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Corticosteroids are so vital for organ maturation that reduced corticosteroid signaling during postembryonic development causes death in terrestrial vertebrates. Indeed, death occurs at metamorphosis in frogs lacking proopiomelanocortin (pomc) or the glucocorticoid receptor (GR; nr3c1). Some residual corticosteroids exist in pomc mutants to activate the wild-type (WT) GR and mineralocorticoid receptor (MR), and the elevated corticosteroids in GR mutants may activate MR. Thus, we expected a more severe developmental phenotype in tadpoles with inactivation of 21-hydroxylase, which should eliminate all interrenal corticosteroid biosynthesis. Using CRISPR/Cas9 in Xenopus tropicalis , we produced an 11-base pair deletion in cyp21a2 , the gene encoding 21-hydroxylase. Growth and development were delayed in cyp21a2 mutant tadpoles, but unlike the other frog models, they survived metamorphosis. Consistent with an absence of 21-hydroxylase, mutant tadpoles had a 95% reduction of aldosterone in tail tissue, but they retained some corticosterone (∼40% of WT siblings), an amount, however, too low for survival in pomc mutants. Decreased corticosteroid signaling was evidenced by reduced expression of corticosteroid-response gene, klf9 , and by impaired negative feedback in the hypothalamus-pituitary-interrenal axis with higher messenger RNA expression levels of crh , pomc , star , and cyp11b2 and an approximately 30-fold increase in tail content of progesterone. In vitro tail-tip culture showed that progesterone can transactivate the frog GR. The inadequate activation of GR by corticosterone in cyp21a2 mutants was likely compensated for by sufficient corticosteroid signaling from other GR ligands to allow survival through the developmental transition from aquatic to terrestrial life. [ABSTRACT FROM AUTHOR]

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders that occur due to defects in steroid synthesis. It is characterised by a deficiency of adrenocortical hormones and an excess of steroid precursors. A deficiency of 21-hydroxylase is the most common type, constituting 90% of the cases. The authors hereby, report a case of a one-month-old baby who presented to the Paediatric Emergency Department with typical features of the salt-wasting form of CAH. The diagnosis was confirmed with elevated levels of 17-hydroxyprogesterone and a Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2) gene mutation. The child was managed with hydrocortisone, fludrocortisone and salt supplementation, along with symptomatic and supportive care. The child is still under regular follow-up and is doing well.

The objective of the study was to evaluate the profile and diagnostic significance of serum autoantibodies in infertile patients with premature ovarian insufficiency (POI). The pilot study included 26 patients of reproductive age with POI and diminished ovarian reserve who received complex treatment using new surgical technologies (Group 1) and 18 patients without POI (Group 2). The profile of serum autoantibodies, including anti-ovarian antibodies, antibodies against thyroid peroxidase (TPO), steroidogenic enzymes, and steroid and gonadotropic hormones, was studied using modified ELISAs and human recombinant steroidogenic enzymes (CYP11A1, CYP19A1, CYP21A2). Patients in Group 1 had higher levels of IgG autoantibodies against steroidogenic enzymes, estradiol, progesterone, and TPO than those in Group 2. Tests for IgG antibodies against CYP11A1, CYP19A1, and CYP21A2 exhibited high sensitivity (65.4–76.9%), specificity (83.3–89.9%), and AUC values (0.842–0.910) for POI, the highest in the first test. Three-antibodies panel screening showed higher diagnostic accuracy (84.1% versus 75–79.6%). The levels of these antibodies correlated with menstrual irregularities and a decrease in the antral follicle count. Thus, antibodies against CYP11A1, CYP19A1, and CYP21A2 have a high diagnostic value for POI. Three-antibody panel screening may improve the accuracy of POI diagnosis and be useful for identifying high-risk groups, early stages of the disease, and predicting POI progression. [ABSTRACT FROM AUTHOR]

Background: Congenital adrenal hyperplasia (CAH) is an autosomal recessive endocrine disorder resulting in 21-hydroxylase enzyme deficiency. Nonclassical congenital adrenal hyperplasia is commonly found in adult patients with menstrual disorders, growth delays, secondary sexual characteristic abnormalities, or infertility. Diagnosing and managing CAH presents several challenges that can hinder patients from achieving therapeutic targets. Case Presentation: A 19-year-old female was referred from the Internal Medicine Polyclinic to the Reproductive Endocrinology and Infertility Polyclinic at Dr. Soetomo General Academic Hospital (RSUD Dr. Soetomo), presenting with primary amenorrhea and no breast development. Examination revealed signs of virilization, such as hirsutism, acne, and clitoromegaly. Ultrasound examination showed a hypoplastic uterus with normal ovaries. Elevated serum 17-OHP and testosterone from laboratory examination confirmed the diagnosis. Treatment with glucocorticoid replacement therapy using hydrocortisone, along with antiandrogenic contraceptive pills, showed therapeutic progress within six months. Discussion: Diagnosing CAH is challenging and often results in delays in patients receiving appropriate care. The primary therapeutic goal of CAH is to prevent hyperandrogenism and provide glucocorticoid replacement therapy to suppress ACTH activity. Long-term administration of hydrocortisone and contraceptive pills for puberty induction is a viable and accessible option. However, long-term therapy can lead to side effects that impact the patient. Conclusion: There are several challenges in diagnosing and managing congenital CAH. Long-term management should be personalized, prioritizing the patient's goals and maximizing the benefits of multidisciplinary therapy. [ABSTRACT FROM AUTHOR]

\nIntroduction: Quantifying differences in service provision for children and young people (CYP) living with congenital adrenal hyperplasia (CAH) across the UK. Methods: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH and via the “Living with CAH” support group mailing list. Results: Total of 195 responses relating to patients aged 0–20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were “completely satisfied” with the service provided, compared to 68% of carers and 76% of patients. While 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further “unsure” responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots and 12% reporting regular urinary steroid metabolites. Conclusion: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes. Congenital adrenal hyperplasia (CAH) is a lifelong condition where the body does not produce enough steroids, and thus patients need to take daily steroid replacement. There are differences of opinion in how CAH is treated, and we aimed to find out about these differences in the UK. We surveyed children and young people living with CAH, their parents or carers, and doctors and nurses who look after them throughout the UK. We received 152 responses from carers, 43 from patients, and 34 from clinicians from a total of 33 different clinics. Overall satisfaction with services was high, although, while 94% of clinicians said they provided formal training to families with CAH, over 80% of both patients and carers said that they had not attended what they considered formal training. Most patients and carers said that they would like to engage with further training. Clinicians said they wanted better access to other support for patients, including psychologists. Treatment of CAH was generally in keeping with international guidelines. New methods of monitoring, such as dripping blood onto a card instead of attending hospital for a formal blood test, are increasing with two-thirds of clinicians reporting this method being used. In conclusion, there is good satisfaction with care provision among patients and carers with CAH in the UK. However, there are opportunities for increasing psychological support and family education about the condition to further improve the lives of those living with this disease. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is a heterogeneous group of autosomal recessive disorders due to defects in adrenal steroid biosynthesis. In about 90% of patients, CAH is caused by pathogenetic variants in CYP21A2 gene, impairing the function of 21-hydroxylase (21-OH) enzyme. CAH can present as classical form (simple virilizing or salt wasting) or as non-classical form (NC-CAH). NC-CAH is due to pathogenetic variants in the CYP21A2 gene that result in 20–70% residual activity of 21-hydroxylase. Early diagnosis may be missed, mainly in childhood, jeopardizing long-term outcome. This paper will review some information on clinical findings, symptoms, diagnostic approaches, and treatments of NC-CAH in childhood, allowing better management and long-term outcome.

Congenital adrenal hyperplasia (CAH) is a heterogeneous group of autosomal recessive disorders due to defects in adrenal steroid biosynthesis. In about 90% of patients, CAH is caused by pathogenetic variants in CYP21A2 gene, impairing the function of 21-hydroxylase (21-OH) enzyme. CAH can present as classical form (simple virilizing or salt wasting) or as non-classical form (NC-CAH). NC-CAH is due to pathogenetic variants in the CYP21A2 gene that result in 20–70% residual activity of 21-hydroxylase. Early diagnosis may be missed, mainly in childhood, jeopardizing long-term outcome. This paper will review some information on clinical findings, symptoms, diagnostic approaches, and treatments of NC-CAH in childhood, allowing better management and long-term outcome. [ABSTRACT FROM AUTHOR]

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders that occur due to defects in steroid synthesis. It is characterised by a deficiency of adrenocortical hormones and an excess of steroid precursors. A deficiency of 21-hydroxylase is the most common type, constituting 90% of the cases. The authors hereby, report a case of a one-month-old baby who presented to the Paediatric Emergency Department with typical features of the salt-wasting form of CAH. The diagnosis was confirmed with elevated levels of 17-hydroxyprogesterone and a Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2) gene mutation. The child was managed with hydrocortisone, fludrocortisone and salt supplementation, along with symptomatic and supportive care. The child is still under regular follow-up and is doing well. [ABSTRACT FROM AUTHOR]

Background: We recently reported that metformin administration has substantial effects on steroid hormone concentrations. In this study, we specifically explored which enzymatic activities were affected before a first treatment versus after a time of metformin treatment. Material and Methods: Twelve male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and seven female subjects (57.2 ± 18.9 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg) were recruited based on an indication of metformin. Prior to the first intake of metformin and after 24 h, urine collections were performed. Urine steroid analysis was completed using gas chromatography–mass spectrometry. Results: The average reduction in steroid hormone concentrations after the metformin treatment was substantial and relatively equally distributed in all metabolites and the sum of all metabolites with 35.4%. An exception was dehydroepiandrosterone, with a decrease of almost three hundred percent of average concentration. In addition, the sum of all cortisol metabolites and 18-OH cortisol (indicative of oxidative stress) were lower after the metformin treatment. Furthermore, significant inhibition of 3ß-HSD activity was detectable. Discussion: Effects prior to and after the metformin treatment on inhibiting 3ß-HSD activity were detected in line with findings from others. Furthermore, the pattern of a reduction, for example, in the sum of all glucocorticoids following the metformin treatment supported an effect on oxidative stress, which was further supported by the reduction in 18-OH cortisol. Nevertheless, we do not understand all steps in the complex pattern of the enzymes that affect steroid hormone metabolism and, consequently, further studies are necessary to improve our understanding. [ABSTRACT FROM AUTHOR]

Context: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids. Objective: To investigate LTL in children with CAH. Methods: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1±0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z. Results: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, −0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (−0.29, P=0.012), in overtreated than in optimally treated patients (−0.07, P=0.002), and patients receiving prednisolone compared with hydrocortisone (−0.34, P< 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P>0.05). Conclusion: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment. [ABSTRACT FROM AUTHOR]

Corticosteroids are so vital for organ maturation that reduced corticosteroid signaling during postembryonic development causes death in terrestrial vertebrates. Indeed, death occurs at metamorphosis in frogs lacking proopiomelanocortin (pomc) or the glucocorticoid receptor (GR; nr3c1). Some residual corticosteroids exist in pomc mutants to activate the wild-type (WT) GR and mineralocorticoid receptor (MR), and the elevated corticosteroids in GR mutants may activate MR. Thus, we expected a more severe developmental phenotype in tadpoles with inactivation of 21-hydroxylase, which should eliminate all interrenal corticosteroid biosynthesis. Using CRISPR/Cas9 in Xenopus tropicalis , we produced an 11-base pair deletion in cyp21a2 , the gene encoding 21-hydroxylase. Growth and development were delayed in cyp21a2 mutant tadpoles, but unlike the other frog models, they survived metamorphosis. Consistent with an absence of 21-hydroxylase, mutant tadpoles had a 95% reduction of aldosterone in tail tissue, but they retained some corticosterone (∼40% of WT siblings), an amount, however, too low for survival in pomc mutants. Decreased corticosteroid signaling was evidenced by reduced expression of corticosteroid-response gene, klf9 , and by impaired negative feedback in the hypothalamus-pituitary-interrenal axis with higher messenger RNA expression levels of crh , pomc , star , and cyp11b2 and an approximately 30-fold increase in tail content of progesterone. In vitro tail-tip culture showed that progesterone can transactivate the frog GR. The inadequate activation of GR by corticosterone in cyp21a2 mutants was likely compensated for by sufficient corticosteroid signaling from other GR ligands to allow survival through the developmental transition from aquatic to terrestrial life. [ABSTRACT FROM AUTHOR]

Steroid 21-hydroxylase is an enzyme of the steroid pathway that is involved in the biosynthesis of cortisol and aldosterone by hydroxylation of 17α-hydroxyprogesterone and progesterone at the C21 position. Mutations in CYP21A2 , the gene encoding 21-hydroxylase, cause the most frequent form of the autosomal recessive disorder congenital adrenal hyperplasia (CAH). In this study, we generated a humanized 21-hydroxylase mouse model as the first step to the generation of mutant mice with different CAH-causing mutations. We replaced the mouse Cyp21a1 gene with the human CYP21A2 gene using homologous recombination in combination with CRISPR/Cas9 technique. The aim of this study was to characterize the new humanized mouse model. All results described are related to the homozygous animals in comparison with wild-type mice. We show analogous expression patterns of human 21-hydroxylase by the murine promoter and regulatory elements in comparison to murine 21-hydroxylase in wild-type animals. As expected, no Cyp21a1 transcript was detected in homozygous CYP21A2 adrenal glands. Alterations in adrenal gene expression were observed for Cyp11a1 , Star , and Cyb11b1. These differences, however, were not pathological. Outward appearance, viability, growth, and fertility were not affected in the humanized CYP21A2 mice. Plasma steroid levels of corticosterone and aldosterone showed no pathological reduction. In addition, adrenal gland morphology and zonation were similar in both the humanized and the wild-type mice. In conclusion, humanized homozygous CYP21A2 mice developed normally and showed no differences in histological analyses, no reduction in adrenal and gonadal gene expression, or in plasma steroids in comparison with wild-type littermates. [ABSTRACT FROM AUTHOR]

The article comments on a study which evaluated the use of crinecerfont in a first clinical application of a corticotropin-releasing hormone (CRH) antagonist in the treatment of congenital adrenal hyperplasia. It cautions potential changes in the function of systems and organs when administering a nonpeptidic CRH antagonist such as crinecerfont. It discusses alterations in the production of adrenocortical hormones in classic CAH due to deficiency in the enzyme 21-hydroxylase.

Summary: The relationship between androgen excess and bone health in patients with congenital adrenal hyperplasia (CAH) with 21-hydroxylase (21-OH) deficiency is not fully understood. This study demonstrated positive correlations between androgen hormones and bone mineral density (BMD) in CAH women with 21-OH deficiency. Purpose: This study aims to assess BMD and its association with androgen excess in women with CAH. Methods: We enrolled 92 women with CAH with 21-OH deficiency and retrospectively reviewed their clinical features, hormone concentrations, body composition, glucocorticoid (GC) dose, and BMD. Results: BMD was not different according to the subtypes of CAH. BMD at the lumbar spine was lower in women with CAH with regular menstruation than those with irregular menstruation (1.081 vs. 1.165 g/cm2, P < 0.05). BMD was lower in women with CAH with 17-hydroxyprogesterone (17-OHP) < 10 ng/mL than in those with ≥ 10 ng/mL (lumbar spine, 1.019 vs. 1.150 g/cm2; femur neck, 0.806 vs. 0.899 g/cm2; total hip, 0.795 vs. 0.943 g/cm2; all P < 0.05). After adjusting for age and BMI in correlation analyses, testosterone concentrations were positively correlated with lumbar spine, femur neck, and total hip BMD (r = 0.46, r = 0.38, and r = 0.35, respectively; all P < 0.05), while 17-OHP was positively correlated with lumbar spine BMD (r = 0.38, P < 0.01). In subgroup analysis, 17-OHP was positively correlated with BMD (lumbar spine, r = 0.22; femur neck, r = 0.22; total hip, r = 0.24; all P < 0.05) only in the group with a total cumulative dose of GC ≥ 156.0 g/m2. Conclusion: Androgen excess may have a protective effect on BMD in women with classic CAH and high cumulative doses of GC. [ABSTRACT FROM AUTHOR]

ObjectivesCD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison’s disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD.MethodsRecombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH.ResultsWe found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated.ConclusionWe have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.

Objectives: CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison's disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. Methods: Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH. Results: We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. Conclusion: We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease. [ABSTRACT FROM AUTHOR]

Non-classic congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency is one of the actual causes of hyperandrogenic manifestations at different age intervals. Timely diagnosis of the disease requires evaluating basal 17-hydroxyprogesterone levels during the comprehensive examination of patients of different age groups with clinical manifestations of androgen excess. This is especially important when examining adolescent girls and women of reproductive age with signs of hyperandrogenism. The obligatory examination of women when establishing the diagnosis of polycystic ovary syndrome should include the exclusion of non-classical NCAH according to all world recommendations. When 17-hydroxyprogesterone levels are in the range of 2–10 ng/ml, it is necessary to carry out cosyntropin stimulation test, which is recognized worldwide as the standard of NCAH diagnosis. The diagnostic threshold for NCAH diagnosis due to 21-hydroxylase deficiency is a level of 17-hydroxyprogesterone, basal or stimulated in cosyntropin test, higher than 10 ng/ml. Genetic testing — determining mutations in the CYP21A2 gene — is an important and necessary tool not only to confirm the diagnosis, but also to identify treatment of the patient with the diagnosis of NCAH and to determine the risk of emergence of a classic form in an unborn child in the presence of allele associated with classic САН. The recent recommendations from 2018 Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline are taken as the basis of the laboratory diagnostic criteria.

Context: The positive predictive value of newborn screening for congenital adrenal hyperplasia (CAH) in New Zealand is approximately 10%. The use of a second tier liquid chromatography-tandem mass spectrometry bloodspot steroid profile test with birth weight- or gestational age-adjusted screening cutoffs may result in further screening improvements.Methods: Three years of newborn screening data with additional second-tier steroid metabolites was evaluated (n = 167 672 births). Data from babies with a negative screening test and confirmed CAH cases were compared. First- and second-tier steroid measurements were correlated with both birth weight and gestational age. Analysis of variance was used to determine birth weight and gestational age groups. Screening cutoffs were determined and applied retrospectively to model screening performance.Results: First-tier immunoassay data correlated better with gestational age than with birth weight, but there was no difference with second-tier steroid measurements. Four distinct birth weight and gestational age groups were established for 17-hydroxyprogesterone and a steroid ratio measurement. Application of 97.5th percentile second-tier birth weight- or gestational age-adjusted cutoffs would result in 10 positive tests over the period of the study with 8 true-positive screens and 2 false-positive tests. The positive predictive value of screening would be increased from 10.8% to 80%.Conclusions: The use of either birth weight- or gestational age-adjusted cutoffs for second-tier screening tests can significantly reduce the false positive rate of newborn screening for CAH in New Zealand without loss in screening sensitivity. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a complicated condition genetically, clinically, and treatment wise. Genetically, there are numerus mutations with different effect on enzyme activity that make genetic diagnosis a challenge. Clinically, there are a wide range of presentations from asymptomatic patients to the severe life-threatening classic CAH. Both an asymptomatic heterozygote and a mildly affected non-classical patient can carry a 'severe' mutation and endow it to their offspring. We present a case of non-classic CAH and discuss the problematic relations between biochemical and genetic diagnosis. By integrating the seemingly contradicting literature, we provide a new simple tool to assess the risk of such patients to give birth to a child with classic CAH. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency varies clinically from asymptomatic or mild disease (non-classic), through 'simple virilizing' type, to a severe life-threatening condition (classic) due to adrenal insufficiency. 'Classic' CAH patient must harbor two 'severe' mutations, one on each of the alleles of the 21OH gene. Prevention of the birth of a child with classic disease is a challenge as the heterozygote carrier of 'severe' mutation is usually asymptomatic with normal biochemical tests, and a 'non-classic' patient can still carry a 'severe' mutation. Genetic diagnosis is a challenge, as there are numerus mutations including deletions, intronic mutations, double and triple mutations, and pseudogenes. In this article, we provide a new simple tool to assess the risk of a couple to give birth to a child with 'classic' disease. [ABSTRACT FROM AUTHOR]

Context: Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison's disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied.Objective: To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics.Methods: An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation.Results: The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%).Conclusion: One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC. [ABSTRACT FROM AUTHOR]

Introduction: Congenital adrenal hyperplasia (CAH) is a condition resulting from a deficiency in enzymes involved in the biosynthesis of steroid hormones in the adrenal cortex. Most cases of CAH are due to impaired 21- hydroxylase production, leading to insufficient cortisol and aldosterone synthesis. The classic form of CAH is subdivided into two types: salt-wasting and simple-virilizing. Case Report: A 2-year-old girl consulted the endocrinology department for reevaluation presenting ambiguous external genitalia. She was first diagnosed at 6 months with salt-wasting 21-hydroxylase-deficiency and was under treatment with hydrocortisone, fludrocortisone, and an additional salt intake of 1g/day. Upon clinical examination the patient had virilization (Prader stage II), increased 17- hydroxyprogesterone (91.3 ng/ml), androstenedione (1.77 ng/ml), and plasma renin (373.3 uUI/ml). She had also developed hypertension (130/90 mmHg). For this reason, the decision to cease fludrocortisone administration was made. The evolution of the patient was good, the hypertension subsided after discontinuing fludrocortisone treatment (105/65 mmHg), the laboratory results showed good control of 17-hydroxyprogesterone and ACTH, as well as normal levels of electrolytes, corticoid, and mineralocorticoid hormones. The diagnosis was revised, and the enzyme deficiency was described as simple-virilizing. On further follow-ups at 3, 4 and 5 years of age, the patient's hormonal levels were well controlled and the blood pressure stayed within the normal range. Discussions : Our case highlights the fact that treatment for this particular genetic disease should be closely monitored and adjusted in accordance to the evolution of the disease to avoid unwanted side effects. The disease was at first identified and treated as a salt-wasting form and although the administration of mineralocorticoids is crucial in preventing adrenal crisis in infants with salt loss, prolonged administration of fludrocortisone was the likely cause of hypertension. This aligns with current literature which suggests that the classification of 21- hydroxylase deficiency as salt-wasting and simple-virilizing is slowly falling out of use as CAH shows a high variability of clinical phenotypes. Moreover, although one mutation in the CYP21A2 gene was detected (P30L mutation), a second mutation could not be detected by the available test. Sequencing to find a possible rare mutation could have explained the unique phenotype of the disease because generally, the P30L mutation is associated with less severe forms of CAH. Conclusions: This case emphasizes the importance of monitoring infants with CAH and shows that the current classification of this disease is not always in accordance with its evolution, thus incorrect treatment can result in iatrogenic adverse effects. [ABSTRACT FROM AUTHOR]

Steroid 21-hydroxylase deficiency accounts for 95% of congenital adrenal hyperplasia (CAH) cases. Newborn screening has allowed for early detection of the disease, and currently, molecular analysis can identify the genotypes of these patients. Phenotype-genotype correlation has been well described in previous studies. In Costa Rica, there is no data about the genetic background of these patients, nor their phenotypic correlation. Design: Observational, retrospective, descriptive study based on the review of patient records who had a diagnosis of CAH and were performed molecular analysis using gene sequencing or MLPA during the period from 2006 to 2018 (N = 58). Objective: To describe the clinical and genetic characteristics of CAH patients due to 21-hydroxylase deficiency at the National Children's Hospital “Dr. Carlos Sáenz Herrera”, Caja Costarricense de Seguro Social (CCSS) in Costa Rica. Results: 53% (31/58) of the patients were male and 80% (37/46) were born full term; 72% (42/58) had salt wasting phenotype, 9% (5/58) simple virilizing phenotype and 19% (11/58) non-classic phenotype. The most frequent variants were c.292+5G>A in 26% (15/58) of patients and Del/Del in 21% (12/58) of them. Conclusions: The most frequent mutation in our study population was the c.292+5G>A, which was found in 15/58 patients. This rare variant has only been reported in three other studies so far but as an infrequent mutation in CAH patients. The genetic characteristics of Costa Rican patients differ from what has been documented worldwide and could respond to a founder effect.

Objective: To evaluate the impact of a liquid chromatography‐tandem mass spectrometry (LCMSMS) second‐tier test on newborn screening for congenital adrenal hyperplasia due to 21‐hydroxylase deficiency (CAH) in New Zealand. Design: In a prospective study, a LCMSMS method to measure 17‐hydroxyprogesterone (17OHP) was adapted to measure four additional steroids. Steroid concentrations were collected on all second‐tier CAH screening tests while protocols remained unchanged. Steroid ratio parameters with recommended or published screening cuts‐offs were evaluated for their impact on newborn screening performance. Measurements: Precision, accuracy, linearity and recovery of the second‐tier LCMSMS method were evaluated. Second‐tier specimens were divided in 3 groups; newborn screening bloodspots from neonates with confirmed CAH (n = 7) and 2 groups specimens from neonates with a birthweight (BW) ≤1500 g (n = 795) and with a BW > 1500 g (n = 806) with a negative newborn screening test. Six protocols using four steroid ratio parameters were evaluated. The sensitivity, specificity, false positive rate and positive predictive value of screening was calculated for each protocol. Results: The LCMSMS method was sufficiently accurate and precise to be used as a second‐tier test for CAH. Screening sensitivity remained at 100% for each protocol apart from (17OHP + androstenedione)/cortisol when the highest cut‐off of 3.75 was applied. The false positive rate was significantly improved when (17OHP + androstenedione)/cortisol and (17OHP + 21‐deoxycortisol)/cortisol were evaluated with cut‐offs of 2.5 and 1.5 respectively (P <.01) and both with a positive predictive value of 64%. Conclusions: A second‐tier LCMSMS newborn screening test for CAH offers significant improvements to screening specificity without any other changes to screening protocols. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome (APS) is a rare group of immune-mediated disorders, which are typically, but not exclusively, related to the presence of endocrine abnormalities. APS type 2 is the most common subtype of the syndrome, more often observed in adulthood, with a characteristic clinical triad, which includes adrenal insufficiency, autoimmune thyroiditis and diabetes mellitus type 1. Adrenal insufficiency is an essential and necessary clinical manifestation of the syndrome, as it is observed in 100 % of the cases, while it can be accompanied by hyperchloremic metabolic acidosis. Herein, we present a 23 years-old patient with adrenal insufficiency in the context of autoimmune polyglandular syndrome type 2 with coexisting autoimmune thyroiditis and metabolic acidosis with an increased anion gap attributed to prolonged malnutrition. Additionally, we analyze the main clinical features of adrenal insufficiency, which is a central component of autoimmune polyglandular syndrome; highlight characteristics that differentiate the major APS subtypes., Competing Interests: Declaration of competing interest There is no conflict of interest regarding this manuscript. All authors have read and have agreed with the final version., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80–90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.

Keywords: adrenal; 21-hydroxylase; human leukocyte antigen locus; extracellular matrix; Ehlers-Danlos syndrome; major histocompatibility locus; CYP21; cytochrome P450 EN adrenal 21-hydroxylase human leukocyte antigen locus extracellular matrix Ehlers-Danlos syndrome major histocompatibility locus CYP21 cytochrome P450 N.PAG N.PAG 12 01/15/21 20210111 NES 210111 Introduction Tenascin-X (TNX) is a large extracellular matrix protein discovered because its I TNXB i gene overlaps the I CYP21A2 i gene encoding steroid 21-hydroxylase (P450c21), whose mutations cause congenital adrenal hyperplasia (CAH). Human I CYP21A2 i encodes P450c21, in mice the I cyp21a1 i gene corresponding to I CYP21A1P i is active ([12], [13]), in cattle both genes function ([4], [14]), and some other mammals have single copies of this locus ([15]); thus the gene duplication post-dates mammalian speciation ([16]). Deletions in the gene causing 21OHD did not appear to extend into the XB gene, but deletions of the XA region were found in 14% of human chromosomes ([18], [19]), suggesting that the 2.7-kb cDNA arose from the XB gene ([17]). Although XA was abundantly expressed in the adrenal, its gene was truncated at its 5' end (compared to XB) by the gene duplication ([16]), suggesting that it is a pseudogene and that XB would be the more important locus. [Extracted from the article]

We aimed to compare detailed fat distribution and lipid profile between young adults with congenital adrenal hyperplasia due to 21‐hydroxylase enzyme deficiency and a control group. We also verified independent associations of treatment duration and daily hydrocortisone dose equivalent (HDE) with lipid profile within patients. This case–control study included 23 patients (7 male and 16 female) matched by an age range of young adults (18–31 years) with 20 control subjects (8 male and 12 female). Dual energy X‐ray absorptiometry was used to measure the fat distribution. Male patients demonstrated elevated indices of fat mass for total (7.7 ± 2.1 vs. 4.5 ± 1.3 kg/m2, p = 0.003), trunk (4.0 ± 1.2 vs. 2.2 ± 0.8 kg/m2, p = 0.005), android (0.63 ± 0.24 vs. 0.32 ± 0.15 kg/m2, p = 0.008), gynoid (1.34 ± 0.43 vs. 0.74 ± 0.24 kg/m2, p = 0.005), arm (0.65 ± 0.16 vs. 0.39 ± 0.10 kg/m2, p = 0.009), and leg regions (2.7 ± 0.8 vs. 1.6 ± 0.4 kg/m2, p = 0.005) than the control group, but not in females. However, female patients demonstrated elevated ratio of low‐density lipoprotein cholesterol to high‐density lipoprotein cholesterol (1.90 ± 0.46 vs. 1.39 ± 0.47, p = 0.009) than the control group, but not in males. Total fat mass was inversely correlated with total testosterone (r = −0.64, p = 0.014) and positively correlated with leptin in males (r = 0.75, p = 0.002). An elevated daily HDE (β = 0.43, p = 0.038 and β = 0.47, p = 0.033) and trunk to total fat mass ratio (β = 0.46, p = 0.025, and β = 0.45, p = 0.037) were independently correlated with impaired lipid profile markers. Although there is no altered lipid profile, male patients demonstrated an increased fat distribution. However, female patients presented with an impaired lipid profile marker but demonstrated close values of normal fat distribution. Interestingly, the dose of glucocorticoid therapy can have some role in the lipid mechanisms. [ABSTRACT FROM AUTHOR]

To explore how women with congenital adrenal hyperplasia (CAH) describe their experiences of gender role behavior, psychosexual development, and intimate relationships. CAH results in increased androgen exposure in affected females, and is the most common reason for unclear sex at birth. Women with CAH have been studied to find answers to the role of androgens in psychosexual development. Nevertheless, factors that may account for the variability of outcomes in women with CAH are unclear. This was a qualitative study with 13 Swedish women (aged ≥18 years) with CAH. Semi-structured interviews were analyzed using inductive content analysis. Direct quotes of patients' experiences derived from interview transcripts were sorted in categories, subcategories, and according to latent theme. The main categories were "forming identity" and "establishing relationships." Forming identity encompasses that of a girl, a tomboy, and/or a woman. Establishing relationships focuses on intimate relationships, pregnancy, and parenthood. A latent theme was interpreted as "shifting perspectives," with CAH being the main focus of some participants' lives but a side issue for others. These women's experiences are varied and describe shifting perspectives on how much CAH affects their lives. Health care providers can play an important role in helping women with CAH to separate what is caused by the condition and what is not. The long-term goal is to help girls and women to feel in control of their condition across their whole life. [ABSTRACT FROM AUTHOR]

In 2013 in territory Regional clinical hospital № 1 by him. prof. S. V. Ochapovskiy, Kuban interregional medico-genetic advice on program was examined 68 501 newborns. The method of research is to define 17aoksigidroprogesteron levei by immunofiuorescent analyses and CYP-21. The frequency of disease is 1:8069 of newborns. The eariy diagnoses of disease prevent the childrens death from solwasting crisis and encourage the correct choice of sexual characteristics in verilization of girls external genitalis.

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficiencies of enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiency which can be classical or non-classical. The severe form also called Classical Congenital Adrenal Hyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is not diagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. We report a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia. The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and life long oral Prednisolone and Fludrocortisone were prescribed.

Introduction and Aim: Congenital adrenal hyperplasia is an autosomal recessive disease caused by the deficiency of one of the enzymes of adrenal steroidogenesis, the most common of which is the deficiency of 21-hydroxylases. It represents a significant cause of morbidity and mortality in the pediatric population, especially in the absence of systematic neonatal screening in Morocco, which makes the management of these patients difficult for clinicians. This study aimed to describe the epidemiological, clinical, laboratory, evolutionary, and therapeutic profile of children followed for congenital adrenal hyperplasia at the pediatric endocrinology unit, Abderrahim Harrouchi Children's Hospital, Casablanca, Morocco. Materials and methods: A retrospective cross-sectional study including 184 children followed for congenital adrenal hyperplasia over a period of 11 years (from January 1, 2013, to December 31, 2023). The diagnosis was confirmed by molecular biology, and all clinical, laboratory, and radiological data were collected retrospectively from medical records., Results: The median age at diagnosis was 1.5 months (birth: 13 years). The consanguinity rate was 54.4% (n=100). A history of death in the family was found in 16.3% (n=30) of cases in a table of salt wasting and infections. The classic form was observed in 72% (n=132) of children compared to 28.3% (n=52) for the non-classical form. The virilizing form with salt wasting and the pure virilizing form represented 45.6% (n=84) and 26% (n=48) of cases, respectively. Deficiency in 21-hydroxylase was found in 91.8% (n=169) of children, while deficiency in 11-β-hydroxylase was identified in 4.9% (n=9) of cases, and in 3-β-hydroxysteroid dehydrogenase in 3.2% (n=6) of cases. A total of 40.7% (n=75) of children underwent corrective surgery of the external genitalia., Conclusion: Congenital adrenal hyperplasia is a group of rare diseases. The best therapeutic alternative would be newborn screening and antenatal diagnosis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bouarab et al.)

Familial hypobetalipoproteinaemia is a disorder of lipid metabolism characterized by low levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. ApoB-related familial hypolipoproteinemia is an autosomal condition with a codominance inheritance pattern. Non-classical congenital adrenal hyperplasia is an autosomal recessive disorder due to mutations in the CYP21A2, a gene encoding for the enzyme 21-hydroxylase, which results in an androgen excess production from adrenal source. We here present the case of a 25-year-old woman with NCAH showing decreased levels of total-cholesterol, low-density lipoprotein cholesterol and triglycerides. Her parent had digestive symptoms and severe hepatic steatosis with elevated liver enzymes, as well as decreased levels of total and low-density lipoprotein cholesterol. A genetic-molecular study of the proband identified a mutation in the APOB gene, which allowed a diagnosis of heterozygous ApoB-related hypolipoproteinaemia to be made., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40–82%). An additive effect on the reduction of enzymatic activity (1–17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH. • All novel amino acid changes had mild effects on enzyme function when expressed alone. • In vitro studies confirmed an additive effect between mild variants on the same allele, leading to a more severe phenotype. • In silico predictions were in line with the in vitro data except for the p.Leu461Pro variant. [ABSTRACT FROM AUTHOR]

Copyright of International Journal of Endocrinology / Mìžnarodnij Endokrinologìčnij Žurnal is the property of Zaslavsky O.Yu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder. [ABSTRACT FROM AUTHOR]

Copyright of Online Turkish Journal of Health Sciences (OTJHS) / Online Türk Sağlık Bilimleri Dergisi is the property of Oguz KARABAY and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Evidence of altered cholesterol and steroid hormones in autism is increasing. However, as boys are more often affected, evidence mainly relates to autistic males, whereas evidence for affected autistic girls is sparse. Therefore, a comprehensive gas chromatography mass spectrometry-based steroid hormone metabolite analysis was conducted from autistic girls. Results show increased levels of several steroid hormones, especially in the class of androgens in autistic girls such as testosterone or androstenediol. The increase of the majority of steroid hormones in autistic girls is probably best explained multifactorially by a higher substrate provision in line with the previously developed cholesterol hypothesis of autism.

Background: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare. Case Series: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age. Conclusions: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control. [ABSTRACT FROM AUTHOR]