Type Of Congenital Adrenal Hyperplasia Research Articles

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.

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

Novel co-occurrence of hypophosphatemic rickets with 46XY DSD (disorder of sex development) due to a CYP17A1 variant

17-α-hydroxylase deficiency causes a rare type of congenital adrenal hyperplasia (CAH). X-linked hypophosphatemic rickets (XLH) is a rare disorder caused by inactivating mutations in the PHEX gene. We report a novel co-occurrence of XLH with 46XY disorder of sex development due to 17-α-hydroxylase deficiency. A young child reared as a girl, presented as a toddler with genu varus, low phosphorus, normal calcium, and parathormone, and was treated as hypophosphatemic rickets. In early childhood, due to short stature and hypertension, the child was investigated for Turner syndrome. Ultrasound revealed intra-abdominal gonads and an absent uterus. The karyotype was 46XY. Investigations revealed low serum cortisol, renin, normal 17-hydroxyprogesterone, and aldosterone. A year later, a bilateral orchidectomy was performed. Two years later, she was referred to us for further management. Adrenocorticotrophic hormone (ACTH), cortisol, renin, deoxycorticosterone, and clinical exome were advised. She was lost to follow-up for 3 years. On follow-up in early adolescence, she was pre-pubertal; biochemical findings of hypophosphatemic rickets, elevated ACTH, low cortisol, and low normal aldosterone were noted. Clinical exome revealed variants in the CYP17A1 gene (homozygous) causing CAH (17-α-hydroxylase) and PHEX (hemizygous) gene causing XLH. Treatment with hydrocortisone, phosphate, cholecalciferol, and calcitriol was commenced. Hypertension is now well-controlled, but genu varus persists and may require surgical correction.

THU186 A Case Of 3beta-hydroxysteroid Dehydrogenase Type2 Deficiency Diagnosed By Whole Genome Sequencing In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: S. Chang: None. C. Kim: None. 3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare type of congenital adrenal hyperplasia (CAH) caused by HSD3B2 gene mutations. The estimated prevalence is less than 0.5% of all CAH and less than 1/1,000,000 at birth. It is a disorder of impaired steroidogenesis and sex steroid deficiency characterized by variable degrees of salt wasting, hypoglycemia, male incomplete masculinization and female virilization. Some newborns with 3βHSD2D have increased level of 17-hydroxyprogesterone (17OHP) that clinicians misdiagnose them as having classic 21-hydroxylase deficiency. A male newborn was referred to our hospital for generalized hyperpigmentation. Laboratory test showed hyponatremia, hyperkalemia and hypoglycemia. Hormonal study showed high level of adrenocorticotropic hormone, 17OHP, progesterone, renin activity, dehydroepiandrosterone (DHEA), androstenedione and low level of aldosterone. Clinically diagnosing with CAH, we administered glucocorticoid and mineralocorticoid replacement. We performed PCR sequencing for CYP21A2 gene mutation to confirm 21 hydroxylase deficiency but revealed normal result. After follow-up for 17 years with replacement treatment, he happened to have the opportunity to perform whole genome sequencing. Whole genome sequencing allowed to detect two pathogenic mutations in the HSD3B2 gene, described in compound heterozygosity (p.Arg249Ter and c.-149_143-1766del). One mutation (c.-149_143-1766del) is inherited from his father and the mother was not done for gene study. While there have been less than 100 cases of 3βHSD2D reported worldwide, in our best knowledge, this is the first case of genetically confirmed 3βHSD2D in Korea. Presentation: Thursday, June 15, 2023

P-588 A comparison of obstetrical and neonatal outcomes in patients with the hyperandrogenic states, polycystic ovarian syndrome(PCOS) and congenital adrenal hyperplasia(CAH): a retrospective population-database study.

Abstract Study question PCOS and CAH are associated with increases in pregnancy complications. Therefore, we evaluated differences in pregnancy and neonatal outcomes between women with PCOS and CAH. Summary answer When comparing these conditions PCOS was associated with pregnancy-induced hypertension and gestational diabetes, whereas CAH had more cesarean sections and small for gestational age infants. What is known already PCOS and CAH are causes of hyperandrogenism among women of reproductive age. Apart from causing hyperandrogenism, they also share characteristics such as menstrual irregularity, polycystic ovaries and insulin resistance with central adiposity. Several meta-analyses have associated PCOS with adverse obstetrical and neonatal outcomes with most studies finding an increased frequency of pregnancy-induced hypertension (PIH), preeclampsia, gestational diabetes (GDM), cesarean section (CS) and preterm delivery. CAH on the other hand, is associated with higher rates of CS and inconsistent evidence about increases in GDM, chorioamnionitis and congenital anomalies. Study design, size, duration A retrospective population-based study utilizing data from the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS), was performed. A dataset of all deliveries between 2004 and 2014 inclusively, was created. Within this group, all deliveries to women who had a diagnosis of PCOS or CAH and pregnancy were identified. Each subject had a delivery or maternal death to be included once per pregnancy. Participants/materials, setting, methods Descriptive analyses were performed to compare the demographic features among both groups, for which chi-squared tests were used. Multivariate logistic regression analysis was performed to calculate unadjusted and adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) and correct for any difference in baseline demographics (P < 0.05) between the groups. According to the Tri-Council Policy statement (2018), institutional review board (IRB) approval was not required, given that data was anonymous and publicly available. Main results and the role of chance A total of 15,179 women with either PCOS or CAH were included. Approximately 98% of those women (14,881) were diagnosed with PCOS, while the rest 2% (298) had CAH. The adjusted analysis for race, obesity, previous CS, multiple gestation and IVF yielded the following results. For pregnancy outcomes PIH (aOR=1.76; 95% CI: 1.12-2.77; p = 0.015) and GDM (aOR=1.68; 95% CI: 1.12-2.52; p = 0.012) were more common among women with PCOS, whereas no statistically significant results were detected for rates of placenta previa, preeclampsia or eclampsia superimposed on pre-existing hypertension or eclampsia. After additional adjusting for PIH and GDM, the delivery outcomes showed CS to be significantly less common in the PCOS group (aOR=0.59; 95% CI 0.44-0.80; p < 0.001), with no significant differences concerning preterm premature rupture of membranes, preterm delivery, abruptio placenta, chorioamnionitis, operative vaginal delivery, hysterectomy, postpartum hemorrhage, wound complications, maternal death and need for transfusion. In neonatal outcomes, women with CAH had higher percentages of SGA neonates (aOR=0.32; 95% CI 0.20-0.52; p < 0.001) and no difference in intrauterine fetal demise and congenital anomalies. Limitations, reasons for caution The limitations of our study are its retrospective nature and the fact that it relies on an administrative database. Furthermore, CAH type was not specified. Information on medication use and compliance was also lacking information about certain potential confounders such as parity, and duration of labor. Wider implications of the findings This is the first study to investigate the differences in obstetrical and neonatal outcomes between these two hyperandrogenic disorders and we noted that the majority of risks were similar, despite the difference in the pathophysiology of these conditions. Rates of certain complications differ and studies are needed to elucidate why. Trial registration number N/A

Factors influencing illness uncertainty in parents of children with congenital adrenal hyperplasia in a developing country: A cross-sectional study.

Illness uncertainty in parents of children with congenital adrenal hyperplasia (CAH) refers to parents' inability to create meaning in events related to their children having CAH. This may influence their role in caring for children with CAH. The study aimed to determine factors associated with illness uncertainty experienced by parents of children with CAH in a developing country. A cross-sectional study was conducted on 80 parents (43 mothers and 37 fathers) of children with CAH, selected using consecutive sampling methods. The Parent's Perception of Uncertainty Scale (PPUS) was used to measure the illness uncertainty levels. Data were collected from March 2020 to October 2020. Independent t-test and chi-square test were used to determine factors (parent's gender, age, educational level, monthly household income, number of children with CAH, history of child death due to CAH, child's age when first diagnosed with CAH, duration of therapy, gender change, type of CAH (salt wasting/SW or simple virilizing/SV), current gender, and genitoplasty) influencing illness uncertainty in parents. The mean scores of PPUS were 42.3 ± 12.91, and the majority of parents had a low PPUS score (49; 61%). Parents of children with SW-CAH showed higher uncertainty (44.2 ± 12.77) than those with SV-CAH (32.6 ± 8.86; p = 0.003). Parents who lost their children due to CAH were more likely to report a moderate illness uncertainty than parents who never experienced child mortality due to CAH (χ2(1, 80) = 4.893; p = 0.027). The factors significantly affecting uncertainty in parents of children with CAH determined in this study might help healthcare professionals, including nurses, to play a pivotal role in giving pertinent information regarding their children's health, disease, and therapy to help manage parental uncertainty.

Clinical and functional analyses of the novel STAR c.558C>A in a patient with classic lipoid congenital adrenal hyperplasia.

Objective: Congenital lipid adrenal hyperplasia (LCAH) is the most serious type of congenital adrenal hyperplasia and is caused by steroid-based acute regulatory (STAR) protein mutations. Herein, we report compound heterozygous mutations c.558C>A (p.S186R) and c.772C>T (p.Q258*) in a newborn 46 XY patient diagnosed with classic LCAH and explore their clinical and functional characteristics. Methods: Peripheral blood samples were collected from LCAH patient and their families. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. The functional consequence and ability to convert cholesterol into progesterone of the identified STAR Q258* and S186R mutations were analyzed by cell transfection and in vitro assays. Results: The proband was presented with severe glucocorticoid and mineralocorticoid deficiency, high adrenocorticotropic hormone, and enlarged adrenals. Heterozygous mutations p. S186R and p. Q258* in the STAR gene were identified in the patient, and her parents were carriers, which is consistent with an autosomal recessive disorder. The STAR p. Q258* mutation has been reported and generates a truncated protein. The p. S186R mutation is a novel variant that disrupts STAR. The residual STAR activities of p. S186R, p. Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins. Conclusion: Our findings reveal the molecular mechanisms underlying LCAH pathogenesis, further expanding the genotype and clinical spectrum of LCAH.

A rare case of salt wasting type of Congenital Adrenal Hyperplasia with Turner Syndrome

A rare case of salt wasting type of Congenital Adrenal Hyperplasia with Turner Syndrome

Genotype of congenital adrenal hyperplasia patients with testicular adrenal rest tumor

Testicular adrenal rest tumor (TART) is one of the important complications that can cause infertility in male patients with congenital adrenal hyperplasia (CAH) and should therefore be diagnosed and treated at an early age. The factors that result in TART in CAH have not been completely understood. The aim of this study is to evaluate the genotype-phenotype correlation in CAH patients with TART. MethodAmong 230 malepatients with CAH who were followed upwith regular scrotal ultrasonography in 11 different centers in Turkey, 40 patients who developed TARTand whose CAH diagnosis was confirmed by genetic testing were included in this study. Different approaches and methods were used for genotype analysis in this multicenter study. A few centers first screened the patients for the ten most common mutations in CYP21A2 and performed Sanger sequencing for the remaining regions only if these prior results were inconclusive while the majority of the departments adopted Sanger sequencing for the whole coding regions and exon-intron boundaries as the primary molecular diagnostic approach for patients with either CYP21A2 orCYP11B1 deficiency. The age of CAH diagnosis and TART diagnosis, type of CAH, and identified mutations were recorded. ResultsTART was detected in 17.4% of the cohort [24 patients with salt-wasting (SW) type, four simple virilizing type, and one with nonclassical type with 21-hydroxylase (CYP21A2) deficiency and 11 patients with 11-beta hydroxylase (CYP11B1) deficiency]. The youngest patients with TART presenting with CYP11B1 and CYP21A2 deficiency were of 2 and 4 years, respectively. Eight different pathogenic variants in CYP21A2were identified. The most common genotypes were c.293-13C>G/c.293-13C>G (31%) followed by c.955C>T/c.955C>T(27.6%) and c.1069C>T/c.1069C>T (17.2%). Seven different pathogenic variants were identified in CYP11B1. The most common mutation in CYP11B1 in our study was c.896T>C (p.Leu299Pro). ConclusionWe found that 83% TART patients were affected with SW typeCYP21A2 deficiency,and the frequent mutations detected were c.955C>T (p.Gln319Ter), c.293-13C>G in CYP21A2 and c.896T>C (p.Leu299Pro) inCYP11B1. Patients with CYP11B1 deficiency may develop TART at an earlier age. This study that examined the genotype–phenotype correlation in TART may benefit further investigations in larger series.

Syrian females with congenital adrenal hyperplasia: a case series

BackgroundOne of the most common types of congenital adrenal hyperplasia is an autosomal recessive disorder with 21-hydroxylase deficiency. The classical form, defined by cortisol insufficiency, is accompanied by prenatal androgen excess causing variable masculinization degrees of external genitalia in babies with a 46, XX karyotype.Cases presentationThese five case reports highlight the management of Syrian females aged between 0 and 32 years with congenital adrenal hyperplasia. Two of the patients have been raised as males, while two had reconstructive surgery and one had hormonal therapy. Becoming mother was achieved by two patientsConclusionThe integrated treatment of females with classical congenital adrenal hyperplasia CAH, which includes appropriate surgical procedures and controlled hormonal therapy, gives these females the opportunity to live as they are, and perhaps as mothers in the future.

Ethnic and National Differences in Congenital Adrenal Hyperplasia Incidence: A Systematic Review and Meta-Analysis

Background: Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions. Objectives: This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH. Methods: PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types. Results: This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient. Conclusions: This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.

Management challenges and therapeutic advances in congenital adrenal hyperplasia

Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.

D2 MTE4 Case 11: Adult CAH, how do I optimize treatment?

28 years, female, born of non-consanguineous marriage, assigned female gender had genital ambiguity and seizures on day 10 of life. She presented to us at 9 years with genital ambiguity and hyperpigmentation. Tanner stage A3P4B2, external genitalia: phallic like structure 4.5 cm, posterior labial fusion, single opening, no palpable gonads. Unstimulated 17 OHP 192 ng/ml, testosterone and DHEAS elevated, low basal cortisol, other biochemical parameters normal, CT scan- bilateral adrenal enlargement, so a diagnosis of simple virilizing type of congenital adrenal hyperplasia was made and was started on T. Hydrocortisone and T. Fludrocortisone, after which pigmentation decreased. Gender role and identity as female. Underwent clitoral reduction and vaginal reconstruction. She had spontaneous puberty with pubarche at 7 years, thelarche at 10.5 years and menarche at 12.5 years. Her 17 OHP remained elevated and had early epiphyseal fusion leading to short stature. She had hirsutism at 16 years so she was started on T. Dexamethasone but was again changed to Hydrocortisone as she developed cushingoid features after 2 years. She is married for past 3 years and is eumenorrhic but now presents with primary infertility. Recent investigations revealed 17 OHP 50 ng/ml (Target: 4-12 ng/ml) and T 6.3 nmol/l. Currently on T. Hydrocortisone divided in 5 doses and T. Fludrocortisone 150 mcg. How to further manage fertility and long-term complications.?

Clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry in rare types of congenital adrenal hyperplasia

BackgroundOur study aims to summarize the clinical characteristics of rare types of congenital adrenal hyperplasia (CAH) other than 21-hydroxylase deficiency (21-OHD), and to explore the clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry (LC-MS/MS) in rare CAH.MethodsWe retrospectively analysed the clinical data of 5 rare cases of CAH admitted to our hospital and summarized their clinical manifestations, auxiliary examinations, diagnosis and mutational spectrum.ResultsAfter gene sequencing, complex heterozygous variants were detected in all patients (2 cases were lipoid congenital adrenal hyperplasia (LCAH), 11β-hydroxylase deficiency (11β-OHD), 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD deficiency) and P450 oxidoreductase deficiency (PORD) each accounted for 1 case), which were consistent with their clinical manifestations. Among them, 4 novel variants were detected, including c.650 + 2 T > A of the StAR gene, c.1145 T > C (p. L382P) of the CYP11B1 gene, c.1622C > T (p. A541V) and c.1804C > T (p. Q602 *) of the POR gene. The LC-MS/MS results for steroid hormones in patients were also consistent with their genetic variants: 2 patients with LCAH showed a decrease in all steroid hormones; 11β-OHD patient showed a significant increase in 11-deoxycortisol and 11-deoxycorticosterone; patient with 3β-HSD deficiency showed a significant increase in DHEA; and PORD patient was mainly characterized by elevated 17OHP, progesterone and impaired synthesis of androgen levels.ConclusionsThe clinical manifestations and classification of CAH are complicated, and there are cases of missed diagnosis or misdiagnosis. It’s necessary to combine the analysis of clinical manifestations and auxiliary examinations for diagnosis; if necessary, LC-MS/MS analysis of steroid hormones or gene sequencing is recommended for confirming diagnosis and typing.

The Effect of Glucocorticoid therapy on Bone Mineral Density in Children and Adolescents with Congenital Adrenal Hyperplasia

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases caused by a deficiency in adrenal enzymes that lead to changes in cortisol and aldosterone levels. Objective: This study aimed to assess the bone mineral density of the spine and femoral head in children and adolescents aged 5 and 20 years, suffering from different types of congenital adrenal hyperplasia and treated with corticosteroids and to study the associated factors. Materials and method: We studies 44 patients, 26 girls and 18 boys, who were treated with corticosteroids with a physiological dose of 15-20 mg/m2 since infancy. A questionnaire was completed by patients and their parents admitted to the Endocrinology Clinic of Imam Reza Hospital of Mashhad. The patients' bone density was then measured, and the association with different factors, such as age, gender, height, weight, type of CAH, type and duration of receiving corticosteroids, the 17-hydroxyprogesterone level, bone activity markers, vitamin D level, and puberty stage, was analyzed, using SPSS software. Result: No significant correlation between the bone density level and variables such as the duration and dose of corticosteroid consumption, age, sex, time of diagnosis, 17-hydroxyprogesterone level, calcium, and phosphorus, was found. Other variables such as height, weight, puberty stage, and vitamin D levels were found to play a significant role in determining the bone density level.Conclusion: It is highly recommended to consider the side effects and complications when starting treatment with corticosteroids in patients with CAH. Bone densitometry should regularly be done, osteoporosis prophylaxis should be considered using weight-bearing exercises and calcium and vitamin D supplements, and the level of vitamin D should be monitored.

Disorders of Sex Development.

Disorders of Sex Development.

Mass spectrometry: an essential tool to be used in discrimination between causes of congenital adrenal hyperplasia, and its benefits versus radioimmunoassay

BackgroundMeasurement of multiple steroids, 17 hydroxyprogesterone, 11 deoxycortisol, and 21 deoxycortisol, is required to discriminate between congenital adrenal hyperplasia due to 21 hydroxylase deficiency and that due to 11 beta hydroxylase deficiency. This work aims at the selection of the more appropriate, cost-effective method among either mass spectrometry or radioimmunoassay for the quantitation of the previous steroids. In this study, blood samples were collected from 31 patients that were newly diagnosed with congenital adrenal hyperplasia; 17 hydroxyprogesterone and 21 deoxycortisol were assayed using tandem mass spectrometry. Eleven deoxycortisol was assayed using 2 methods: radioimmunoassay and tandem mass spectrometry.ResultsMeasuring 11 deoxycortisol using tandem mass spectrometry could significantly discriminate patients with 11 beta hydroxylase deficiency from those with 21 hydroxylase deficiency (p = 0.002), whereas radioimmunoassay failed (p = 0.095). Moreover, the former was highly predictive of 11 beta hydroxylase deficiency at a cutoff ≥ 11 ng/ml with 100% sensitivity and 92.3% specificity. Simultaneous measurement of 21 deoxycortisol and 11 deoxycortisol and their enrollment in an equation yielded an overall predictive accuracy 96.8% for diagnosis of CAH due to both enzymatic deficiencies.ConclusionsMeasurement of 11 deoxycortisol using mass spectrometric approach is mandated as a part of work up to differentiate types of congenital adrenal hyperplasia.

Three cases of 3β-hydroxysteroid dehydrogenase deficiency: Clinical analysis.

3β-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations. In order to improve the understanding and diagnosis of the disease, we analyzed and summarized the clinical characteristics, genetic variants and treatment for 3 children with 3β-HSD deficiency in this study. A summary of the clinical data, hormone levels (17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, testosterone, dehydroepiandrosterone, androstenedione, renin, and aldosterone), therapeutic drugs, and gene sequencing results from 3 3β-HSD deficiency patients was created. The 3 patients developed external genital abnormalities and adrenal insufficiency in infancy. Steroid hormone levels were consistent with 3β-hydroxysteroid dehydrogenase deficiency. Gene sequencing for the 3 patients detected complex heterozygous mutations in the HSD3B2 gene, which confirmed the diagnosis of 3β-HSD deficiency type II. Among the mutation types, c.154_162delinsTCCTGTT and c.674T>A have not been reported in the literature. The 3 children were treated with glucocorticoid and mineralocorticoid replacement, which controlled the adrenal insufficiency satisfactorily. In 2 male patients, external genital dysplasia manifested as hypospadias and small penis. After long-acting testosterone intramuscular injection to increase the penis size, the hypospadias were repaired. Mild masculinization in the female patient resulted in skin pigmentation and clitoral hypertrophy; however, no surgical intervention was required. The main clinical manifestations of 3β-HSD deficiency were adrenal insufficiency and sex hormone synthesis dysfunction. There was a strong phenotype correlation between the observed clinical manifestations in conjunction with steroid hormone levels and HSD3B2 mutations. The novel mutations c.154_162delinsTCCTGTT and c.674T>A were classified as pathogenic variants. Adrenal cortical function control was satisfactory after hormone replacement therapy, and hypospadias and small penis were attenuated using testosterone replacement therapy during mini-puberty for optimal surgical outcome.

Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population.

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that leads to impaired cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the most common type of CAH. Severe cases of 21-OHD may result in death during the neonatal or infancy periods or sterility in later life. The early detection and timely treatment of 21-OHD are essential. This study aimed to summarize the clinical and genotype characteristics of 21-OHD patients detected by neonatal screening in Nanjing, Jiangsu province of China from 2000 to 2019.Methods: Through a retrospective analysis of medical records, the clinical presentations, laboratory data, and molecular characteristics of 21-OHD patients detected by neonatal screening were evaluated.Results: Of the 1,211,322 newborns who were screened, 62 cases were diagnosed with 21-OHD with an incidence of 1:19858. 58 patients were identified with the classical salt-wasting type (SW) 21-OHD and four patients were identified with simple virilizing type (SV) 21-OHD. Amongst these patients, 19 cases patients accepted genetic analysis, and another 40 cases were received from other cities in Eastern China. Eighteen different variants were found in the CYP21A2 gene. The most frequent variants was c.293-13A/C>G (36.29%). The most severe clinical manifestations were caused by large deletions or conversions of CYP21A2.Conclusions: This study suggested that neonatal screening effectively leads to the early diagnosis of 21-OHD and reduces fatal adrenal crisis. Our data provide additional information on the occurrence and genotype-phenotype correlation of 21-OHD in the Chinese population which can be used to better inform treatment and improve prognosis.

Clinical and Genetic Characteristics of Patients with Common and Rare Types of Congenital Adrenal Hyperplasia: Novel Variants in STAR and CYP17A1.

ObjectivesCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases characterized by salt wasting or virilization. 21 hydroxylase deficiency (21-OHD) accounts for 90–95% of all cases of CAH and caused by the genetic defects of CYP21A2. Other forms include 3-β-hydroxysteroid dehydrogenase deficiency, 11-β-hydroxylase deficiency (11β-OHD) (%5-8), 17-α-hydroxylase deficiency (17α-OHD), and steroidogenic acute regulatory protein (STAR) defects (congenital lipoid adrenal hyperplasia) with mutations in HSD3B2, CYP11B1, CYP17A1, and STAR, respectively. Objectives: Herein, we aimed to present the clinical and genetic features of 64 patients with various types of CAH.MethodsSixty-four patients with CAH, monitored in the Izmir Dr. Behcet Uz Children Hospital Division of Pediatric Endocrinology, were retrospectively analyzed for the clinical, laboratory, and genetic data.ResultsFifty-six patients (87.5%) had 21-OHD and four patients (6.3%) had 17α-OHD, three patients (4.7%) had 11β-OHD, and one patient (1.5%) had STAR defect. The most common presenting features in 21-OHD were ambiguous genitalia. Patients with 21-OHD were diagnosed earlier than the rare groups. Disease-causing variants of CYP21A2 were identified in 46 patients. The most common mutations were IVS2, Q318X, I172N, and large deletions. Three patients with 11β-OHD were presented with enlargement of penis and early pubic hair at the median presenting age of 26 months. 17α-OHD deficiency was detected in 4 cases. Genetic analysis revealed two different homozygous CYP17A1 variants. The patient with STAR defect was presented with dehydration and cholestasis in 44 days of the life. Genetic analysis of patient with STAR deficiency revealed a novel homozygous variant.ConclusionThe current study reported a genotype-phenotype correlation consistent with literature data in CAH cases with 21-OHD. This study also reported novel homozygous variants in STAR and CYP17A1 genes that lead to rare types of CAH.

11-Keto-testosterone and other androgens of adrenal origin.

The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic potency of these adrenal-derived compounds were not well known, but some recent studies have shown that the production of 11-oxo- and 11beta-hydroxy-derived testosterone and dihydrotestosterone evidently have high androgenic activity. This fact has clinical importance, for instance, in various types of congenital adrenal hyperplasia with androgenization or polycystic ovarian syndrome, and laboratory determinations of these substances could help to better evaluate the total androgen pressure in patients with these disorders. Another area of concern is the treatment of prostate cancer with androgen deprivation, which loses effectiveness after a certain time. The concurrent blocking of the secretion of adrenal C(19)-steroids, whether using corticoids or adrenostatics, could increase the effectiveness of androgen-deprivation therapy.