Identifying the First Val281L Mutation Causing Nonclassic Congenital Adrenal Hyperplasia in the Central-East Region of Tunisia.

Nonclassic congenital adrenal hyperplasia (NCAH) is a genetic disorder characterized by mutations in the genes encoding enzymes involved in cortisol production, most commonly the 21-hydroxylase enzyme. Unlike classic congenital adrenal hyperplasia (CAH), NCAH typically presents later in life with milder symptoms. The diagnosis of NCAH can be challenging due to its nonspecific symptoms and variable presentation. Early detection is crucial for timely intervention and management, particularly in families with a history of the condition. We report a case of NCAH in a patient from the Central-East Region of Tunisia, in whom the subsequent genetic testing revealed a Val281Leu (V281L) mutation in the CYP21A2 gene. A 26-year-old female presented with facial hirsutism and irregular menstrual cycles. Physical examination revealed mild hirsutism and laboratory tests showed elevated levels of testosterone and 17-hydroxyprogesterone (17-OHP). A provisional diagnosis of NCAH was made, subsequently confirmed by an adrenocorticotropic hormone (ACTH) stimulation test demonstrating an exaggerated 17-OHP response. Genetic testing revealed heterozygosity for the V281L mutation. Family testing showed the patient's mother to be homozygous and the father heterozygous for the mutation. This report highlights the importance of recognizing subtle symptoms of NCAH for early diagnosis and management. Genetic testing aids in confirming the diagnosis and identifying carriers within families. Treatment with glucocorticoids aims to suppress adrenal androgen production and manage symptoms. Regular follow-up is essential to monitor treatment response and adjust medication as needed. NCAH can present with subtle symptoms, necessitating a high index of suspicion for a proper diagnosis. Genetic testing plays a crucial role in confirming the diagnosis and identifying carriers within families. Early intervention and regular follow-up improve outcomes in affected individuals. This report also underscores the significance of genetic testing in the management of NCAH and highlights the need for increased awareness about this condition among healthcare providers.

Expression of genes and enzymes involved in ovarian steroidogenesis in relation to human follicular development.

Introduction: Granulosa cells (GCs) and theca cells (TCs) play a pivotal role in human ovarian steroidogenesis, facilitating the conversion of cholesterol into sex steroids that regulate normal reproductive function. This study aims to explore the expression patterns of key enzymes that govern human ovarian steroidogenesis throughout follicle development, employing both genomic and immunological methodologies. Methods: Follicles and GCs obtained from women undergoing ovarian tissue cryopreservation (OTC) and in vitro fertilisation treatment were utilized. Gene expression data were obtained from a Chinese study using RNA sequencing and from microarray data generated in our laboratory to comprehensively analyse gene expression profiles across distinct stages of follicular development. To corroborate the localisation of key enzymes within GCs and TCs, immunohistochemistry analyses utilizing colourimetric and fluorescent techniques were conducted. Results: Steroidogenesis-related enzymes displayed low gene expression levels during early follicle development. However, a notable upregulation of HSD3B2 was observed in GCs as follicles progressed to the antral/preovulatory stage, confirmed consistently using both microarray and RNA sequencing methodologies. Furthermore, immunohistochemical analyses effectively demonstrated that HSD3B2 were not only expressed in GCs, but co-localised with CYP17A1 within a specific subset of TCs surrounding human small antral follicles. Contributing to an enhanced progesterone production during the second half of the follicular phase was a significant upregulation of CYB5A in both microarray and RNA-seq datasets as follicles transition from the antral stage to the pre-ovulatory stage. Moreover, an augmented expression of DHCR24 and LDLR in both types of data, along with HMGCR expression expression in the microarray data, indicates increased substrate availability for ovarian steroidogenesis. Discussion: This study confirms and extends that GCs gradually augment expression of HSD3B2 thereby enhancing their capacity for progesterone synthesis as follicles reach the size of selection at around 10 mm in diameter. This is supported by the expression CYB5A and possibly augmented availability of steroid precursors. A subset of TCs exhibit concurrent expression of CYP17A1 and HSD3B2, collectively contributing to the synthesis of 17-hydroxyprogesterone. These data significantly enhance our understanding of the dynamic regulation of progesterone throughout the process of follicular development.

Mineralocorticoid replacement therapy in salt-wasting congenital adrenal hyperplasia.

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.

Clinical Patterns and Linear Growth in Children with Congenital Adrenal Hyperplasia, an 11-Year Experience.

OBJECTIVE: An important goal in treating children with congenital adrenal hyperplasia (CAH) is to achieve a normal final adult height (FH). The aim of this study was to describe the clinical presentations and evaluate linear growth and possible factors affecting it in children with CAH. METHODS: This is a retrospective study of 56 patients with CAH followed up in a tertiary center for 11 years. Patient's data including demographics, clinical, anthropometric, and laboratory information at presentation and during follow-up period were collected from medical records. RESULTS: Fifty-six children (31 females) with CAH were seen at KAMC-Jeddah over 11-year period and 91% were 21-hydroxylase deficient. Of these, 46.4% had hyponatremia and 28.6% had hyperkalemia (21.4% had hyponatremia and hyperkalemia) at presentation. Positive family history was documented in 53.6%. Ambiguous genitalia were present in 72% of females and the majority required corrective surgery. Males had significantly decreased HtSDS versus females and females had significantly higher body mass index. The HtSDS of children who had had higher 17OHP or salt-losing crisis during treatment was significantly lower than those who had normal 17OHP and those who did not have salt-losing crisis, respectively. CONCLUSION: The final height outcome in our patients with CAH treated with glucocorticoids is lower than the population norm. Proper control of the disease clinically and biochemically through strict compliance to medical therapy as well as close clinical and laboratory monitoring is an important key to achieve normal final adult height in these patients. Side effects, including overweight, obesity, and hypertension are true risk associations and need timely diagnosis and early management.

Newborn Screening for Congenital Adrenal Hyperplasia in India: What Do We Need to Watch Out for?

BACKGROUND: Congenital Adrenal Hyperplasia (CAH) is a disorder-an ideal candidate to deserve newborn screening. CAH accounts for a significant mortality and morbidity in India, and its awareness among obstetricians should be treated as highly important to prevent the problem. PURPOSE OF THE STUDY: It is very important for a country like India as the incidence of CAH is reasonably high justifying screening program. However, there are simple logistics that need to be followed, and the treating physicians need to be aware of, if one has to reduce the number of false positives and recalls. METHODS: This article takes one through the steps involved in the analysis, interpretation, and reasons for false positives, why the false positives, so that unnecessary calls to parents for repeat sampling are minimized along with the emphasis and the need for the routine screening for CAH. RESULTS/CONCLUSION: The results of samples can vary depending on the gestational age of the baby, weight of the baby, sampling time, and the knowledge of these data to the treating Obstetrician and Pediatrician is of paramount importance in preventing repeat samples and frustration for the family and the people involved.

Congenital Adrenal Hyperplasia with Non-functional Mutations in Both Alleles in a Clinically Unaffected Infant.

BACKGROUND: Results in neonatal screening programs aiming at detection of congenital adrenal hyperplasia (CAH) can only report elevated levels of 17-hydroxy-progesterone (17-OHP), without being able to differentiate presence or absence of salt loss. AIM: To predict presence or absence of salt loss in newborn infants with CAH. METHODS: The first specimen of suspected CAH in samples sent from People's Democratic Republic of Laos (Lao PDR) was investigated for known mutations in CAH associated with salt loss. RESULTS: Molecular genetic diagnosis revealed mutations associated with loss of function in both alleles; however, the infant was clinically unaffected even without any corticosteroid substitution therapy. CONCLUSIONS: Although molecular genetic methods can theoretically predict loss of function in CAH, our infant was clinically unaffected even without therapy at 6 years of age. We speculate that in CAH, remaining enzyme activity can be sufficiently high, despite the presence of loss of function mutations, which do not affect infants clinically.

Pathways and genes involved in steroid hormone metabolism in male pigs: a review and update.

This paper reviews state-of-the-art knowledge on steroid biosynthesis pathways in the pig and provides an updated characterization of the porcine genes involved in these pathways with particular focus on androgens, estrogens, and 16-androstenes. At least 21 different enzymes appear to be involved in these pathways in porcine tissues together with at least five cofactors. Until now, data on several porcine genes were scarce or confusing. We characterized the complete genomic and transcript sequences of the single porcine CYP11B gene. We analyzed the porcine AKR1 gene cluster and identified four AKR1C, one AKR1C like genes and one AKR1E2 gene. We provide evidence that porcine AKR1C genes are not orthologous to human AKR1C. A new nomenclature is thus needed for this gene family in the pig. Thirty-two genes are now described: transcript (30+2 characterized in this study) and genomic (complete: 18+1 and partial: 12+1) sequences are identified. However, despite increasing knowledge on steroid metabolism in the pig, there is still no explanation of why porcine testes can produce androstenone and epiandrosterone, but not dihydrotestosterone (DHT), which is also a reduced steroid.

Clinical Analysis of 19 Patients with 21 Hydroxylase Deficiency / 上海第二医科大学学报

Objective Clinical data of 19 Chinese patients with 21 hydroxylase deficiency (21OHD) were analyzed to improve the diagnosis and treatment level. Methods Clinical features and laboratory data were collected from 19 patients with 21OHD before and after treatment. Results In male patients, the average age of early appearance of secondary sexual character was (9.3?2.8)yrs, and excess androgen resulted in phallic enlargement. Primary amenorrhea was the most common complaint in female(87.5%), and the signs included a varying degree of labioscrotal fusion and clitoral enlargement. The average level of 17-hydroxy progesterone(17OHP) was (63.42?35.07) ?g/L, and adrenocorticotrophic hormone(ACTH), dehydroepiandrosterone(sodium) sulfate(DHEAS) and testosterone(T) were obviously elevated. CT scan showed bilateral adrenal hyperplasia. The level of 17OHP was significantly decreased after treatment[(63.42?35.07) ?g/L vs (3.15?2.71) ?g/L](P