Cardiometabolic Aspects of Congenital Adrenal Hyperplasia.

Treatment of classic congenital adrenal hyperplasia (CAH) is directed at replacing deficient hormones and reducing androgen excess. However, even in the era of early diagnosis and lifelong hormonal substitution, the presence of CAH is still associated with numerous complications and also with increased mortality. The aim of this article was to create an authoritative and balanced review concerning cardiometabolic risk in patients with CAH. The authors searched all major databases and scanned reference lists of all potentially eligible articles to find relevant articles. The risk was compared with that in other forms of adrenal insufficiency. The reviewed articles, most of which were published recently, provided conflicting results, which can be partially explained by differences in the inclusion criteria and treatment, small sample sizes and gene-environmental interactions. However, many studies showed that the presence of CAH is associated with an increased risk of weight gain, worsening of insulin sensitivity, high blood pressure, endothelial dysfunction, early atherosclerotic changes in the vascular wall and left ventricular diastolic dysfunction. These complications were more consistently reported in patients with classic than non-classic CAH and were in part related to hormonal and functional abnormalities associated with this disorder and/or to the impact of over- and undertreatment. An analysis of available studies suggests that individuals with classic CAH are at increased cardiometabolic risk. Excess cardiovascular and metabolic morbidity is likely multifactorial, related to glucocorticoid overtreatment, imperfect adrenal hormone replacement therapy, androgen excess and adrenomedullary failure. Cardiometabolic effects of new therapeutic approaches require future targeted studies.

Temporal Trends in Acute Adrenal Insufficiency Events in Children With Congenital Adrenal Hyperplasia During 2019-2022.

Background: It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events. Aim: Study temporal trends of AI related AE in the I-CAH Registry. Methods: In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019. Results: In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 (P = .01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort (P = .02). Conclusion: The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring.

Plasma 21-deoxycortisone: a sensitive additive tool in 21-hydroxylase deficiency in newborns.

OBJECTIVE, DESIGN, AND METHODS: Although 17-hydroxyprogesterone (17OHP) has historically been the steroid assayed in the diagnosis of congenital adrenal 21-hydroxylase deficiency (CAH-21D), its C11-hydroxylated metabolite, 21-deoxycortisol (21DF), which is strictly of adrenal origin, is assayed in parallel in this pathology. This steroid (21DF) is oxidized by 11beta-hydroxysteroid dehydrogenase type 2 into 21-deoxycortisone (21DE). In the context of CAH-21D confirmation testing, confounding factors (such as intensive care unit admission, stress, prematurity, early sampling, and variations of sex development) can interfere with the interpretation of the gold-standard biomarkers (17OHP and 21DF). Since its tissue concentrations are especially high in the placenta, we hypothesized that 21DE quantification in the neonatal periods could be an interesting biomarker in addition to 17OHP and 21DF. To verify this hypothesis, we developed a new mass spectrometry-based assay for 21DE in serum and applied it to newborns screened for CAH-21D. RESULTS: In newborns with CAH-21D, the mean serum levels of 21DE reached 17.56 ng/mL (ranging from 8.58 ng/mL to 23.20 ng/mL), and the mean 21DE:21DF ratio was 4.99. In contrast, in newborns without CAH-21D, the 21DE serum levels were low and not statistically different from the analytical 21DE limit of quantification (0.01 ng/mL). CONCLUSION: Basal serum 21DE appears to be a novel sensitive and specific biomarker of CAH-21D in newborns.

Relationship between adipokines and androgens in children and young adults with congenital adrenal hyperplasia.

Introduction: Children and young adults with congenital adrenal hyperplasia (CAH) are at increased risk of obesity and insulin resistance. There is evidence that children with CAH have increased visceral adiposity, which has been linked to metabolic syndrome and cardiovascular disease (CVD). The adipokine adiponectin has been shown to correlate with reduced metabolic risk, whereas the adipokines visfatin and leptin have been linked to visceral fat and adipocyte inflammation and can serve as biomarkers of increased metabolic risk. Few studies to date have characterized adipokine levels in children and young adults with congenital adrenal hyperplasia. We sought to investigate the relationship between adiponectin, leptin and visfatin levels to metabolic risk factors and androgen levels in children and young adults with CAH. Methods: Fasting blood was obtained for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol (TC), triglycerides (TG) and HbA1c, as well as standard laboratory tests to assess adrenal control, from children with CAH due to 21-hydroxylase deficiency. HOMA-IR was calculated based on fasting glucose and insulin. Anthropomorphic measurements of BMI and waist-to-hip ratio were also obtained. Results: Adiponectin and androstenedione were inversely correlated (R = -0.57, p =0.016). There was a positive correlation between leptin and BMI percentile (R = 0.63, p <0.001) as well as leptin and HOMA-IR (R = 0.63, p <0.01). Glucocorticoid dose had a positive correlation with HOMA-IR (R=0.56, p = 0.021). Visfatin was inversely correlated with HDL cholesterol (R = -0.54, p = 0.026) and total cholesterol (R = -0.49, p <0.05). Overweight children and young adults had a significantly higher leptin (p = 0.02) and HOMA-IR (p=0.001) than non-overweight children and young adults. Conclusion: The inverse relationship between adiponectin and androstenedione suggests that better CAH control can reduce the risk of insulin resistance and metabolic syndrome. However, a high glucocorticoid dose appears to increase the risk of insulin resistance, underscoring the delicate balance required when treating CAH.

Long-read sequencing solves complex structure of CYP21A2 in a large 21-hydroxylase deficiency cohort.

CONTEXT: Genetic testing for 21-hydroxylase deficiency (21-OHD) is always challenging. Current approaches, short-read sequencing and multiplex ligation-dependent probe amplification (MLPA), are insufficient for the detection of chimeric genes or complicated variants from multiple copies. Recently developed long-read sequencing (LRS) can solve this problem. OBJECTIVE: To investigate the clinical utility of LRS in precision diagnosis of 21-hydroxylase deficiency. METHODS: In the cohort of 832 patients with 21-OHD, the current approaches provided the precise molecular diagnosis for 81.7% (680/832) of cases. LRS was performed to solve the remaining 144 cases with complex chimeric variants and eight cases with variants from multiple copies. Clinical manifestations in patients with continuous deletions of CYP21A2 extending to TNXB (namely CAH-X) were further evaluated. RESULTS: Using LRS in combination with previous genetic test results, a total of 16.9% (281/1664) CYP21A1P/CYP21A2 or TNXA/TNXB chimeric alleles were identified in 832 patients, with CYP21A1P/CYP21A2 accounting for 10.4% and TNXA/TNXB for 6.5%. The top three common chimeras were CYP21 CH-1, TNX CH-1 and TNX CH-2, accounting for 77.2% (217/281) of all chimeric alleles. The eight patients with variants on multiple copies of CYP21A2 were accurately identified with LRS. The prevalence of CAH-X in our cohort was 12.1%, and a high frequency of connective tissue-related symptoms was observed in CAH-X patients. CONCLUSION: LRS can detect all types of CYP21A2 variants, including complex chimeras and pathogenic variants on multiple copies in patients with 21-OHD, which could be utilized as a first-tier routine test for the precision diagnosis and categorization of congenital adrenal hyperplasia.

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.

Current Advances in the Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.

Congenital Adrenal Hyperplasia - A Comprehensive Review of Genetic Studies on 21-Hydroxylase Deficiency from India.

Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the CYP21A2 gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene CYP21A1P imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of CYP21A2 gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of CYP21A2 mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on CYP21A2 gene reported from India. The results of these studies insist the compelling need for large-scale CYP21A2 genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of CYP21A2 gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.

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.

Abiraterone in Classic Congenital Adrenal Hyperplasia: Results of Medical Therapy Before Adrenalectomy.

We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.

Genetic Disruption of cyp21a2 Leads to Systemic Glucocorticoid Deficiency and Tissues Hyperplasia in the Teleost Fish Medaka (Oryzias latipes).

cytochrome P-450, 21-hydroxylase (cyp21a2), encodes an enzyme required for cortisol biosynthesis, and its mutations are the major genetic cause of congenital adrenal hyperplasia (CAH) in humans. Here, we have generated a null allele for the medaka cyp21a2 with a nine base-pair insertion which led to a truncated protein. We have observed a delay in hatching and a low survival rate in homozygous mutants. The interrenal gland (adrenal counterpart in teleosts) exhibits hyperplasia and the number of pomca-expressing cells in the pituitary increases in the homozygous mutant. A mass spectrometry-based analysis of whole larvae confirmed a lack of cortisol biosynthesis, while its corresponding precursors were significantly increased, indicating a systemic glucocorticoid deficiency in our mutant model. Furthermore, these phenotypes at the larval stage are rescued by cortisol. In addition, females showed complete sterility with accumulated follicles in the ovary while male homozygous mutants were fully fertile in the adult mutants. These results demonstrate that the mutant medaka recapitulates several aspects of cyp21a2-deficiency observed in humans, making it a valuable model for studying steroidogenesis in CAH.

Challenging Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency: Case Series and Novel Variants of CYP21A2 Gene.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the CYP21A2 gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The CYP21A2 gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, CYP21A2 and its pseudogene CYP21A1P are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype-phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies.

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.

Isotretinoin-unresponsive acne as a sign of a congenital disorder: a case of 21-hydroxylase deficiency.

Acne is a multifactorial and common disorder among young people and a frequent reason for dermatology consultation. When moderate-to-severe acne is not responsive to conventional treatments, oral isotretinoin is a very effective solution. However, there are cases in which this treatment fails to produce the expected results. In this case, an 18-year-old male patient with acne, unresponsive to traditional acne therapies, experienced only a partial benefit from oral isotretinoin. Endocrinology consultation and hormonal work-up revealed androgen metabolism anomalies suggestive of a non-classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In this case report, the authors discuss when to suspect, how to diagnose, and how to manage similar cases.

Landscape of congenital adrenal hyperplasia cases in adult endocrinology clinics of Türkiye-a nation-wide multicentre study.

BACKGROUND AND AIMS: Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive pattern. The clinical and biochemical manifestations of the disorder are diverse, ranging from varying degrees of anomalies of the external genitalia to life-threatening adrenal insufficiency. This multicenter study aimed to determine the demographics, biochemical, clinical, and genetic characteristics besides the current status of adult patients with CAH nationwide. METHODS: The medical records of 223 patients with all forms of CAH were evaluated in the study, which included 19 adult endocrinology clinics. A form inquiring about demographical, etiological, and genetic (where available) data of all forms of CAH patients was filled out and returned by the centers. RESULTS: Among 223 cases 181 (81.16%) patients had 21-hydroxylase deficiency (21OHD), 27 (12.10%) had 11-beta-hydroxylase deficiency (110HD), 13 (5.82%) had 17-hydroxylase deficiency (17OHD) and 2 (0.89%) had 3-beta-hydroxysteroid-dehydrogenase deficiency. 21OHD was the most prevalent CAH form in our national series. There were 102 (56.4%) classical and 79 (43.6%) non-classical 210HD cases in our cohort. The age of the patients was 24.9 ± 6.1 (minimum-maximum: 17-44) for classical CAH patients and 30.2 ± 11.2 (minimum-maximum: 17-67). More patients in the nonclassical CAH group were married and had children. Reconstructive genital surgery was performed in 54 (78.3%) of classical CAH females and 42 (77.8%) of them had no children. Thirty-two (50.8%) NCAH cases had homogenous and 31 (49.2%) had heterogeneous CYP21A2 gene mutations. V281L pathological variation was the most prevalent mutation, it was detected in 35 (55.6%) of 21OHD NCAH patients. CONCLUSION: Our findings are compatible with the current literature except for the higher frequency of 110HD and 17OHD, which may be attributed to unidentified genetic causes. A new classification for CAH cases rather than classical and non-classical may be helpful as the disease exhibits a large clinical and biochemical continuum. Affected cases should be informed of the possible complications they may face. The study concludes that a better understanding of the clinical characteristics of patients with CAH can improve the management of the disorder in daily practice.

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.

Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency through molecular genetic analysis of the CYP21A2 gene.

PURPOSE: Deficiency of 21-hydroxylase (21-OHD) is an autosomal recessively inherited disorder that is characterized by adrenal insufficiency and androgen excess. This study was performed to investigate the clinical utility of prenatal diagnosis of 21-OHD using molecular genetic testing in families at risk. METHODS: This study included 27 pregnant women who had previously borne a child with 21-OHD. Fetal tissues were obtained using chorionic villus sampling (CVS) or amniocentesis. After the genomic DNA was isolated, Sanger sequencing of CYP21A2 and multiplex ligation-dependent probe amplification were performed. The clinical and endocrinological findings were reviewed retrospectively. RESULTS: A total of 39 prenatal genetic tests was performed on 27 pregnant women and their fetal tissues. The mean gestational age at the time of testing was 11.7 weeks for CVS and 17.5 weeks for amniocentesis. Eleven fetuses (28.2%) were diagnosed with 21-OHD. Among them, 10 fetuses (90.9%) harbored the same mutation as siblings who were previously diagnosed with 21-OHD. Among these, 4 fetuses (3 males and 1 female) identified as affected were born alive. All 4 patients have been treated with hydrocortisone, 9α-fludrocortisone, and sodium chloride since a mean of 3.7 days of life. The male patients did not show hyponatremia and dehydration, although they harbored pathogenic variants associated with the salt-wasting type of 21-OHD. CONCLUSION: This study demonstrated the diagnostic efficacy and clinical consequences of diagnosis by prenatal genetic testing in families at risk for 21-OHD. All patients identified as affected were treated with hydrocortisone and 9α-fludrocortisone early after birth, which can prevent a life-threatening adrenal crisis.

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.

[The androgenital syndrome: Don't just think about it in childhood!] / Das adrenogenitale Syndrom: Nicht nur im Kindesalter daran denken!

The androgenital syndrome: Don't just think about it in childhood!In adrenogenital syndrome, the body permanently produces too many male sex hormones. Rare, congenital metabolic diseases are usually discovered in infancy and can be treated at an early stage treated at an early stage, but sometimes they only become apparent in adolescence and adulthood.This article provides background knowledge for GPs.

Predictors of Cardiovascular Morbidities in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

CONTEXT: The prevalence of cardiovascular and metabolic complications among adults with 21-hydroxylase deficiency (21OHD) is unknown. OBJECTIVE: We sought to determine the prevalence of cardiovascular and metabolic morbidities among adults with 21OHD and to identify clinical factors and biomarkers associated with cardiovascular outcomes. METHODS: A 10-year retrospective cross-sectional analysis was conducted on adult patients with confirmed 21OHD, aged 18 to 70 years, who had at least one clinical visit for assessment at the University of Michigan. The presence of cardiovascular diseases (CVDs) and other metabolic comorbidities was extracted from medical records based on International Classification of Diseases (ICD) codes. Medical treatments, glucocorticoid (GC) and mineralocorticoid doses, as well as specific biomarkers of disease control since age 18, were collected for analysis. RESULTS: A total of 254 patients with 21OHD, median age of 35 years (interquartile range, 28.25-46 y), were included in the analysis. The prevalence of CVDs in the entire cohort was 7.5%. An increase in prevalence was seen from early adulthood, reaching 25% in patients older than 60 years. Increasing age (adjusted odds ratio [OR], 1.05; 95% CI, 1.01-1.09), hypertension (OR, 4.27; 95% CI, 1.41-12.92), and higher GC doses (OR, 1.51; 95% CI, 1.11-2.06) were significantly associated with prevalent CVDs. Higher plasma renin activity was significantly associated with CVDs (OR, 1.07; 95% CI, 1.01-1.15) but not other biochemical markers of disease. CONCLUSION: Cardiometabolic morbidities are prevalent among adults with 21OHD. Hypertension, age, and GC exposure are the main predictive factors of established CVDs in our cohort.