast. Urine steroid profiling showed elevated tetrahydro-11 deoxycortisol (THS), which is associated with adrenal malignancy. Laparoscopic adrenalectomy was performed, and histopathology diagnosed adrenal oncocytoma. Serum and urinary biochemistry resolved post-operatively and remained normal at 1-year follow-up. LEARNING POINTS: Differential diagnosis of adrenal masses is challenging. Current techniques for differentiating between tumour types lack sensitivity and specificity. 24-h urinary steroid profiling is a useful tool for reflecting steroid output from adrenal glands. Gas chromatography-mass spectrometry (GC-MS) of urinary steroid metabolites has sensitivity and specificity of 90% for diagnosing adrenocortical carcinoma. Adrenal oncocytoma are rare tumours. Differentiating between benign and malignant types is difficult. Data guiding prognostication and management are sparse.