RESUMO
BACKGROUND: Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. METHODS: Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99 years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8 bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. RESULTS: Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. CONCLUSION: Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.
Assuntos
Hiperplasia Suprarrenal Congênita , Cortisona/biossíntese , Esteroide 21-Hidroxilase/genética , Virilismo , Desequilíbrio Hidroeletrolítico , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/fisiopatologia , Criança , Egito/epidemiologia , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Lactente , Masculino , Mutação , Seleção de Pacientes , Virilismo/diagnóstico , Virilismo/epidemiologia , Virilismo/genética , Desequilíbrio Hidroeletrolítico/diagnóstico , Desequilíbrio Hidroeletrolítico/epidemiologia , Desequilíbrio Hidroeletrolítico/genética , Adulto JovemRESUMO
Objective: To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male. Methods: A national database was created. The data of patients were asked to be recorded in the data form. Results: The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%. Conclusion: It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Hiperplasia Suprarrenal Congênita , Virilismo , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/epidemiologia , Transtornos 46, XX do Desenvolvimento Sexual/terapia , Adolescente , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/terapia , Adulto , Criança , Pré-Escolar , Escolaridade , Feminino , Seguimentos , Terapia de Reposição Hormonal , Humanos , Lactente , Masculino , Estudos Retrospectivos , Cirurgia de Readequação Sexual , Virilismo/diagnóstico , Virilismo/epidemiologia , Virilismo/terapia , Adulto JovemAssuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Estatura , Hipertensão , Virilismo , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Feminino , Humanos , Hipertensão/enzimologia , Hipertensão/epidemiologia , Hipopotassemia/enzimologia , Hipopotassemia/epidemiologia , Mutação , Esteroide 11-beta-Hidroxilase/genética , Virilismo/diagnóstico , Virilismo/enzimologia , Virilismo/epidemiologia , Adulto JovemRESUMO
Childhood adrenocortical tumors (ACTs) are rare, representing â¼0.2% of all pediatric malignancies and having an incidence of 0.2-0.3 new cases per million per year in the United States, but incidences are remarkably higher in Southern Brazil. At diagnosis, most children show signs and symptoms of virilization, Cushing syndrome, or both. Less than 10% of patients with ACT exhibit no endocrine syndrome at presentation, although some show abnormal concentrations of adrenal cortex hormones. Pediatric ACT is commonly associated with constitutional genetic and/or epigenetic alterations, represented by germline TP53 mutations or chromosome 11p abnormalities. Complete tumor resection is required to achieve cure. The role of chemotherapy is not established, although definitive responses to several anticancer drugs are documented. For patients undergoing complete tumor resection, favorable prognostic factors include young age, small tumor size, virilization, and adenoma histology. Prospective studies are necessary to further elucidate the pathogenesis of ACT and improve patient outcomes.
Assuntos
Adenoma/epidemiologia , Neoplasias do Córtex Suprarrenal/epidemiologia , Adenoma/diagnóstico , Adenoma/genética , Adenoma/patologia , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Idade de Início , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Prognóstico , Estudos Prospectivos , Virilismo/epidemiologia , Virilismo/etiologiaRESUMO
The aim of the study was to investigate the molecular mechanisms in childhood adrenocortical tumors (ACTs), which is still unclear.A total of 9 girls and 4 boys with ACTs were enrolled. Relevant clinical features were obtained from records. Immunohistochemistry of vimentin, chromogranin A, S100, synaptophysin, cytokeratin (CK), type 2 3ß-hydroxysteroid dehydrogenase (3ßHSD), cytochrome P45017α, p53, p21, p27, cyclin D1, Ki-67, insulin growth facter-2 (IGF-2), and ß-catenin were undertaken for 13 tumors and 3 adjacent normal tissues. TP53 mutations in exon 2-11 were analyzed for 6 tumors and 3 blood samples.Virilization was the most common presentation (8/13, 61.5%). Immunohistochemically, p53 was positive in 8 of 13 ACTs and none in controls while p21 was positive in 12 of 13 ACTs and none in controls (Pâ=â.0036). Ki-67 was positive in 10 of 13 ACTs, but not in normal tissues (Pâ=â.0089). Although the expression of p27, cyclin D1, IGF-2 and ß-catenin were similar between the ACTs and controls, ß-catenin was noted in nuclear of 3 ACTs but not in controls. The difference of type 2 3ßHSD and P450c17α was not significant (Pâ>â.05, respectively). Four variants of TP53 were identified in the 6 tumors. C215G variant was found in 5 of 6 while A701G and G743A variants were found in 1 case, respectively. A novel C680G variant was also noted in 1 case. It was notable that C215G variant was found in the blood mononuclear cell of 3 patients.In conclusion, p53 variant and p21 overexpression, and abnormal ß-catenin distribution may be involved in the etiology and mechanism of childhood ACTs.
Assuntos
Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/patologia , Virilismo/epidemiologia , 3-Hidroxiesteroide Desidrogenases/biossíntese , Neoplasias do Córtex Suprarrenal/cirurgia , Fatores Etários , Criança , Pré-Escolar , Cromogranina A/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Lactente , Fator de Crescimento Insulin-Like II/biossíntese , Queratinas/biossíntese , Antígeno Ki-67/biossíntese , Masculino , Proteínas de Ligação a Poli-ADP-Ribose/biossíntese , Fatores Sexuais , Sinaptofisina/biossíntese , Vimentina/biossínteseRESUMO
CONTEXT: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions. OBJECTIVE: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test). DESIGN AND SETTING: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice. PATIENTS: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included. INTERVENTION: DEX was offered after informed consent to pregnant women. MAIN OUTCOME MEASURE: The sensitivity of an early SRY test was evaluated after data collection. RESULTS: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero. CONCLUSIONS: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Terapias Fetais , Troca Materno-Fetal , Diagnóstico Pré-Natal/métodos , Análise para Determinação do Sexo/métodos , Hiperplasia Suprarrenal Congênita/sangue , Análise Química do Sangue , Estudos de Coortes , Feminino , Terapias Fetais/métodos , Terapias Fetais/estatística & dados numéricos , França/epidemiologia , Humanos , Masculino , Gravidez/sangue , Diagnóstico Pré-Natal/estatística & dados numéricos , Fatores de Risco , Virilismo/epidemiologia , Virilismo/prevenção & controleAssuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Virilismo/prevenção & controle , Hiperplasia Suprarrenal Congênita/epidemiologia , Ensaios Clínicos como Assunto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Estudos Multicêntricos como Assunto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fatores de Risco , Suécia , Virilismo/epidemiologiaRESUMO
OBJECTIVES: To estimate the incidence of clinically diagnosed congenital adrenal hyperplasia (CAH), clinical features and age at first presentation. To assess the potential benefit of newborn screening for CAH. DESIGN: Active surveillance through the British Paediatric Surveillance Unit of all children aged under 16 years with newly diagnosed CAH, undertaken prospectively between August 2007 and August 2009. Twelve laboratories testing for CAH reported new diagnoses between August 2007 and January 2009. Reporting clinicians completed clinical questionnaires. SETTING: England, Wales and Scotland. RESULTS: 144 children with CAH were reported, of whom 132 (92%) had 21-hydroxylase deficiency. Thirty-six (25%) children were Asian and 62 (43%; 95% CI 35% to 51%) were boys. Incidence of new diagnoses in children ≤ 16 years was 0.60 (95% CI 0.50 to 0.71) per 100,000. Eighty-six (59%; 36 boys) children were diagnosed in the first year of life (estimated birth prevalence 5.48 (95% CI 4.42 to 6.81) per 100,000), most (77; 89%) of whom presented in the first month of life. Virilised genitalia were found in three-quarters of girls. Twenty-seven newborns first presented with salt-wasting crises, of whom 18 (67%; 16 boys) presented on or after 14 days of age. CONCLUSIONS: Approximately one child in every 18 000 born in Great Britain has CAH. Similar numbers of boys and girls present clinically in the first year of life, but boys present with more severe manifestations, such as salt-wasting crises. Around 70% of newborns who first present with salt-wasting crisis would be detected earlier through newborn screening.
Assuntos
Hiperplasia Suprarrenal Congênita/epidemiologia , Adolescente , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Distribuição por Idade , Criança , Pré-Escolar , Métodos Epidemiológicos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Distribuição por Sexo , Esteroide 21-Hidroxilase/sangue , Reino Unido/epidemiologia , Virilismo/epidemiologia , Virilismo/etiologiaRESUMO
The long-term impacts on marine ecosystems of the recent dramatic worldwide increase in the incidence of coastal hypoxia are unknown. Here, we show widespread reproductive disruption in Atlantic croakers collected from hypoxic sites approximately 120 km apart in the extensive northern Gulf of Mexico continental shelf hypoxic zone. Gonadal growth and gamete production were impaired in croakers from hypoxic sites compared with fish from reference normoxic sites east of the Mississippi River Delta. Male germ cells were detected in approximately 19 per cent of croaker ovaries collected in the hypoxic region, but were absent in ovaries from normoxic sites. In addition, the sex ratio was skewed towards males at the hypoxic sites. The masculinization and other reproductive disruptions were associated with declines in neuroendocrine function, as well as ovarian and brain expression of aromatase (the enzyme that converts androgens to oestrogens). A similar incidence of ovarian masculinization and decline in ovarian aromatase expression were observed in croaker after chronic laboratory hypoxia exposure, indicating that ovarian masculinization is a specific hypoxia response and is due to decreased aromatase activity. The results suggest severe reproductive impairment can occur over large coastal regions in marine fish populations exposed to seasonal hypoxia, with potential long-term impacts on population abundance.
Assuntos
Aromatase/metabolismo , Doenças dos Peixes/fisiopatologia , Ovário/fisiopatologia , Perciformes/crescimento & desenvolvimento , Reprodução , Virilismo/veterinária , Anaerobiose , Animais , Monitoramento Ambiental , Ensaio de Imunoadsorção Enzimática/veterinária , Monitoramento Epidemiológico , Feminino , Doenças dos Peixes/epidemiologia , Doenças dos Peixes/etiologia , Golfo do México/epidemiologia , Louisiana/epidemiologia , Masculino , Oxigênio , RNA Mensageiro/metabolismo , Radioimunoensaio/veterinária , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Estações do Ano , Virilismo/epidemiologia , Virilismo/etiologia , Virilismo/fisiopatologiaRESUMO
Classical congenital adrenal hyperplasia (CAH) is characterized by the defects in cortisol and aldosterone secretion, and accompanied with adrenal hyperandrogenism. It is likely that the impaired adrenocortical function and intermittent treatment-related hypercortisolism may predispose patients to the development of metabolic syndrome in adulthood. Our aim was to assess the impact of hyperandrogenism on metabolic profiles in CAH women without glucocorticosteroid treatment. We evaluated the clinical characteristics and metabolic profiles in 30 untreated Chinese female adults with simple virilizing congenital adrenal hyperplasia (SV-CAH). Mutation analysis was performed by sequencing the entire 21-hydroxylase gene (CYP21A2). As compared with the controls, CAH patients had higher BMI (BMI, 21.5±2.1 vs. 20.0±1.8 kg/m2, P<0.05), higher 2 h post-load plasma glucose levels (6. 35±1.74 vs. 5. 35±1.17 mmol/l, P<0.05), higher serum triglycerides (TG) (1.12±0.64 vs. 0.63±0.15 mmol/l, P<0.01), and lower high-density lipoprotein cholesterol (HDL-c) (1.30±0.39 vs. 1.67±0.29 mmol/l, P<0.01). Moreover, CAH patients had higher fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (1.81±0.99 vs. 1.24±0.50, P<0.05), while ΔIns30/ΔGlu30 showed no statistically significant difference in two groups. In addition, a marked reduction of serum adiponectin levels were observed in CAH patients (7.0±3.3 vs. 13.2±4.8 µg/ml, P<0.001), however, serum CRP levels were not different between patients and the controls. Further regression analysis showed that higher serum testosterone concentrations were associated with metabolic disorder indexes and reduction of serum adiponectin. Our study demonstrates that untreated CAH patients are prone to have metabolic disorders in association with elevated serum testosterone levels and reduced insulin insensitivity.
Assuntos
Hiperplasia Suprarrenal Congênita/metabolismo , Resistência à Insulina/fisiologia , Doenças Metabólicas/metabolismo , Esteroide 21-Hidroxilase/genética , Virilismo/metabolismo , Adiponectina/sangue , Adolescente , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/genética , Adulto , Índice de Massa Corporal , Análise Mutacional de DNA , Feminino , Humanos , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Fatores de Risco , Testosterona/sangue , Virilismo/epidemiologia , Virilismo/genética , Adulto JovemRESUMO
While understanding somatic variability among wild primates can provide insight into natural patterns of developmental plasticity, published data for living populations are rare. Here we provide such information for two distinct wild populations of Lemur catta. Variants observed include microtia, athelia, and female virilization. Dental variants observed include individuals with supernumerary teeth, rotated teeth, maxillary incisor agenesis, and severe malocclusion. There was a sex bias in incisor agenesis, with 5 of 7 examples (71%) found in males. The frequency of dental variants in our sample is lower than that seen in many other lemuriformes, as well as other primates. This may be a product of their less derived dental formula and/or their relatively fast dental development. Amassing such data is a critical first step to assess if wild primate populations are exhibiting normal variability or are being affected by potential inbreeding and/or environmental effects.
Assuntos
Lemur/anatomia & histologia , Fenótipo , Doenças dos Primatas/epidemiologia , Anormalidades Dentárias/veterinária , Virilismo/veterinária , Animais , Animais Selvagens , Orelha Externa/anormalidades , Feminino , Dedos/anormalidades , Variação Genética , Genitália Feminina/anormalidades , Lemur/anormalidades , Madagáscar/epidemiologia , Masculino , Má Oclusão/epidemiologia , Má Oclusão/veterinária , Mamilos/anormalidades , Fatores Sexuais , Anormalidades Dentárias/epidemiologia , Virilismo/epidemiologiaRESUMO
The aim of our study was to investigate clinical, hormonal and histological features of ovarian stromal hyperthecosis We have studied 104 patients with a histological diagnosis of ovarian stromal hyperthecosis and hyperplasia. Analyzing the results we can conclude that clinical features of ovarian stromal hyperthecosis and hyperplasia with polycystic ovarian disease and without it were identical and characterised by virilization syndrome, disorders of menstrual cycle and reproductive function; metabolic and vegeto-vascular disorders; breast and endometrial hyperplasias, high blood level of testosterone . The histological study of ovarian stromal hyperthecosis has showed that superficial part of ovarian cortex is hypocellular and fibrotic, contains scattered follicles with few granulosa cells, luteinized internal theca cells, hyperplasia of deep cortex and medulla, corpus luteus is absent.
Assuntos
Neoplasias Ovarianas/patologia , Tumor da Célula Tecal/patologia , Adulto , Amenorreia/epidemiologia , Feminino , Humanos , Hiperplasia/epidemiologia , Hiperplasia/patologia , Hiperplasia/cirurgia , Infertilidade Feminina/epidemiologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/cirurgia , Tumor da Célula Tecal/epidemiologia , Tumor da Célula Tecal/cirurgia , Virilismo/epidemiologiaRESUMO
By clinical examination of 700 adolescent girls aged 11-17 high frequency of androgen depended manifestations, such as acne, seborrhea, hypertrichosis or their combination was detected in prepubertal and pubertal periods (4.7%, 6.8%, 2.9% and 20.6%, 5.3%, 3.0% correspondingly). Above-mentioned signs developed as a result of activation of androgens secretion by adrenal glands and ovaries, which are physiological processes during pubertal period. The combination of these signs with hirsutism and menstrual disorders may be a manifestation of endocrine- reproductive disorders. Results of our data indicate to infirmity, expediency and importance of prophylactic examination among adolescent girls. Low rate of attendance to medical care among adolescents with clinical manifestations with probable endocrine and reproductive disorders indicates to the importance of their early diagnosis during adolescence and timely initiation of the treatment.