Congenital Adrenal Hyperplasia in Children: The Relationship between Plasma Renin Activity and Hypertension.

Background: Children with Congenital Adrenal Hyperplasia (CAH) have a higher chance of hypertension. The likelihood of hypertension is higher in CAH children who get fludrocortisone medication and have an over-suppression. Plasma renin activity (PRA) is a sensitive indicator when the fludrocortisone dose is insufficient. The objective of this study is to assess the relationship between plasma renin activity with hypertension in 21-hydroxylase-deficient (21-OHD) CAH children. Methods: This cross-sectional observational analytical study was conducted in 2019 at the Pediatric Endocrinology Outpatient Clinic in Dr. Cipto Mangunkusumo Hospital (RSCM), Jakarta, Indonesia. The subjects were 21-OHD CAH children, aged >6 months to 18 years who had already taken hydrocortisone with or without fludrocortisone for at least 6 months, and were divided into hypertension and non-hypertension groups. The subjects were selected by a consecutive sampling method. Data was analyzed using SPSS software (version 23.0) with unpaired t test analysis and multiple logistic regression test. Statistical significance was achieved if P<0.05. Results: Forty 21-OHD CAH patients were included, and 20 subjects (50%) had hypertension. A higher incidence of hypertension was found in salt-wasting CAH than in simple virilizing types (59.3% vs 30.8%). There was a significant mean difference in PRA levels between hypertension and non-hypertension groups in salt-wasting patients (P=0.016). A significant difference between the last dose of hydrocortisone with the number of hypertension patients in salt-wasting patients (P=0.032) was found, and low PRA levels showed a 1.09 times higher risk of hypertension. Conclusion: Children with salt-wasting CAH with low PRA levels had a higher risk of getting hypertension.

A differential expression of an identical mutation in CYP17A1 gene in two infertility patients: a case report.

BACKGROUND: 17-Hydroxylase deficiency is the rarest form of congenital adrenal hyperplasia, a disorder that affects steroidogenesis, causing abnormal hormone levels. Studies have shown a clear association between 17-hydroxylase deficiency and primary infertility, but a definite protocol to treat the disorder has not been determined yet. CASE PRESENTATION: Case I presents a 24-year-old Caucasian Israeli-Arab female who experienced 6 years of infertility. Before her initial visit to our clinic, she underwent three laparoscopic ovarian cystectomies, had an unsuccessful in vitro fertilization cycle, and was treated with combined oral contraceptives. Her hormonal profile was tested, and the results led to genetic counseling and the diagnosis of non-classical congenital adrenal hyperplasia. She was treated with estradiol, glucocorticoids, and transdermal testosterone. After hormonal levels were lowered, in vitro fertilization cycles were initiated, and the patient had a spontaneous ovulation. In case II, a 20-year-old Caucasian Israeli-Arab female presented for infertility evaluation owing to her oligomenorrhea. Her vitals and physical examination had normal results. The investigation of her abnormal hormonal profile led her to be referred to genetic testing, where the results showed the same genetic mutation as seen in case I. CONCLUSION: Both cases highlight the distinctiveness of the condition, where an identical mutation in the gene responsible for the same enzyme can bring about diverse phenotypes. Case I offers a potential treatment protocol for this rare disorder.

Uncommon adrenal rest tumors and massive adrenal enlargement in adult with congenital adrenal hyperplasia mimicking metastasis from pleomorphic sarcoma.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.

Classic congenital adrenal hyperplasia with unilateral functional adrenal cortical adenoma: case report.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to adrenal steroid biosynthesis, and mainly caused by mutations in the CYP21A2 gene encoding 21-hydroxylase. Adrenal tumors are common in CAH, but functional adrenal tumors are rare. Here, we report a 17-year-old female with virilized external genitalia and primary amenorrhea, accompanied by a right adrenal tumor. Her 17-OHP level was normal, cortisol and androgen levels were significantly elevated, and the tumor pathology showed adrenal cortical adenoma. Gene testing for CYP21A2 showed c.518T > A in exon 4 and c.29313C > G in intron 2. The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

BACKGROUND: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. METHODS: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. RESULTS: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. CONCLUSIONS: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Genito-urinary Reconstruction in Female Children With Congenital Adrenal Hyperplasia: Favorable Surgical Outcomes can be Achieved by Contemporary Techniques and a Dedicated Multidisciplinary Management.

INTRODUCTION: Congenital adrenal hyperplasia (CAH) is the most common cause of genital atypia in females. A dedicated multidisciplinary team (MDT) should be included for an optimal management. Here, we aimed to review our surgical experience and to assess long-term urinary, gynecological and endocrine outcomes after primary genitoplasty in this specific cohort. METHODS: Patients born with CAH and who underwent feminizing genitoplasty in our institution were retrospectively identified (2001-2021). We analyzed patients' characteristics, intraoperative details, and postoperative urinary, gynecological, and endocrine outcomes. RESULTS: Forty patients were included and followed-up for a median (IQR) time of 7 (1-19) years. Thirty-eight (95%) had 21-hydroxylase deficiency. After multidisciplinary decision and written consent from patient and/or family, a single-stage reconstructive surgery was performed at a median age of 10 (3-165) months. Median length of hospital stay was 5 (1-7) days. Procedures were: PUM (N = 35 (87.5%)), TUM (N = 3 (7.5%)), urogenital mobilization was unnecessary in 2 (5%). Reduction clitoroplasty was done in 33 (82.5%) patients. Only 3 (7.5%) experienced significant Clavien-Dindo complications requiring additional surgery during the follow-up period. Recurrent urinary tract infections (UTI) occurred in 6 (15%), one required ureteric reimplantation for symptomatic high-grade vesicoureteric reflux. All patients over 3 years were toilet-trained without incontinence. Severe vaginal stenosis occurred in 1 (2.5%) patient. In patients who achieved puberty, 6/9 had vaginal calibration at a median age of 17.3 (16-21) years without detected stenosis. One (2.5%) had major hypertrophy of the right labia minora requiring labiaplasty. Nine (22.5%) reached puberty. Two (5%) patients developed acne/hirsutism. Short stature was noted in 11 (27.5%) and obesity in 18 (45%). CONCLUSION: Based on our contemporary series, genitourinary reconstructive surgery for female patients born with CAH is technically feasible and safe with a low complication rate. A regular follow-up with a MDT to assess long-term complications is necessary, and it is vital to inform patients and families about the different management options with all the risks and benefits of surgery. TYPE OF THE STUDY: original research, clinical research. LEVEL OF EVIDENCE: Level 3 retrospective study.

Memory in female adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: In females with congenital adrenal hyperplasia (CAH), the influence of hyperandrogenism and glucocorticoid supplementation on neurocognition is controversial. OBJECTIVES: To identify possible differences in visual working memory and verbal memory in adolescent girls with CAH due to 21-hydroxylase deficiency and matched controls. Moreover, to study if any relationship between variables associated with CAH and the scores of the selected memory tests was present. MATERIAL AND METHODS: In total 39 individuals were studied, female adolescents with CAH and age and pubertal stage matched healthy male and female controls (13 in each group). Sociodemographic, clinical, hormonal, and neurocognitive variables were explored. In female adolescents with CAH, variables related to the disease (age at diagnosis, clinical form, time since diagnosis, and glucocorticoid doses) were correlated with the scores obtained for neurocognitive variables. RESULTS: The mean age was 13.9 ± 3.3 years. In female adolescents with CAH the results were worse compared to controls in Free Recall (p = 0.039) and in Visual Memory Span score (p = 0.016). Age at diagnosis was negatively correlated to number of hits (p = 0.04), number recalled backward (p = 0.03), Visual Memory Span test score (p = 0.04) and Total Free Recall (p = 0.04), i.e., memory was worse with later diagnosis. CONCLUSIONS: Female adolescents with CAH had worse visual working memory compared to matched controls, but not in verbal memory. Age at diagnosis was negatively associated with the memory tests.

Successful live birth in women with partial 17α-hydroxylase deficiency: report of two cases.

RESEARCH QUESTION: Can women with partial 17α-hydroxylase deficiency (17-OHD) conceive naturally with adequate hormonal control and endometrial preparation? DESIGN: This report presents two cases of women with partial 17-OHD who achieved successful pregnancies. The first case involved a 27-year-old Chinese woman with recurrent cysts and infertility, and the second case involved a 32-year-old Chinese woman with a complex disorder requiring IVF. Both cases were treated with oral prednisone to control hormone concentrations and underwent endometrial preparation. RESULTS: In the first case, the patient resumed spontaneous ovulation, conceived naturally, and gave birth to a healthy baby. In the second case, after cryopreserving embryos due to a thin endometrium, the patient underwent frozen embryo transfer and achieved a singleton pregnancy. CONCLUSION: This study suggests that women with partial 17-OHD can conceive naturally with appropriate hormonal management and endometrial preparation. These findings provide valuable insights into the reproductive potential of women with this disorder, and highlight the importance of further research in this area.

Infertility risk assessment with ultrasound in congenital adrenal hyperplasia male patients.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = - 0.83, P < 0.001) and progressive motility (rs = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

Long-term outcomes in non-CAH 46,XX DSD.

Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.

Case report: Development of central precocious puberty in a girl with late-diagnosed simple virilizing congenital adrenal hyperplasia complicated with Williams syndrome.

Congenital adrenal hyperplasia (CAH) and Williams Syndrome (WS; MIM # 194050) are distinct genetic conditions characterized by unique clinical features. 21-Hydroxylase deficiency (21-OHD; MIM #201910), the most common form of CAH, arises from mutations in the CYP21A2 gene, resulting in virilization of the external genitalia in affected females, early puberty in males, and short stature. Williams syndrome, caused by a microdeletion of 7q11.23, presents with distinctive facial features, intellectual disability, unique personality traits, early puberty, and short stature. This case report describe the clinical features of a 4-year-old girl referred due to progressive virilization and developmental delay. Genetic analysis confirmed concurrent CAH and WS, identifying a novel mutation in the CYP21A2 gene (c.1442T>C). Following corticosteroid therapy initiation, the patient developed central precocious puberty. This case report delves into the pubertal change patterns in a patient affected by overlapping genetic conditions, providing valuable insights in to the intricate clinical manifestation and management of these rare complex disorders.

Giant Bilateral Adrenal Myelolipomas in a Non-Compliant Patient with Congenital Adrenal Hyperplasia.

BACKGROUND 21-hydroxylase deficiency, an essential enzyme for glucocorticoid and mineralocorticoid synthesis, is the cause of congenital adrenal hyperplasia (CAH) in more than 95% of cases. It is an autosomal recessive disorder encoded by the CYP21A2 gene, categorized into classical forms, which encompass the salt-wasting (SW) and simple virilizing (SV) forms, as well as the nonclassical form (NC). The aim of medical treatment is to replace missing glucocorticoids and, if necessary, mineralocorticoids, while also reducing elevated adrenal androgens. CASE REPORT We present the case of a 42-year-old woman with CAH who discontinued therapy during adolescence and was admitted to hospital with fatigue, nausea, and severe abdominal pain. A CT scan showed an extreme enlargement of the adrenal glands. Laboratory tests revealed elevated levels of 17-hydroxyprogesterone and other adrenal androgens, along with normal plasma metanephrine levels. Decreased morning cortisol levels suggested partial adrenal insufficiency requiring glucocorticoid replacement therapy. Due to the development of several serious complications and clinical deterioration, the multidisciplinary team recommended bilateral removal of masses measuring 300×250×200 mm on the right side and 250×200×200 mm on the left side. Histological and immunochemical examination confirmed the presence of giant myelolipomas with adrenal cortex hyperplasia. CONCLUSIONS Adrenal tumors, particularly myelolipomas, have a higher prevalence in patients with CAH. Our case report provides further evidence of the suspected link between non-compliant CAH therapy and the development of myelolipomas, along with promotion of their pronounced growth.

Frequency of stress dosing and adrenal crisis in paediatric and adult patients with congenital adrenal hyperplasia: a prospective study.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents. DESIGN: Prospective, observational study. METHODS: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed. RESULTS: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026). CONCLUSION: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.

Cushing's syndrome diagnosed incidentally on CT imaging.

In this case report, we describe an uncommon presentation of Cushing's syndrome in a patient in their 60s who presented to the emergency department with left-sided chest pain. The initial workup for the patient was unremarkable except for an elevated blood pressure and elevated fasting plasma glucose. A CT scan of the chest, abdomen and pelvis was performed, demonstrating a splenic artery thrombus with multiple splenic infarcts, in addition to a combination of macronodular adrenal hyperplasia, bilateral gynecomastia, centripetal fat distribution and suspected mild bone demineralisation. Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia, a rare aetiology responsible for Cushing's syndrome, was raised as a potential unifying diagnosis for the patient's hypercoagulable status, which was subsequently confirmed on an endocrinological investigation. The case report underscores the importance of communicating clinically relevant details to the imaging specialist in combination with considering a broad differential, including endocrine disorders, when evaluating an undifferentiated patient with atypical imaging findings.

Congenital adrenal hyperplasia complicated by gonadotropin-dependent precocious puberty.

Precocious puberty, characterised by the early appearance of secondary sexual characteristics, poses challenges in diagnosis and management. Here, we describe a case of precocious puberty diagnosed in a boy in middle childhood, who presented with progressive phallus enlargement, pubic hair development and increased aggressive behaviour. Hormonal evaluation confirmed the diagnosis of congenital adrenal hyperplasia (CAH), complicated by gonadotropin-dependent precocious puberty. The case highlights the importance of assessment of testicular volume in a patient presenting with precocious puberty. Symmetrical testicular enlargement in a patient with CAH suggests premature activation of the hypothalamic-pituitary-gonadal axis. The patient received glucocorticoid therapy to suppress androgen production related to CAH and gonadotropin-releasing hormone analogue therapy to control premature activation of the hypothalamic-pituitary-gonadal axis. Follow-up visits showed regression of secondary sexual characteristics and improved growth velocity.

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.

Testicular tumours in adrenogenital syndrome.

Congenital adrenal hyperplasia (CAH) arises from genetic enzyme defects, often in CYP21A2, causing primary adrenal insufficiency. In this case report, a man in his late 20s with lifelong CAH faced challenges in adhering to medication. Suboptimal treatment led to the development of testicular adrenal rest tumours, diagnosed by ultrasound, and hypogonadism. Enhanced adherence restored hormone levels, promoting eugonadism. Adherence plays a crucial role in diminishing tumour size and preventing complications, potentially necessitating orchiectomy in severe cases.