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Objetivo: Descrever o diagnóstico e manejo clínico da deficiência da 21-hidroxilase (D-21OH), no contexto atual de inclusão da doença nos programas de triagem neonatal, bem como características genéticas, fisiopatológicas e manifestações na infância e adolescência. Fonte de Dados: Revisão integrativa realizada nas bases de dados MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science nos últimos vinte anos, em língua inglesa e portuguesa; população-alvo: crianças da primeira infância à adolescência; com o uso dos termos "triagem neonatal", "hiperplasia adrenal congênita", "deficiência da 21-hidroxilase", "glucocorticoide" e "polimorfismos do gene NR3C1". Síntese de Dados: A hiperplasia adrenal congênita (HAC) constitui um grupo de doenças caracterizadas por deficiências enzimáticas na esteroidogênese do córtex adrenal. A D-21OH é responsável por 95% dos casos e, se não tratada precocemente, pode levar ao óbito no período neonatal em sua forma clássica. A triagem neonatal para a HAC consiste na dosagem do precursor 17-hidroxiprogesterona (17OHP) no sangue de recém-nascidos, permitindo rápida confirmação diagnóstica e instituição da terapêutica. A implantação da triagem neonatal constitui um avanço, mas o controle dos pacientes pediátricos com D-21OH é complexo e deve ser sempre individualizado. Conclusão: A instituição dos programas de triagem neonatal para HAC tem trazido benefícios para o prognóstico das crianças com D-21OH. Seu manejo é multiprofissional, individualizado e ainda um desafio mesmo para o especialista. Ampla divulgação do conhecimento sobre a doença é desejável para permitir melhor condução dessas crianças, especialmente de meninas com a doença que apresentam genitália atípica.
Objective: To describe the diagnosis and clinical management of 21-hydroxylase deficiency (21OH-D), in the current context of including the disease in neonatal screening programs, as well as genetic, pathophysiological characteristics, and manifestations in childhood and adolescence. Data Source: Integrative review performed in MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science databases in the last twenty years, in English and Portuguese; target population: children from early childhood to adolescence; with the use of the terms "neonatal screening"; "congenital adrenal hyperplasia"; "21-hydroxylase deficiency"; "glucocorticoid"; "polymorphisms of the NR3C1 gene". Data Synthesis: Congenital adrenal hyperplasia (CAH) is a group of diseases characterized by enzyme deficiencies in adrenal cortex steroidogenesis. 21OH-D is responsible for 95% of cases and, if not treated early, can lead to death in the neonatal period in its classic form. Neonatal screening for CAH consists of measuring the precursor 17-hydroxyprogesterone (17OHP) in the blood of newborns, allowing rapid diagnostic confirmation and institution of therapy. The implementation of neonatal screening is an advance, but the control of pediatric patients with 21OH-D is complex and must always be individualized. Conclusion: The institution of newborn screening programs for CAH has benefits for the prognosis of children with 21OH-D. Its management is multi-professional, individualized and still a challenge even for the specialist. Wide dissemination of knowledge about the disease is desirable to allow better management of these children, especially girls with the disease who have atypical genitalia.
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Humanos , Masculino , Femenino , Niño , Adolescente , Esteroide 21-Hidroxilasa/metabolismo , Hiperplasia Suprarrenal Congénita/terapia , Polimorfismo Genético/genética , Tamizaje Neonatal , Hiperplasia Suprarrenal Congénita/diagnóstico , 17-alfa-Hidroxiprogesterona/metabolismoRESUMEN
BACKGROUND: Lifelong glucocorticoid (GC) replacement is the mainstay treatment of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21-OHD). Challenges posed by therapeutic management of these patients are well known, but novel insights into the variability in clinical response to GC highlight a role for single nucleotide polymorphisms (SNPs) of the glucocorticoid receptor gene (NR3C1). AIM: To assess whether six commonly studied NR3C1 SNPs, which were previously associated with modified response to GC, are associated with CAH. We further assessed the linkage disequilibrium (LD) among these NR3C1 SNPs and their combination into haplotypes. METHODS: Genotypes were determined by Taqman allele discrimination assays for Tth111I (rs10052957), ER22 (rs6189), 23 EK (rs6190), N363S (rs56149945), BclI (rs41423247) and 9ß (rs6198) in a Brazilian cohort of 102 unrelated 21-OHD patients and 163 unrelated healthy subjects (controls). Haplotypes were estimated using Haplo.stats, and LD among SNPs using Haploview. RESULTS: Heterozygous subjects for Tth111I were more frequent in 21-OHD patients (P = 0.004), while heterozygous for BclI were more frequent in controls (P = 0.049). We found a strong LD among the six NR3C1 SNPs, and four out of six common haplotypes contained the Tth111I-variant. Although we found no significant differences in overall haplotype analysis, the BclI-haplotype was less frequent among 21-OHD patients (P = 0.0180). CONCLUSIONS: BclI-haplotype was less common and heterozygous for Tth111I were more frequent in 21-OHD patients, while heterozygous for BclI were more frequent in controls. Our novel findings may contribute to further clinical studies on the prognostic value of NR3C1 haplotypes towards individualized treatment for 21-OHD patients.
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Hiperplasia Suprarrenal Congénita/genética , Polimorfismo de Nucleótido Simple , Receptores de Glucocorticoides/genética , Adolescente , Brasil , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , MasculinoRESUMEN
ABSTRACT Objective: To contribute to the assessment of normal parameters of carotid intima-media thickness (CIMT) in healthy adolescents. Methods: A cross-sectional study was conducted through clinical, laboratory and ultrasound evaluation in 61 healthy adolescents. The inclusion criteria consisted of being in good health. The exclusion criteria were: presence or history of any chronic disease; being obese or overweight according to the World Health Organization (WHO) established criterion; continuous use of medication; or presenting a febrile condition or requiring medication within 48-hours prior to assessment. The pubertal stages were evaluated using the Tanner criteria. The high-resolution B-mode ultrasound examinations were performed according to the recommendations of the Consensus Statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Results: Adolescents were 14±2.6 years old, 62.3% female, 19 (31%) at early puberty (Tanner II and III), and 38 (62%) at late puberty (Tanner IV and V). They presented normal clinical and laboratorial parameters. CIMT values were 0.46±0.04 to 0.55±0.04 mm on the right and 0.48±0.02 to 0.53±0.04 mm on the left, according to pubertal maturation. CIMT values increased significantly on the right and left sides, according to pubertal stage (p<0.001 and p=0.016), and maximum internal diameters of the common carotid artery (p<0.025 and p<0.003). It was higher in males compared to females. Conclusions: An increase in CIMT in the healthy adolescents group, according to both age, and the degree of pubertal maturation should be considered when evaluating adolescents in diagnostic procedures.
RESUMO Objetivo: Contribuir para a avaliação dos parâmetros normais da espessura médio-intimal carotídea (EMIC) em adolescentes saudáveis. Métodos: Estudo transversal realizado por meio de avaliações clínicas, laboratoriais e ultrassonográficas em 61 adolescentes saudáveis. O critério de inclusão foi ter boa saúde. Os critérios de exclusão foram: presença ou histórico de doença crônica; obesidade ou sobrepeso segundo os parâmetros estabelecidos pela Organização Mundial da Saúde (OMS); uso contínuo de medicação; e quadro febril ou que necessitasse de uso de medicação nas 48 horas anteriores à avaliação. Os estágios puberais foram avaliados pela escala de Tanner. As ultrassonografias em modo B de alta resolução foram realizadas seguindo as recomendações do Consensus Statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force (Declaração de Consenso da Força Tarefa da Sociedade Americana de Ecocardiografia sobre Espessura Médio-Intimal Carotídea). Resultados: Os adolescentes tinham 14±2,6 anos, 62,3% eram do sexo feminino, 19 (31%) estavam em estágios iniciais da puberdade (2 e 3) e 38 (62%) em estágios avançados (4 e 5) de acordo com a escala de Tanner. Todos apresentavam parâmetros clínicos e laboratoriais normais. Os valores da EMIC variaram de 0,46±0,04 a 0,55±0,04 mm do lado direito e 0,48±0,02 a 0,53±0,04 mm do lado esquerdo, conforme a maturação puberal. Houve aumento significativo nos valores da EMIC em ambos os lados de acordo com o estágio puberal (p<0,001 e p=0,016) e os diâmetros internos máximos da artéria carótida comum (p<0,025 e p<0,003). A EMIC foi maior em participantes do sexo masculino em relação ao feminino. Conclusões: O aumento da EMIC em adolescentes saudáveis, conforme a idade e o grau de maturação puberal, deve ser levado em consideração nas avaliações diagnósticas.
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Humanos , Masculino , Femenino , Niño , Adolescente , Adulto Joven , Pubertad/psicología , Grosor Intima-Media Carotídeo , Estudios Transversales , Salud del Adolescente , Voluntarios SanosRESUMEN
OBJECTIVE: To contribute to the assessment of normal parameters of carotid intima-media thickness (CIMT) in healthy adolescents. METHODS: A cross-sectional study was conducted through clinical, laboratory and ultrasound evaluation in 61 healthy adolescents. The inclusion criteria consisted of being in good health. The exclusion criteria were: presence or history of any chronic disease; being obese or overweight according to the World Health Organization (WHO) established criterion; continuous use of medication; or presenting a febrile condition or requiring medication within 48-hours prior to assessment. The pubertal stages were evaluated using the Tanner criteria. The high-resolution B-mode ultrasound examinations were performed according to the recommendations of the Consensus Statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. RESULTS: Adolescents were 14±2.6 years old, 62.3% female, 19 (31%) at early puberty (Tanner II and III), and 38 (62%) at late puberty (Tanner IV and V). They presented normal clinical and laboratorial parameters. CIMT values were 0.46±0.04 to 0.55±0.04 mm on the right and 0.48±0.02 to 0.53±0.04 mm on the left, according to pubertal maturation. CIMT values increased significantly on the right and left sides, according to pubertal stage (p<0.001 and p=0.016), and maximum internal diameters of the common carotid artery (p<0.025 and p<0.003). It was higher in males compared to females. CONCLUSIONS: An increase in CIMT in the healthy adolescents group, according to both age, and the degree of pubertal maturation should be considered when evaluating adolescents in diagnostic procedures.
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Grosor Intima-Media Carotídeo , Pubertad/fisiología , Adolescente , Salud del Adolescente , Niño , Estudios Transversales , Femenino , Voluntarios Sanos , Humanos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: Increased arterial intima-media thickness has been observed in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). CAH has also been associated with obesity, insulin resistance, and hypertension. The aim of the present study was to compare youths with CAH with healthy, normal-weight individuals, evaluating carotid intima-media thickness (CIMT) and indicative factors of cardiovascular risk to seek for abnormalities in the CAH group. SUBJECTS AND METHODS: Clinical, biochemical, and ultrasonographic evaluations, according to published criteria, were performed in 113 subjects (5 to 20 years old): 40 patients with 21-OHD and 73 healthy individuals matched for gender, pubertal status, and age. RESULTS: Most CAH patients were female (80%), salt-losers (72.5%), and pubescent (80%); 10 (25%) patients were overweight. An increase in CIMT was observed both on the right (p = 0.0240) and left (p = 0.0003) sides in 38 CAH patients compared with the healthy individuals. The body mass index, BMI/age Z score, and systolic blood pressure (SBP) were higher in patients compared with controls (p < 0.000 and p = 0.0219, respectively). CONCLUSIONS: Findings of increased CIMT, BMI, and SBP in young patients with 21-OHD indicate the need for early identification and intervention regarding cardiovascular risk. Validating these findings might result in improved therapeutic approaches for children with 21-OHD in the future.
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Hiperplasia Suprarrenal Congénita/diagnóstico por imagen , Presión Arterial/fisiología , Aterosclerosis/diagnóstico por imagen , Índice de Masa Corporal , Grosor Intima-Media Carotídeo , Adolescente , Hiperplasia Suprarrenal Congénita/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Arterias Carótidas/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Masculino , Sobrepeso/diagnóstico por imagen , Factores de Riesgo , Adulto JovenRESUMEN
ABSTRACT Objective Increased arterial intima-media thickness has been observed in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). CAH has also been associated with obesity, insulin resistance, and hypertension. The aim of the present study was to compare youths with CAH with healthy, normal-weight individuals, evaluating carotid intima-media thickness (CIMT) and indicative factors of cardiovascular risk to seek for abnormalities in the CAH group. Subjects and methods Clinical, biochemical, and ultrasonographic evaluations, according to published criteria, were performed in 113 subjects (5 to 20 years old): 40 patients with 21-OHD and 73 healthy individuals matched for gender, pubertal status, and age. Results Most CAH patients were female (80%), salt-losers (72.5%), and pubescent (80%); 10 (25%) patients were overweight. An increase in CIMT was observed both on the right (p = 0.0240) and left (p = 0.0003) sides in 38 CAH patients compared with the healthy individuals. The body mass index, BMI/age Z score, and systolic blood pressure (SBP) were higher in patients compared with controls (p < 0.000 and p = 0.0219, respectively). Conclusions Findings of increased CIMT, BMI, and SBP in young patients with 21-OHD indicate the need for early identification and intervention regarding cardiovascular risk. Validating these findings might result in improved therapeutic approaches for children with 21-OHD in the future. Arch Endocrinol Metab. 2015;59(6):541-7.
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Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Hiperplasia Suprarrenal Congénita , Presión Arterial/fisiología , Aterosclerosis , Índice de Masa Corporal , Grosor Intima-Media Carotídeo , Hiperplasia Suprarrenal Congénita/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Arterias Carótidas , Sobrepeso , Factores de RiesgoRESUMEN
BACKGROUND: The same reference values for cortisol have been used for adults and children, but laboratory results obtained from an adult population might not be suitable for pediatric patients. AIMS: To determine morning serum basal cortisol levels in children and adolescents. METHODS: The study was conducted on 120 suitable reference individuals, healthy Brazilian children and adolescents from both genders aged 4-19 years old. The method used for cortisol assessment was the chemiluminescent enzyme immunoassay (VITROS® 5600 MicroWell; Johnson & Johnson, High Wycombe, UK, 2009), and the kit reference interval was 4.46-22.7 µg/dl (122.7-626.2 nmol/l). The setting limits were calculated according to the Clinical Laboratory Standards Institute guidelines. RESULTS: The morning serum basal cortisol levels increased with age and pubertal maturation, but there were no differences based on gender. The cortisol reference values were established based on the 2.5th and 97.5th percentiles as 2.97 µg/dl [81.9 nmol/l, 90% confidence interval (CI) 1.44-3.69 µg/dl] and 23.4 µg/dl (645.5 nmol/l; 90% CI 16.3-26.4 µg/dl), respectively. CONCLUSIONS: The assessment of the morning serum basal cortisol levels showed a unique pattern, with a different lower limit for the cohort compared to current values established for adult subjects.
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Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Pubertad/sangre , Adolescente , Factores de Edad , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
A vacina recombinante quadrivalente contra o HPV (Gardasil®, Merck), qHPV, protege contra verrugas e neoplasia genitais. No Brasil, foi incorporada ao Programa Nacional de Imunizações a partir de 2014. Desde então, veículos de mídia brasileiros relataram a ocorrência de reações adversas graves atribuídas à vacina, como reações autoimunes e acometimentos neurológicos. Tais relatos têm como consequência o surgimento de uma postura de desconfiança por parte tanto da comunidade leiga quanto da comunidade médica em relação à sua segurança, levando à diminuição da adesão à segunda fase do programa de vacinação. A presente revisão sistemática busca o embasamento científico em relação à segurança da qHPV, como forma de avaliar a pertinência da desconfiança criada em relação à vacina.
The recombinant quadrivalent HPV vaccine (Gardasil®, Merck), qHPV, protects against genital warts and cancer, and in Brazil has been part of the National Immunization Program from 2014. Since then, Brazilian media outlets have reported the occurrence of serious adverse reactions attributed to the vaccine, such as autoimmune reactions and neurological effects. Such reports have resulted in increasing distrust amongst both the general public and the medical community regarding the vaccine's safety, leading to a decrease in adhesion to the second phase of the vaccination program. This systematic review aims to provide the scientific basis for proving the security of qHPV and assessing whether the mistrust created in relation to the vaccine is well founded.
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OBJECTIVE: The effectiveness of neonatal screening for reducing morbimortality in children with congenital adrenal hyperplasia (CAH) is the main justification for its implementation. One of the challenges for its implementation is to determine the cutoff value for laboratory measurement of 17-hydroxyprogesterone (17OHP) with appropriate cost-effectiveness. This study identified factors affecting the results of the pilot project of newborn screening for CAH, performed in the state of Minas Gerais, Brazil. METHODS: Neonatal screening performed between September, 2007 and May, 2008, with 17OHP measurements performed in blood samples taken from the heel (filter paper), on the 5(th) day of life, processed by the UMELISA 17-OH Progesterona NEONATAL(®) method. The cutoff value was 80 and 160 nmol/L for healthy children or not, respectively. RESULTS: The incidence of CAH was 1:19,939 in 159,415 children screened. The 99(th) percentile (p99) of 17OHP in the first sample was 108 nmol/L. In 13,298 newborns whose weight had been reported, the p99 of 17OHP were, respectively: 344 nmol/L for weight < 1,500 g; 260 nmol/L for weight between 1,500 and 1,999 g; 221 nmol/L for weight between 2,000 and 2,499 g; 109 nmol/L for weight ≥ 2,500g. The rate of recall for medical consultation was 0.31%. The test sensitivity was 100%, specificity was 99.6%, and the positive predictive value was 2.2%. By adjusting the cutoff values of 17OHP to 110 nmol/L and 220 nmol/L, a 76% decrease in consultation referrals was projected. CONCLUSION: The use of 17OHP cutoff values, considering birth weight, was a cost-effective measure to reduce false positives. The results of this pilot study suggest that screening for CAH might benefit the pediatric population.
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17-alfa-Hidroxiprogesterona/sangre , Hiperplasia Suprarrenal Congénita/diagnóstico , Peso al Nacer/fisiología , Tamizaje Neonatal/economía , Hiperplasia Suprarrenal Congénita/epidemiología , Brasil/epidemiología , Análisis Costo-Beneficio , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Recién Nacido , Masculino , Proyectos Piloto , Valor Predictivo de las Pruebas , Radioinmunoensayo , Valores de ReferenciaRESUMEN
OBJETIVO: A eficácia da triagem neonatal para redução de morbimortalidade das crianças com hiperplasia adrenal congênita (HAC) é a principal justificativa para sua implantação. Um dos desafios para sua realização é a determinação do ponto de corte para a medida laboratorial da 17-hidroxiprogesterona (17OHP) que apresente adequado custo/benefício. Neste estudo foram identificados fatores intervenientes nos resultados do projeto-piloto de triagem neonatal para HAC, realizado em Minas Gerais. MÉTODOS: Rastreamento neonatal entre 09/2007 e 05/2008, com dosagens da 17OHP de amostras de sangue colhidas no calcanhar, no 5º dia de vida (papel-filtro), processadas pelo método UMELISA 17-OH Progesterona NEONATAL®. Os pontos de corte foram 80 e 160 nmol/L, para crianças saudáveis ou não, respectivamente. RESULTADOS: A incidência de HAC foi 1:19.939 em 159.415 crianças triadas. O percentil 99 (p99) da 17OHP, na primeira amostra, foi 108 nmol/L. Em 13.298 recém-nascidos com peso informado, os p99 da 17OHP foram, respectivamente, 344 nmol/L para <1500 g, 260 nmol/L para 1500 a 1999 g, 221 nmol/L para 2000 a 2499 g, e 109 nmol/L para > 2500 g. A taxa de reconvocação para consulta médica foi 0,31%. A sensibilidade do teste foi 100%, a especificidade, 99,6% e o valor preditivo positivo, 2,2%. Ajustando-se o ponto de corte da 17OHP para 110 nmol/L e 220 nmol/L, projetou-se redução em 76% dos encaminhamentos para consulta. CONCLUSÃO: Adoção dos pontos de corte para 17OHP, considerando peso de nascimento, apresentou-se como medida custo-efetiva para redução de falso-positivos. Os resultados desse estudo piloto sugerem que a triagem para HAC possa beneficiar a população infantil.
OBJECTIVE: The effectiveness of neonatal screening for reducing morbimortality in children with congenital adrenal hyperplasia (CAH) is the main justification for its implementation. One of the challenges for its implementation is to determine the cutoff value for laboratory measurement of 17-hydroxyprogesterone (17OHP) with appropriate cost-effectiveness. This study identified factors affecting the results of the pilot project of newborn screening for CAH, performed in the state of Minas Gerais, Brazil. METHODS: Neonatal screening performed between September, 2007 and May, 2008, with 17OHP measurements performed in blood samples taken from the heel (filter paper), on the 5th day of life, processed by the UMELISA 17-OH Progesterona NEONATAL® method. The cutoff value was 80 and 160 nmol/L for healthy children or not, respectively. RESULTS: The incidence of CAH was 1:19,939 in 159,415 children screened. The 99th percentile (p99) of 17OHP in the first sample was 108 nmol/L. In 13,298 newborns whose weight had been reported, the p99 of 17OHP were, respectively: 344 nmol/L for weight < 1,500 g; 260 nmol/L for weight between 1,500 and 1,999 g; 221 nmol/L for weight between 2,000 and 2,499 g; 109 nmol/L for weight > 2,500g. The rate of recall for medical consultation was 0.31%. The test sensitivity was 100%, specificity was 99.6%, and the positive predictive value was 2.2%. By adjusting the cutoff values of 17OHP to 110 nmol/L and 220 nmol/L, a 76% decrease in consultation referrals was projected. CONCLUSION: The use of 17OHP cutoff values, considering birth weight, was a cost-effective measure to reduce false positives. The results of this pilot study suggest that screening for CAH might benefit the pediatric population.