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1.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166269, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34537368

RESUMO

OBJECTIVE: To explore the clinical features, fetal outcomes and serum bile acids (BAs) metabolism in asymptomatic hypercholanemia of pregnancy (AHP), as well as the comparison with those in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies. METHODS: A study containing 676 pregnant women was performed to investigate the clinical informations, routine biochemical features and obstetric outcomes of AHP by the comparison with ICP and normal pregnancies. Within the study subjects, 203 pregnant women received prospective determination for 55 serum individual BAs based on a validated UPLC-QTOF-MS/MS method. The differences in clinical features and serum BAs metabolism among the three groups were then investigated. RESULTS: The risk of adverse fetal outcomes in AHP (28.3%) was significantly higher than that in normal pregnancies (8.9%, p < 0.001), but lower than that in ICP group (52.1%, p < 0.001). Multivariate statistics analysis indicated a distinctive serum BAs metabolic profiling among the three groups (PLS-DA, R2Y = 0.580, Q2 = 0.537). Levels of serum BAs especially for deoxycholic acid species were found remarkably elevated in AHP as compared to those in ICP. CONCLUSIONS: AHP group had distinguished clinical features and serum BAs metabolism as compared to ICP group and normal pregnancies.


Assuntos
Ácidos e Sais Biliares/sangue , Colestase Intra-Hepática/metabolismo , Ácidos Cólicos/sangue , Metabolismo dos Lipídeos , Complicações na Gravidez/metabolismo , Erros Inatos do Metabolismo de Esteroides/metabolismo , Adulto , Doenças Assintomáticas/epidemiologia , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/epidemiologia , Colestase Intra-Hepática/patologia , Ácidos Cólicos/metabolismo , Feminino , Feto , Humanos , Metabolômica/normas , Análise Multivariada , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/patologia , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/epidemiologia , Erros Inatos do Metabolismo de Esteroides/patologia , Espectrometria de Massas em Tandem
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(12): 1233-1236, 2021 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-34839514

RESUMO

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with 5α-reductase type 2 deficiency. METHODS: Clinical data of the child was retrospectively analyzed. Targeted capture-next generation sequencing and Sanger sequencing were carried out to detect potential variants. RESULTS: The patient's main features included micropenis and hypospadia. He was found to harbor compound heterozygous c.680G>A (p.R227Q) and c.3G>T (p.M1I) variants of the SRD5A2 gene. Among these, c.680G>A (p.R227Q) was inherited from his father and was a known pathogenic mutation, while c.3G>T (p.M1I) was inherited from his mother and was unreported previously. CONCLUSION: The compound heterozygous variants of the SRD5A2 gene probably underlay the disease in this child, who was eventually diagnosed with 5α-reductase 2 deficiency.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Hipospadia , Erros Inatos do Metabolismo de Esteroides , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Criança , Humanos , Masculino , Proteínas de Membrana/genética , Mutação , Estudos Retrospectivos , Esteroides
4.
J Pediatr Urol ; 17(1): 39-47, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33246831

RESUMO

Gender assignment in infants born with a difference in sexual development (DSD) remains one of the many difficult decisions faced by the multi-disciplinary treatment team as some of these children develop gender identity disorder (GID) when they become adults. In this systematic review and meta-analysis we have analyzed the prevalence of GID in adolescent and adults with DSD. The secondary outcome of this review is to help physicians in appropriate sex assignment of DSD children so that development of GID in later life can be reduced. METHODS: Pubmed/Index medicus were searched for "intersex" [All fields] OR "disorders of sexual differentiation AND "gender identity disorder OR gender dysphoria" [MeSH] for articles published between 2005 and 2020. Typical diagnoses included were congenital adrenal hyperplasia (CAH); complete androgen insensitivity syndrome (CAIS); partial androgen insensitivity syndrome (PAIS); 5 alpha reductase deficiency (5ARD); 17-hydroxysteroid dehydrogenase deficiency (17HSD); mixed gonadal dysgenesis (MGD) and complete gonadal dysgenesis (CGD). GID or gender dysphoria (a strong feeling of dissatisfaction about oneself as male or female) prevalence in DSD patients older than 12 years of age was extracted. Within each condition, GID percentage was compared between female and male rearing. RESULTS: The I2statistics for prevalence of GID in DSD showed high heterogeneity with I2 of 93% (95% C.I 90-95%) among the 20 articles included. The overall prevalence of GID among those with DSD was 15% (95% C.I 13-17%). CAH reared females had 4% GID while CAH reared males had significantly higher GID at 15% (p = 0.0056). All CAIS patients were raised as females and the prevalence of GID was 1.7%. GID prevalence was 12% in PAIS raised as females while 25% in those raised as males with no significant difference (p = 0.134). GID was significantly high in 5ARD (53%) and 17HSD (53%) reared as females with half of them virilizing at puberty forcing a gender change. Among sex chromosome DSD 22% of those reared as females had GID while none in those raised as male with no significant difference. CONCLUSIONS: GID is low in women with CAH, CAIS and CGD favoring female sex of rearing in these conditions. GID is high in women with 5ARD/17HSD favoring male sex of rearing in these conditions. GID is variable in PAIS or MGD and no recommendations on sex of rearing could be made in these conditions. Each DSD patient is unique and they warrant multi-disciplinary care and long term psycho sexual support.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Transtornos do Desenvolvimento Sexual , Disforia de Gênero , Erros Inatos do Metabolismo de Esteroides , Adolescente , Adulto , Criança , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/epidemiologia , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/epidemiologia , Feminino , Disforia de Gênero/diagnóstico , Disforia de Gênero/epidemiologia , Identidade de Gênero , Humanos , Masculino , Desenvolvimento Sexual
5.
Georgian Med News ; (307): 154-157, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33270595

RESUMO

The article describes one of the forms of 46 XY DSD which is related to androgen peripheral actions. There are two disorders related to DSD with preserved testosterone production by the testes, which are Androgen insensitivity syndrome (AIS) and type 5α-reductase deficiency. Although the above-mentioned conditions have similar clinical manifestations, they are initiated by different pathogenetic mechanisms. AIS has X-linked recessive inheritance pattern and is presented by total or partial insensitivity of androgen receptors to male sex hormones.


Assuntos
Síndrome de Resistência a Andrógenos , Transtorno 46,XY do Desenvolvimento Sexual , Erros Inatos do Metabolismo de Esteroides , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Humanos , Masculino , Mutação , Receptores Androgênicos/genética
7.
Pan Afr Med J ; 36: 48, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32774624

RESUMO

Subjects with 47XYY often have normal amounts of gonadotropin-releasing hormone. In these subjects the association between 47XYY and 5-alpha reductase deficiency is rare. The common clinical manifestation of 5-alpha reductase deficiency is male pseudohermaphrodism, rarely it has been revealed by micropenis. Testosterone enanthate does not give good results in patients with 5-alpha reductase deficiency; dihydrotestosterone (DHT) has proven effectiveness in these cases. We report the case of a 17-year old patient, referred to our Hospital with micropenis. The patient didn't respond to two enanthate testosterone therapies. Assessment showed normal testosterone levels, amounts of gonadotropin-releasing hormone at the upper limit of normal, low DHT, elevated testosterone/DHT ratio>20, karyotype 47 XYY. This study highlights that 5-alpha reductase deficiency in these subjects raises the issue of simple coincidence or effective link.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Doenças dos Genitais Masculinos/etiologia , Hipospadia/diagnóstico , Pênis/anormalidades , Transtornos dos Cromossomos Sexuais/diagnóstico , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Cariótipo XYY/diagnóstico , Adolescente , Doenças dos Genitais Masculinos/genética , Hormônio Liberador de Gonadotropina/sangue , Humanos , Masculino , Testosterona/sangue
8.
Gene ; 757: 144949, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32679290

RESUMO

Melanocortin-2 receptor accessory protein (MRAP) has an unusual dual topology and influences the expression, localisation, signalling and internalisation of the melanocortin receptor 2 (MC2); the adrenocorticotropic hormone (ACTH) receptor. Mutations in MRAP are associated with familial glucocorticoid deficiency type-2 and evidence is emerging of the importance of MRAP in adrenal development and ACTH signalling. Human MRAP has two functional splice variants: MRAP-α and MRAP-ß, unlike MRAP-ß, MRAP-α has little expression in brain but is highly expressed in ovary. MRAP2, identified through whole human genome sequence analysis, has approximately 40% sequence homology to MRAP. MRAP2 facilitates MC2 localisation to the cell surface but not ACTH signalling. MRAP and MRAP2 have been found to regulate the surface expression and signalling of all melanocortin receptors (MC1-5). Additionally, MRAP2 moderates the signalling of the G-protein coupled receptors (GCPRs): orexin, prokineticin and GHSR1a; the ghrelin receptor. Whilst MRAP appears to be mainly involved in glucocorticoid synthesis, an important role is emerging for MRAP2 in regulating appetite and energy homeostasis. Transgenic models indicate the importance of MRAP in adrenal gland formation. Like MC3R and MC4R knockout mice, MRAP2 knockout mice have an obese phenotype. In vitro studies indicate that MRAP2 enhances the MC3 and MC4 response to the agonist αMSH, which, like ACTH, is produced through precursor polypeptide proopiomelanocortin (POMC) cleavage. Analysis of cohorts of individuals with obesity have revealed several MRAP2 genetic variants with loss of function mutations which are causative of monogenic hyperphagic obesity with hyperglycaemia and hypertension. MRAP2 may also be associated with female infertility. This review summarises current knowledge of MRAP and MRAP2, their influence on GPCR signalling, and focusses on pathophysiology, particularly familial glucocorticoid deficiency type-2 and obesity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Insuficiência Adrenal/genética , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo de Esteroides/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Insuficiência Adrenal/metabolismo , Animais , Regulação do Apetite , Humanos , Insulina/metabolismo , Melanocortinas/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/metabolismo
9.
Biomed Res Int ; 2020: 1789514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596280

RESUMO

Background: A deficiency in steroid 5α-reductase type 2 is an autosomal recessive disorder. Affected individuals manifested ambiguous genitalia, which is caused by decreased dihydrotestosterone (DHT) synthesis in the fetus. Methods: We analyzed 25 patients with 5α-reductase deficiency in China. Seventeen of the 25 patients (68%) were initially raised as females. Sixteen patients changed their social gender from female to male after puberty. Results: Eighteen mutations were identified in these patients. p.Gly203Ser and p.Gln6∗ were found to be the most prevalent mutations. On the basis of the genotype of these patients, we divided them into different groups. There was no significant difference in hormone levels and external masculinization score (EMS) in patients with or without these prevalent mutations. Twelve common single-nucleotide polymorphisms (SNPs) near the p.Gln6∗ mutation were chosen for haplotype analysis. Three haplotypes were observed in 6 patients who had the p.Gln6∗ mutation (12 alleles). Conclusion: We analyzed mutations of the SRD5A2 gene in Chinese patients with 5α-reductase deficiency. Although hotspot mutations exist, no founder effect of prevalent mutations in the SRD5A2 gene was detected in the Chinese population.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Criança , Pré-Escolar , China , Di-Hidrotestosterona/sangue , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/epidemiologia , Feminino , Haplótipos/genética , Humanos , Hipospadia/sangue , Hipospadia/epidemiologia , Lactente , Recém-Nascido , Masculino , Mutação/genética , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/epidemiologia , Adulto Jovem
10.
Ann Saudi Med ; 40(2): 81-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32241166

RESUMO

BACKGROUND: The relationship between breast arterial calcification (BAC) and angiographic coronary artery disease (CAD) is uncertain. Some studies have shown a positive association between BAC and angiographically proven CAD, while other studies have shown no association. OBJECTIVE: Examine the association between visually detected BAC on mammography and CAD found on invasive coronary angiography (ICA) in women and compare the frequency of risk factors for CAD between women with normal and abnormal ICA. DESIGN: Retrospective. SETTING: Single tertiary care center. PATIENTS AND METHODS: A review of the radiology databases was performed for female patients who underwent both ICA and mammography within six months of each other. Cases were excluded if there was a history of CAD, such as coronary artery bypass graft or prior percutaneous coronary intervention. MAIN OUTCOME MEASURES: BAC as a predictor of obstructive CAD on ICA. SAMPLE SIZE: 203 Saudi women RESULTS: The association between age at catheterization and ICA was statistically significant ( P=.01). There was no association between BAC and abnormal ICA ( P=.108). Women with abnormal ICA were older than women with a normal ICA ( P=.01). There was a higher frequency of CAD risk factors among the patients with abnormal ICA, except for smoking. In the multiple logistic regression model, ICA was associated with age, a family history of CAD, diabetes mellitus, hypertension and hypercholesterolemia. BAC-positive women were older than BAC-negative women ( P=.0001). BAC was associated with age, diabetes, hypertension, and chronic kidney disease in the multiple logistic regression model. CONCLUSIONS: BAC on mammography did not predict angiographically proven CAD. There was a strong association between BAC and age and many other conventional CAD risk factors. LIMITATIONS: Relatively small sample, single-center retrospective study. CONFLICT OF INTEREST: None.


Assuntos
Mama/irrigação sanguínea , Doença da Artéria Coronariana/epidemiologia , Estenose Coronária/epidemiologia , Calcificação Vascular/epidemiologia , Fatores Etários , Idoso , Mama/diagnóstico por imagem , Cateterismo Cardíaco , Ácidos Cólicos/sangue , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Estenose Coronária/diagnóstico , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Modelos Logísticos , Mamografia , Pessoa de Meia-Idade , Arábia Saudita/epidemiologia , Erros Inatos do Metabolismo de Esteroides/epidemiologia , Calcificação Vascular/diagnóstico por imagem
11.
World J Gastroenterol ; 26(5): 550-561, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32089630

RESUMO

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) encompasses a group of autosomal recessive disorders with high morbidity and mortality. Variants in the gene encoding tight junction protein-2 (TJP2) have been linked to PFIC type 4 (PFIC4), which predominantly presents in childhood. However, there are only limited data from adults with TJP2-related PFIC4. We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4. CASE SUMMARY: The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers. In 2018, he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019. Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4 (TJP2([NM_004817.3]:c.[3334C>T]; [3334C>T])). The consanguineous family consists of the father and mother (both heterozygous) and their 12 children, of which five carry the variant in a homozygous state; however, these five siblings have highly variable expression of PFIC4. Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36. Two other homozygous brothers, age 23 and 19, and the homozygous sister, age 21, have elevated liver enzymes but presently no cirrhosis, which may suggest an age-dependent penetrance. In addition, five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state, respectively. CONCLUSION: This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.


Assuntos
Colestase/genética , Erros Inatos do Metabolismo de Esteroides/genética , Proteína da Zônula de Oclusão-2/genética , Adulto , Idoso , Biópsia , Colestase/diagnóstico , Colestase/patologia , Consanguinidade , Dinamarca , Emigrantes e Imigrantes , Feminino , Heterozigoto , Homozigoto , Humanos , Fígado/patologia , Masculino , Anamnese , Pessoa de Meia-Idade , Linhagem , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Erros Inatos do Metabolismo de Esteroides/patologia , Síria , Adulto Jovem
12.
J Ayub Med Coll Abbottabad ; 31(3): 454-458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535527

RESUMO

The term intersex used in the past has been replaced by "Disorders of Sex Differentiation". In this condition the development of chromosomal, gonadal or anatomical sex is atypical. This problem creates anxiety to the parents and a challenge for attending doctor. The problems faced by the individual are sexual, reproductive, sex of raring, placement in the society and psychological impact. The optimal management of the patient should be individualized by multidisciplinary team. Three cases of Disorders of Sex Differentiation (DSD) are presented with different causes and presentations. Two cases carrying XY karyotype pattern, while one case was of XX. The diagnosis of swyers syndrome, 5 alpha reductase deficiency and congenital adrenal hyperplasia was made on the basis of genital tract development, hormonal analysis and karyotyping. The strange feature which was common in all these cases was the wish of patients as well as family members to adopt sex of raring as male.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Hiperplasia Suprarrenal Congênita/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Disgenesia Gonadal 46 XY/diagnóstico , Hipospadia/diagnóstico , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Adolescente , Hiperplasia Suprarrenal Congênita/terapia , Criança , Transtorno 46,XY do Desenvolvimento Sexual/terapia , Feminino , Disgenesia Gonadal 46 XY/terapia , Humanos , Hipospadia/terapia , Masculino , Erros Inatos do Metabolismo de Esteroides/terapia , Adulto Jovem
13.
J Pak Med Assoc ; 69(8): 1090-1093, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431758

RESUMO

OBJECTIVE: To determine diagnostic accuracy of human chorionic gonadotropins stimulation test in differentiating androgen insensitivity syndrome and 5-alpha reductase deficiency, keeping testosterone to dihydrotestosterone ratio as the gold standard. METHODS: The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to December, 2016, and comprised patients aged 01 day to 20 years having XY chromosomes on karyotyping and with a spectrum of phenotypes. Blood samples were collected from each subject for basal serum testosterone, serum luteinizing hormone and serum follicular stimulating hormone level. Human chorionic gonadotropins stimulation test was performed in every subject as per the protocol. Sandwich chemiluminescence immunoassay technique was used to analyse serum samples. Serum dihydrotestosterone level was also detected to determine testosterone and dihydrotestosterone ratio. Data was analysed using SPSS 24. . RESULTS: Of the 104 subjects with a mean age of 1.78}0.95 years,96(92.3%) were diagnosed as cases of androgen insensitivity syndrome on the basis of human chorionic gonadotropins stimulation response level, which was 2-9 times of basal serum testosterone level. Also, 8(7.7%) subjects were diagnosed to have 5-alpha reductase deficiency syndrome. In such subjects, post-human chorionic gonadotropins response level of serum testosterone was more than 10 times of the basal level. CONCLUSIONS: The human chorionic gonadotropins stimulation test was found to be comparable to testosterone-to dihydrotestosterone ratio in differentiating between case of androgen insensitivity syndrome and 5-alpha reductase deficiency.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Síndrome de Resistência a Andrógenos/diagnóstico , Gonadotropina Coriônica , Di-Hidrotestosterona/sangue , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Hipospadia/diagnóstico , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Testosterona/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Adolescente , Síndrome de Resistência a Andrógenos/sangue , Criança , Pré-Escolar , Diagnóstico Diferencial , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hipospadia/sangue , Lactente , Recém-Nascido , Hormônio Luteinizante/sangue , Masculino , Valor Preditivo dos Testes , Erros Inatos do Metabolismo de Esteroides/sangue , Adulto Jovem
14.
Endocr Rev ; 40(6): 1605-1625, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31294783

RESUMO

Steroid biosynthesis and metabolism are reflected by the serum steroid metabolome and, in even more detail, by the 24-hour urine steroid metabolome, which can provide unique insights into alterations of steroid flow and output indicative of underlying conditions. Mass spectrometry-based steroid metabolome profiling has allowed for the identification of unique multisteroid signatures associated with disorders of steroid biosynthesis and metabolism that can be used for personalized approaches to diagnosis, differential diagnosis, and prognostic prediction. Additionally, steroid metabolome analysis has been used successfully as a discovery tool, for the identification of novel steroidogenic disorders and pathways as well as revealing insights into the pathophysiology of adrenal disease. Increased availability and technological advances in mass spectrometry-based methodologies have refocused attention on steroid metabolome profiling and facilitated the development of high-throughput steroid profiling methods soon to reach clinical practice. Furthermore, steroid metabolomics, the combination of mass spectrometry-based steroid analysis with machine learning-based approaches, has facilitated the development of powerful customized diagnostic approaches. In this review, we provide a comprehensive up-to-date overview of the utility of steroid metabolome analysis for the diagnosis and management of inborn disorders of steroidogenesis and autonomous adrenal steroid excess in the context of adrenal tumors.


Assuntos
Doenças das Glândulas Suprarrenais/metabolismo , Metaboloma , Erros Inatos do Metabolismo de Esteroides/metabolismo , Doenças das Glândulas Suprarrenais/diagnóstico , Diagnóstico Diferencial , Humanos , Erros Inatos do Metabolismo de Esteroides/diagnóstico
16.
J Med Genet ; 56(10): 685-692, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31186340

RESUMO

BACKGROUND: The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype-genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis. METHODS: 190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed. RESULTS: Hypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001). CONCLUSIONS: This study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype-phenotype correlation of SRD5A2.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Criança , Pré-Escolar , China , Estudos de Coortes , Éxons/genética , Feminino , Efeito Fundador , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo
17.
Endocr J ; 66(9): 837-842, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31178538

RESUMO

Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5ß-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Di-Hidrotestosterona/administração & dosagem , Transtorno 46,XY do Desenvolvimento Sexual/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Hipospadia/tratamento farmacológico , Pênis/anormalidades , Pênis/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/tratamento farmacológico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Esquema de Medicação , Doenças dos Genitais Masculinos/sangue , Doenças dos Genitais Masculinos/genética , Humanos , Hipospadia/sangue , Hipospadia/genética , Hipospadia/patologia , Estudos Longitudinais , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Mutação , Pênis/crescimento & desenvolvimento , Pênis/patologia , Puberdade/fisiologia , Maturidade Sexual/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/genética , Erros Inatos do Metabolismo de Esteroides/patologia , Testosterona/sangue , Fatores de Tempo , Resultado do Tratamento
18.
J Pak Med Assoc ; 69(5): 711-717, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31105293

RESUMO

Disorders of sex development (DSD) are defined as discrepancy between chromosomal, gonadal and anatomic sex. The basic principles for the management of DSD include a multidisciplinary approach for gender assignment. Clinical assessment includes a detailed history and examination of external genitalia. Most of the disorders with symmetrical gonades indicate hormonal cause while asymmetrical gonades are found in chromosomal DSDs. Karyotyping will indicate a 46XX DSD, 46 XY DSD or mosicism. Internal anatomy is defined by ultrasonography, genitoscopy and laparoscopy. Human chorionic gonadotrophins (hCG) stimulation test is carried out in under-virilised males to see the function of Leydig cells in testes. The Most common cause of 46XX DSD is congenital adrenal hyperplasia (CAH). The decision of gender assignment surgery is to be taken in a multidisciplinary environment and with informed consent of the parents. Most of 46 XX CAH patients, even if markedly virilised, and 46 XY complete androgen insensitivity syndrome are raised as females. Similarly, most of 5-α reductase deficiency and 17-ß hydroxysteroid dehydrogenase deficiency patients are assigned to the male gender. The decision in cases of mixed gondal dysgenesis and ovotesticular DSD is based on the development of external and internal genitalia. Patients with androgen biosynthetic defects, partial androgen insensitivity syndrome are usually assigned to the male gender.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , 17-Hidroxiesteroide Desidrogenases/deficiência , Hiperplasia Suprarrenal Congênita/diagnóstico , Síndrome de Resistência a Andrógenos/diagnóstico , Colestenona 5 alfa-Redutase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Feminino , Disgenesia Gonadal/diagnóstico , Ginecomastia/diagnóstico , Humanos , Cariotipagem , Masculino , Erros Inatos do Metabolismo de Esteroides/diagnóstico
19.
Asian J Androl ; 21(6): 577-581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031332

RESUMO

In this study, we investigated the genetics, clinical features, and therapeutic approach of 14 patients with 5α-reductase deficiency in China. Genotyping analysis was performed by direct sequencing of PCR products of the steroid 5α-reductase type 2 gene (SRD5A2). The 5α-reductase activities of three novel mutations were investigated by mutagenesis and an in vitro transfection assay. Most patients presented with a microphallus, variable degrees of hypospadias, and cryptorchidism. Eight of 14 patients (57.1%) were initially reared as females and changed their social gender from female to male after puberty. Nine mutations were identified in the 14 patients. p.G203S, p.Q6X, and p.R227Q were the most prevalent mutations. Three mutations (p.K35N, p.H162P, and p.Y136X) have not been reported previously. The nonsense mutation p.Y136X abolished enzymatic activity, whereas p.K35N and p.H162P retained partial enzymatic activity. Topical administration of dihydrotestosterone during infancy or early childhood combined with hypospadia repair surgery had good therapeutic results. In conclusion, we expand the mutation profile of SRD5A2 in the Chinese population. A rational clinical approach to this disorder requires early and accurate diagnosis, especially genetic diagnosis.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Criança , Pré-Escolar , China , Hormônio Foliculoestimulante/sangue , Genitália Masculina/anormalidades , Humanos , Hormônio Luteinizante/sangue , Masculino , Mutação/genética , Alinhamento de Sequência , Testosterona/sangue , Adulto Jovem
20.
Clin Endocrinol (Oxf) ; 91(2): 237-244, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31004515

RESUMO

BACKGROUND: Discordance between gonadal type and gender identity has often led to an assumption of infertility in patients with differences in sex development (DSD). However, there is now greater recognition of fertility being an important issue for this group of patients. Currently, gonadal tissue that may have fertility potential is not being stored for individuals with DSD and, where gonadectomy forms part of management, is often discarded. The area of fertility preservation has been predominantly driven by oncofertility which is a field dedicated to preserving the fertility of patients undergoing gonadotoxic cancer treatment. The use of fertility preservation techniques could be expanded to include individuals with DSD where functioning gonads are present. METHODS: This is a systematic literature review evaluating original research articles and relevant reviews between 1974 and 2018 addressing DSD and fertility, in vitro maturation of sperm, and histological/ultrastructural assessment of gonadal tissue in complete and partial androgen insensitivity syndrome, 17ß-hydroxysteroid dehydrogenase type 3 and 5α-reductase deficiency. CONCLUSION: Successful clinical outcomes of ovarian tissue cryopreservation are paving the way for similar research being conducted using testicular tissue and sperm. There have been promising results from both animal and human studies leading to cryopreservation of testicular tissue now being offered to boys prior to cancer treatment. Although data are limited, there is evidence to suggest the presence of reproductive potential in the gonads of some individuals with DSD. Larger, more detailed studies are required, but if these continue to be encouraging, individuals with DSD should be given the same information, opportunities and access to fertility preservation as other patient groups.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Criopreservação/métodos , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Transtornos do Desenvolvimento Sexual/fisiopatologia , Preservação da Fertilidade/métodos , Hipospadia/fisiopatologia , Erros Inatos do Metabolismo de Esteroides/fisiopatologia , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/diagnóstico , Feminino , Humanos , Hipospadia/diagnóstico , Masculino , Ovário/fisiologia , Reprodução/fisiologia , Espermatozoides/fisiologia , Erros Inatos do Metabolismo de Esteroides/diagnóstico
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