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1.
Gynecol Endocrinol ; 35(1): 23-27, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29909741

RESUMEN

11ß-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH11ß). In females, the clinical phenotype of CAH11ß classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11ß-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH11ß have also been briefly discussed. The presented case of an adult woman with CAH11ß shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility.


Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Infertilidad Femenina/genética , Mutación , Esteroide 11-beta-Hidroxilasa/genética , Acné Vulgar/genética , Adulto , Femenino , Estudios de Seguimiento , Hirsutismo/genética , Humanos , Trastornos de la Menstruación/genética , Persona de Mediana Edad
3.
Biomedicines ; 12(7)2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-39062101

RESUMEN

AIMS: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. METHODS: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. RESULTS: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. CONCLUSIONS: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.

4.
Rheumatol Int ; 33(8): 2031-8, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23388696

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects mainly females. Therefore, interrelations between the reproductive and immune system have been assumed. Considering the complex influence of hormones and receptors, we aimed to investigate the influence of androgens and androgen receptor (AR) polymorphism in women with SLE. One hundred and sixteen patients and 44 healthy women were investigated. Testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulphate (DHEAS) concentrations and AR (CAG)n polymorphism were determined. SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls. No differences in the CAG repeat length between the groups were established. Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of SHBG (101.51 ± 61.81 vs. 69.22 ± 45.93 nmol/l, p = 0.015) and DHEAS (3.11 ± 2.65 vs. 2.11 ± 3.06 µmol/l, p = 0.007) and a tendency to higher testosterone concentrations (2.35 ± 2.10 vs. 1.71 ± 1.70 nmol/l, p = 0.056) in comparison with other women. The CAG repeat length in the relatively longer (CAG)n allele was inversely related to the Systemic Lupus International Collaborating Clinics/ACR index (r = -0.258, p = 0.009). In conclusion, the androgen receptor (CAG)n polymorphism is not related to the development of SLE, but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women.


Asunto(s)
Andrógenos/sangre , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Receptores Androgénicos/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes , Humanos , Lupus Eritematoso Sistémico/sangre , Persona de Mediana Edad
5.
Front Biosci (Landmark Ed) ; 28(6): 122, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37395040

RESUMEN

BACKGROUND: The development of assisted reproductive techniques has significantly improved fertility chances in many women, but recurrent implantation failure (RIF) and miscarriages (RM) might preclude successful pregnancy. Alterations in the intrinsic secretory patterns of melatonin and cortisol influence reproduction in humans, and imperfection of receptor - dependent signaling may additionally compromise the hormonal effects. Therefore, the present study aims to investigate the influence of certain melatonin and cortisol receptor polymorphisms in infertile women. METHODS: A total of 111 female infertile patients suffering from implantation failure and/or miscarriages were genotyped for MTNR1B rs1562444, MTNR1Brs10830962, GCCR rs41423247, and GCCR ER22/23EK variants. Additionally, 106 female volunteers were genotyped for the same polymorphisms. RESULTS: The allele and genotype distribution of the investigated polymorphisms did not differ between infertile women and the control group. Significantly more women with history of RIF have MTNR1B rs1562444 G-allele-containing genotypes in comparison to AA carriers (19.3% vs. 3.6%, p = 0.004). The minor allele of the ER22/23EK variant was more frequent in infertile patients with three or more unsuccessful implantation attempts than in other women (12.5% vs. 2.4%, p = 0.025). CONCLUSIONS: Melatonin receptor 1B polymorphisms might affect embryo implantation and early pregnancy loss, while their influence on late pregnancy complications needs further evaluation. The possible association between the cortisol receptor ER22/23EK variant and recurrent implantation failure might help to differentiate women who could benefit from corticosteroid treatment.


Asunto(s)
Aborto Espontáneo , Infertilidad Femenina , Melatonina , Femenino , Humanos , Embarazo , Hidrocortisona , Infertilidad Femenina/genética , Receptores de Melatonina , Receptores de Esteroides/genética
6.
J Pediatr Genet ; 11(3): 253-256, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35990027

RESUMEN

Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. Pontocerebellar hypoplasia type 1B is caused by mutations in EXOSC3 gene. High prevalence of the p.Gly31Ala mutation was found recently, especially in the Roma ethnic minority. We present a young Bulgarian Roma family with two deceased newborn children manifesting severe neuromuscular disorder including severe muscle weakness, respiratory distress, and multiple joint contractures. Based on the clinical signs and family's population characteristics, DNA testing for the previously described EXOSC3 in Bulgarian Roma mutation c.92G > C; p.Gly31Ala was performed on blood samples of both parents and they were found to be heterozygous carriers. This finding indirectly confirmed the diagnosis of pontocerebellar hypoplasia type B in the deceased offspring. Knowledge of population-specific molecular bases of genetic conditions was the key to final diagnosis in the presented family. Designing of population-based clinical-genetic panels may be a powerful diagnostic tool for patients with such origin. Preconception carrier screening in high-risk population groups is a feasible option to discuss.

7.
Endocr Connect ; 11(12)2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36228316

RESUMEN

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

8.
Sex Dev ; 11(1): 21-28, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28110336

RESUMEN

Disorders/differences of sexual development (DSD) are a group of conditions, some of which can be clinically indistinguishable mainly due to their phenotypic variability. Defining the molecular basis of their wide spectrum is still in progress. The diagnosis of 5-alpha-reductase type 2 (5α-reductase-2) deficiency is difficult especially in newborns and pre-pubertal individuals, and as a result its frequency might be underestimated. In the present study, we describe the clinical characteristics and molecular defects in 3 nonrelated 5α-reductase-2 deficiency patients of Bulgarian descent. Sequencing analysis revealed the mutations p.Y188CfsX9 and p.G196S, and MLPA analysis showed a deletion of exon 1 in the SRD5A2 gene. The observed genetic substitutions were not detected in 76 additionally screened unrelated controls, but a heterozygous healthy carrier of the p.R171S mutation was found. This is the first study on the molecular basis of 5α-reductase-2 deficiency in Bulgaria. It suggests that the carrier frequency of mutations in the SRD5A2 gene might be noteworthy worldwide. There is no correlation between cultural aspects, location, and/or population size and the number of different mutations in SRD5A2 detected, and more efforts should be made to determine the prevalence of this condition in different geographic areas. Our study supports the importance of genetic testing in 46,XY DSD patients, especially in countries or regions where 5α-reductase-2 deficiency has not been reported so far.


Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/deficiencia , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Trastornos del Desarrollo Sexual/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Mutación/genética , Bulgaria , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/metabolismo , Trastornos del Desarrollo Sexual/genética , Humanos
9.
Sex Dev ; 9(6): 333-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26871559

RESUMEN

46,XY complete gonadal dysgenesis (CGD) is a disorder of sexual development that can result from different mutations in genes associated with sex determination. Patients are phenotypically females, and the disease is often diagnosed in late adolescence because of delayed puberty. Here, we present the clinical and molecular data of a 46,XY female CGD patient with gonadoblastoma with dysgerminoma and incidentally found inherited thrombophilia. The clinical significance of the described de novo SRY gene mutation c.325T>C (p.F109L) is discussed. This case report supports the critical role of the HGM domain in the SRY gene and the need of a multidisciplinary approach for CGD patients.


Asunto(s)
Genes sry , Disgenesia Gonadal 46 XY/genética , Adolescente , Sustitución de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Disgerminoma/genética , Disgerminoma/patología , Femenino , Disgenesia Gonadal 46 XY/patología , Gonadoblastoma/genética , Gonadoblastoma/patología , Humanos , Mutación Missense , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína de la Región Y Determinante del Sexo/genética
11.
Prenat Diagn ; 24(3): 202-8, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15057954

RESUMEN

OBJECTIVE: The aim of our study was to estimate the observed heterozygosity and informativeness of 6 STR markers on chromosomes 18 and 21 in the Bulgarian population. We have evaluated the applicability of these markers used from other investigators for QF-PCR prenatal diagnosis of the most common autosomal aneuploidies in Bulgaria. METHODS: DNA samples (n = 486) were extracted from different fetal tissues (amniotic fluid cells, chorionic villus samples, and fetal tissue after abortions). PCR amplifications of 4 STR markers located on chromosome 21 (D21S11, D21S1411, D21S1270, and D21S1440) and 2 on chromosome 18 (D18S535 and D18S51) were performed. They were analysed on an automated sequencer, and the allele dosage ratios were calculated. RESULTS: The results indicate the selected markers as highly informative for our population and suitable for QF-PCR prenatal diagnosis in Bulgaria. All samples with trisomy 21 (n = 8), trisomy 18 (n = 4) and triploidy (n = 1) were correctly detected by our analysis. Thus, no false-negative results were observed. CONCLUSION: QF-PCR analysis could be an applicable alternative in prenatal and postnatal diagnosis in cases with a strong suspicion for particular autosomal aneuploidies (including chromosomes 21, 18, and 13) in small countries with limited resources like Bulgaria.


Asunto(s)
Aneuploidia , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 21 , ADN/análisis , Reacción en Cadena de la Polimerasa/métodos , Diagnóstico Prenatal/métodos , Bulgaria , Trastornos de los Cromosomas/genética , Electroforesis , Femenino , Fluorescencia , Marcadores Genéticos , Edad Gestacional , Humanos , Embarazo , Trisomía/diagnóstico
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