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JCEM Case Reports Jun 2024A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of...
A mutation in the steroidogenic acute regulatory protein () gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of congenital adrenal hyperplasia (CAH) known as lipoid CAH (LCAH). LCAH presents with primary adrenal insufficiency (PAI) as well as atypical genitalia. Individuals with LCAH require adrenal steroid hormone supplements for survival. Masculinization in males with deficiency varies from incomplete to normal virilization. Radiological examinations reveal enlarged and lipid-laden adrenals. A 10-year-old boy born of second-degree consanguinity presented with weight gain and hyperpigmentation for 1 year. He was diagnosed with PAI at age 7 months and treated with hydrocortisone and fludrocortisone. Dynamic adrenal gland testing revealed undetectable hormone reserves. Imaging detected hypoplastic adrenals and a small testis with testicular adrenal rests (TART). Genetic analysis indicated a novel homozygous pathogenic variant of in exon 7, c.814C > G(pArg272Gly) associated with LCAH (OMIM No. 201710). Testing revealed that asymptomatic family members and relatives were heterozygotes for the variant. The patient was diagnosed with nonclassic LCAH with hypoplastic adrenals and TART. Adequate hormone supplementation resulted in TART regression. This genetic variation is reported for the first time.
PubMed: 38803511
DOI: 10.1210/jcemcr/luae089 -
Scientific Reports May 2024Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and...
Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (r = - 0.83, P < 0.001) and progressive motility (r = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.
Topics: Humans; Male; Adrenal Hyperplasia, Congenital; Adult; Retrospective Studies; Infertility, Male; Ultrasonography; Risk Assessment; Semen Analysis; Testis; Young Adult; Adrenal Rest Tumor
PubMed: 38802468
DOI: 10.1038/s41598-024-62954-8 -
JCEM Case Reports Jun 2024We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite...
We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.
PubMed: 38798742
DOI: 10.1210/jcemcr/luae077 -
F&S Science May 2024To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary...
OBJECTIVE
To investigate potential differences in pregnancy, delivery, and neonatal outcomes between 2 hyperandrogenic conditions in reproductive-aged women: polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH).
DESIGN
Retrospective population-based study with data from the Health Care Cost and Utilization Project-Nationwide Inpatient Sample Database from 2004-2014.
SETTING
Not applicable.
PATIENT(S)
A total of 14,881 women with PCOS and 298 women with CAH.
INTERVENTION(S)
Not applicable.
MAIN OUTCOME MEASURE(S)
Gestational diabetes mellitus, placenta previa, pregnancy-induced hypertension (HTN), gestational HTN, preeclampsia, eclampsia, preeclampsia and eclampsia superimposed on HTN, preterm birth, preterm premature rupture of membrane, abruptio placenta, chorioamnionitis, mode of delivery, maternal infection, hysterectomy, blood transfusion, venous thromboembolism (deep vein thrombosis and pulmonary embolism during pregnancy, intrapartum, or postpartum), maternal death, chorioamnionitis, septicemia during labor, postpartum endometritis, septic pelvic, peritonitis, small for gestational age, congenital anomalies, and intrauterine fetal demise.
RESULT(S)
After adjusting for potential confounders, we found that women with PCOS were at increased risk of developing pregnancy-induced HTN (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI]: 1.12-2.77) and gestational diabetes (adjusted OR = 1.68; 95% CI: 1.12-2.52) when compared with women with CAH. Contrary women with CAH were at increased risk for delivery via cesarean section (adjusted OR = 0.59; 95% CI: 0.44-0.80) and small for gestational age neonates (adjusted OR = 0.32; 95% CI: 0.20-0.52).
CONCLUSION(S)
To our knowledge, this study is the first to directly compare obstetric and neonatal outcomes between patients with PCOS and CAH. Despite the similar phenotypes and some common hormonal and biochemical profiles, such as insulin resistance, hyperinsulinemia, and hyperandrogenism, our results suggest the existence of additional metabolic pathways implicated in the pathogenesis of pregnancy complications.
PubMed: 38795844
DOI: 10.1016/j.xfss.2024.05.001 -
International Journal of Molecular... May 2024Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent...
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
Topics: Animals; Adrenal Hyperplasia, Congenital; Disease Models, Animal; Steroid 21-Hydroxylase; Mice; Female; Male; Humans; Corticosterone; Aldosterone; Adrenal Glands; Mutation; Progesterone
PubMed: 38791102
DOI: 10.3390/ijms25105062 -
Investigating GABA Neuron-Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS.Endocrinology May 2024Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links...
Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.
Topics: Animals; Polycystic Ovary Syndrome; Female; Receptors, Androgen; Mice, Knockout; Mice; Disease Models, Animal; GABAergic Neurons; Hyperandrogenism; Ovary; Androgens; Pregnancy; Gonadotropin-Releasing Hormone; Prenatal Exposure Delayed Effects
PubMed: 38788194
DOI: 10.1210/endocr/bqae060 -
Current Issues in Molecular Biology May 2024Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has...
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, and its pseudogene are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype-phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies.
PubMed: 38785559
DOI: 10.3390/cimb46050291 -
Oxford Medical Case Reports May 2024We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and...
We report the case of a 5-year-old boy diagnosed with congenital adrenal hyperplasia due to 11-hydroxylase deficiency, revealed by disorders of sex development (DSD) and acute pulmonary edema due to severe hypertension. We considered the diagnosis based on biological and radiological examinations. The sociocultural background and the delayed diagnosis had a significant impact on the therapeutic decisions. All babies should be screened for 11 beta-hydroxylase deficiency, there should be specialized and interdisciplinary medical centers, and early detection is essential to avoiding serious complications of this disease.
PubMed: 38784773
DOI: 10.1093/omcr/omae042 -
Frontiers in Endocrinology 2024Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent... (Review)
Review
Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.
Topics: Female; Humans; Male; 46, XX Disorders of Sex Development; Adrenal Hyperplasia, Congenital; Disorders of Sex Development; Fertility; Gender Identity; Quality of Life
PubMed: 38752171
DOI: 10.3389/fendo.2024.1372887 -
Medicine and Pharmacy Reports Apr 2024Congenital adrenal hyperplasia (CAH) is determined in the vast majority of cases by mutations in the gene, which cause the deficiency of the 21 hydroxylase enzyme,...
Approaching fertility in congenital adrenal hyperplasia: exploring P30L mutation-induced 21-hydroxylase deficiency with a presentation between non-classical and simple virilizing phenotypes. A case report.
Congenital adrenal hyperplasia (CAH) is determined in the vast majority of cases by mutations in the gene, which cause the deficiency of the 21 hydroxylase enzyme, which is involved in the synthesis of cortisol and aldosterone. Generally, CAH phenotype and disease severity can be predicted with the genotypes and is related to the residual activity of 21 hydroxylase enzyme. It is divided into classical CAH with salt wasting and simple virilizing forms and non-classical or late-onset CAH forms, respectively. Patients with 21 hydroxylase deficiency, including those with non-classic forms face immense challenges to their fertility. Glucocorticoid therapy has been shown to be useful in obtaining and maintaining a pregnancy among these patients, but it must be used with caution. Given the relevance of CAH in reproductive medicine as well as the diagnostic challenges posed by the phenotypic overlap with polycystic ovary syndrome and by overlap of its own phenotypes (classic CAH-nonclassic CAH), we present the case of a woman with CAH due to 21 hydroxylase deficiency caused by the P30L mutation with a clinical and biochemical presentation between the non-classical form and the classic simple virilizing form. Further, the successful fertility management in this patient and an overview of fertility management in CAH is depicted, as well.
PubMed: 38746038
DOI: 10.15386/mpr-2580