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Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH)
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Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH)

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Laboratory Medicine".

Deadline for manuscript submissions: closed (25 February 2024) | Viewed by 23326

Special Issue Editor

Dr. Paola Concolino

E-Mail Website
Guest Editor
Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Interests: molecular diagnostics; NGS; breast and ovarian cancer molecular diagnosis; molecular diagnosis of endocrine diseases; congenital adrenal hyperplasia

Special Issue Information

Dear Colleagues,

Congenital adrenal hyperplasia (CAH) represents one of the most challenging endocrine disorders caused by a group of autosomal recessive diseases related to pathogenic variants in genes encoding enzymes involved in cortisol biosynthesis: 21-hydroxylase (21OH), 11β-hydroxylase (11βOH), 17α-hydroxylase (17OH, also known as 17,20-lyase), 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2), steroidogenic acute regulatory protein (StAR), P450 cholesterol side-chain cleavage enzyme (SCC), and P450 oxidoreductase (POR). Clinical presentation includes a range of clinical and biochemical phenotypes related to severe (classic) or mild (non-classic) forms. Challenges in the treatment of CAH include the avoidance of glucocorticoid overtreatment and the control of sex hormone imbalances. Molecular genetic testing for CAH is offered worldwide, and is of importance for differential diagnosis, carrier detection, and adequate genetic counseling, particularly for family planning. New approaches based on next-generation sequencing (NGS) allow the simultaneous screening of all candidate genes, increasing the efficiency of molecular diagnosis.

The aim of this Special Issue is to explain the molecular basis, clinical spectrum, diagnostic approach, and the treatment advances of CAH.

Dr. Paola Concolino
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • congenital adrenal hyperplasia (CAH)
  • 21-hydroxylase deficiency (21OH)
  • 11β-hydroxylase (11βOH)
  • cortisol biosynthesis
  • pathogenic variants
  • genetic testing
  • 17-hydroxyprogesterone
  • adrenal steroidogenesis

Published Papers (6 papers)

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Research

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9 pages, 668 KiB  
Article
Premature Pubarche: Time to Revise the Diagnostic Approach?
by Federico Baronio, Alice Marzatico, Rosaria De Iasio, Rita Ortolano, Antonio Fanolla, Giorgio Radetti, Antonio Balsamo, Andrea Pession and Alessandra Cassio
J. Clin. Med. 2023, 12(6), 2187; https://doi.org/10.3390/jcm12062187 - 11 Mar 2023
Cited by 1 | Viewed by 1684
Abstract
Premature pubarche (PP) could represent the first manifestation of non-classic congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (NC21OHD) (10–30% of cases). In the last 20 years, the necessity of performing an ACTH test to diagnose NC21OHD in all cases with PP has [...] Read more.
Premature pubarche (PP) could represent the first manifestation of non-classic congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (NC21OHD) (10–30% of cases). In the last 20 years, the necessity of performing an ACTH test to diagnose NC21OHD in all cases with PP has been questioned, with conflicting results. This study aims to retrospectively evaluate the predictive value of the basal androgens, 17-OHP levels, and auxological features in suggesting the presence of NC21OHD and, thus, the need for a standard ACTH test to confirm the diagnosis. In all, 111 consecutive patients (87 females) with PP and advanced bone age underwent an ACTH test. Of these, 6/111 cases (1 male) were diagnosed with NC21OHD. The mean baseline 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), delta 4 androstenedione (Δ4A), and testosterone serum levels were higher in NC21OHD patients than in the others (p < 0.05). We found three predictive features for NC21OHD: basal 17 OHP of >200 ng/mL, bone age advance of >2 years, and DHEA-S levels of >228 ng/mL with sensitivity and specificity of 83.3% and 97.1%, 83.3% and 65.7%, and 83.3% and 96.2%, respectively. Our data confirm that the prevalence of NC21OHD is low among patients with PP. Serum 17-OHP of >200 ng/mL could be helpful to decide, in most cases, which patients should undergo the ACTH test. Bone age advance represented an inadequately specific predictive marker of NC21OHD. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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17 pages, 2892 KiB  
Article
Antihyperglycemic Potential of Spondias mangifera Fruits via Inhibition of 11β-HSD Type 1 Enzyme: In Silico and In Vivo Approach
by Shadma Wahab, Mohammad Khalid, Mohammed H. Alqarni, Mohamed Fadul A. Elagib, Ghadah Khaled Bahamdan, Ahmed I. Foudah, Tariq M. Aljarba, Mons S. Mohamed, Nazik Salih Mohamed and Muhammad Arif
J. Clin. Med. 2023, 12(6), 2152; https://doi.org/10.3390/jcm12062152 - 09 Mar 2023
Cited by 1 | Viewed by 1859
Abstract
The 11 β- hydroxysteroid dehydrogenase 1 (11 β-HSD1) is hypothesized to play a role in the pathogenesis of type 2 diabetes and its related complications. Because high glucocorticoid levels are a risk factor for metabolic disorders, 11β-HSD1 might be a viable therapeutic target. [...] Read more.
The 11 β- hydroxysteroid dehydrogenase 1 (11 β-HSD1) is hypothesized to play a role in the pathogenesis of type 2 diabetes and its related complications. Because high glucocorticoid levels are a risk factor for metabolic disorders, 11β-HSD1 might be a viable therapeutic target. In this investigation, docking experiments were performed on the main constituents of Spondias mangifera (SM) oleanolic acid, β-amyrin, and β-sitosterol to ascertain their affinity and binding interaction in the human 11β-hydroxysteroid dehydrogenase-1 enzyme’s active region. The results of in vitro 11β HSD1 inhibitory assay demonstrated that the extract of S. mangifera had a significant (p < 0.05) decrease in the 11-HSD1% inhibition (63.97%) in comparison to STZ (31.79%). Additionally, a non-insulin-dependent diabetic mice model was used to examine the sub-acute anti-hyperlipidemic and anti-diabetic effects of SM fruits. Results revealed that, in comparison to the diabetic control group, SM fruit extract (SMFE) extract at doses of 200 and 400 mg/kg body weight considerably (p < 0.05 and p < 0.01) lowered blood glucose levels at 21 and 28 days, as well as significantly decreased total cholesterol (TC) and triglycerides (TG) and enhanced the levels of high-density lipoprotein (HDL). After 120 and 180 s of receiving 200 and 400 mg/kg SMFE, respectively, disease control mice showed significantly poorer blood glucose tolerance (p < 0.05 and p < 0.01). SMFE extract 200 (p < 0.05), SMFE extract 400 (p < 0.01), and Glibenclamide at a dosage of 5 mg/kg body weight all resulted in statistically significant weight increase (p < 0.01) when compared to the diabetic control group after 28 days of treatment. According to in silico, in vitro, and in vivo validation, SMFE is a prospective medication with anti-diabetic and hypoglycemic effects. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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Review

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12 pages, 4032 KiB  
Review
Clinical Update on Congenital Adrenal Hyperplasia: Recommendations from a Multidisciplinary Adrenal Program
by Thomas Uslar, Roberto Olmos, Alejandro Martínez-Aguayo and René Baudrand
J. Clin. Med. 2023, 12(9), 3128; https://doi.org/10.3390/jcm12093128 - 26 Apr 2023
Cited by 4 | Viewed by 4452
Abstract
Congenital adrenal hyperplasia (CAH) is a common genetic disorder in endocrinology, especially its milder clinical presentation, often caused by a partial or total deficiency of the 21-hydroxylase enzyme located in the adrenal cortex. CAH is characterized by the overproduction of androgen, along with [...] Read more.
Congenital adrenal hyperplasia (CAH) is a common genetic disorder in endocrinology, especially its milder clinical presentation, often caused by a partial or total deficiency of the 21-hydroxylase enzyme located in the adrenal cortex. CAH is characterized by the overproduction of androgen, along with variable degrees of cortisol and aldosterone deficiency. The age at diagnosis can provide some information about underlying mutations, with those diagnosed at birth/early infancy more likely to have severe enzymatic defects, which may include adrenal insufficiency, sexual development disorders, short stature in adulthood, hirsutism, and a higher risk for metabolic syndrome and infertility. Non-classic CAH, a milder form of CAH, is usually manifested later in life and is a common differential diagnosis of Polycystic Ovary Syndrome and should be actively evaluated during initial studies of clinical or biochemical hyperandrogenism. The main goals of CAH treatment are hormone supplementation for severe cases, controlling adrenal androgen overproduction to minimize long-term side effects, managing fertility and genetic counseling, and optimizing patients’ quality of life. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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16 pages, 5153 KiB  
Review
Characteristics of Congenital Adrenal Hyperplasia Diagnosed in Adulthood: A Literature Review and Case Series
by Joanna Hubska, Anna Kępczyńska-Nyk, Katarzyna Czady-Jurszewicz and Urszula Ambroziak
J. Clin. Med. 2023, 12(2), 653; https://doi.org/10.3390/jcm12020653 - 13 Jan 2023
Viewed by 6708
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. CAH, depending on its clinical form, is usually diagnosed in the neonatal period, later in childhood, in adolescence, or in young adults. Herein, we report a case [...] Read more.
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. CAH, depending on its clinical form, is usually diagnosed in the neonatal period, later in childhood, in adolescence, or in young adults. Herein, we report a case series of eight individuals in whom CAH was diagnosed between the ages of 18 and 81 years. Methods: We report on clinical presentations, hormonal tests, adrenal/gonadal imaging, and genetic findings. The clinical data of eight people with CAH, including four women (46, XX) and four men (46, XY), were reviewed. A genetic analysis of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene was performed in six patients. A comprehensive literature review was also conducted. Case series: Partial cortisol deficiency was found in all patients. The most frequent genotype was the homozygotic I173N mutation in CYP21A2. Adrenal masses were detected in seven patients, except for the youngest. Most of the patients were of short stature. Hypogonadotropic hypogonadism was detected in two males, and three females presented with primary amenorrhea. Hirsutism was noticeable in three females. All of the patients developed insulin resistance, and half of them were obese. Conclusions: The clinical presentations of different forms of CAH overlapped. Genotype–phenotype correlations were strong but not absolute. The management of CAH should be individualized and based on clinical and laboratory findings. Furthermore, the assessment of the cortisol response to adrenocorticotrophic hormone stimulation should be mandatory in all adults with CAH. Additionally, the regular long-term screening of cardiometabolic status is required in the CAH population. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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16 pages, 703 KiB  
Review
Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia
by Gianluca Cera, Pietro Locantore, Roberto Novizio, Ettore Maggio, Vittoria Ramunno, Andrea Corsello, Caterina Policola, Paola Concolino, Rosa Maria Paragliola and Alfredo Pontecorvi
J. Clin. Med. 2022, 11(20), 6156; https://doi.org/10.3390/jcm11206156 - 19 Oct 2022
Cited by 7 | Viewed by 5808
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal [...] Read more.
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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Other

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8 pages, 846 KiB  
Case Report
Genetic Testing for a Patient with Suspected 3 Beta-Hydroxysteroid Dehydrogenase Deficiency: A Case of Unreported Genetic Variants
by Elisa Menegatti, Daniele Tessaris, Alice Barinotti, Patrizia Matarazzo and Silvia Einaudi
J. Clin. Med. 2022, 11(19), 5767; https://doi.org/10.3390/jcm11195767 - 29 Sep 2022
Viewed by 1436
Abstract
3beta-hydroxysteroid dehydrogenase type II deficiency (HSD3B2 deficiency), a rare form of congenital adrenal hyperplasia (CAH), is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. We report the case of a [...] Read more.
3beta-hydroxysteroid dehydrogenase type II deficiency (HSD3B2 deficiency), a rare form of congenital adrenal hyperplasia (CAH), is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. We report the case of a patient (46XY) showing salt loss and incomplete masculinization, markedly elevated levels of 17OHP (17 hydroxyprogesterone), ACTH (Adreno Cortico Tropic Hormone), testosterone and delta4androstenedione (delta4A), low levels of cortisol and absence of bone skeletal alterations that frequently characterize POR (Cytochrome P450 oxidoreductase) deficiency. Mutation analysis by Sanger sequencing of the HSD3B2 gene showed that the patient presented with a compound heterozygote for two novel variants c.370A>G p.Ser124Gly and c.308-6 G>A. The two HSD3B2 gene variants were also present in the patient’s older brother showing only incomplete masculinization. The in silico analysis revealed a probable damaging effect of c.370A>G p.Ser124Gly: residue p.Ser124 is highly conserved among species and seems to be located in the catalytic site of the enzyme, playing a pivotal role in NAD(H) binding to its substrate. Intronic c.308-6G>A variant is predicted to be likely pathogenic; the substitution seems to cause a change in the splice acceptor site located 6bp downstream of the variant. The two siblings seem to be affected by 3β-HSD2 deficiency; nevertheless, the two novel variants are likely to cause variable expressivity of the disease. Full article
(This article belongs to the Special Issue Clinical and Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH))
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