Determinación de valores de corte de 17 hidroxiprogesterona ajustados por edad gestacional para la pesquisa neonatal de la hiperplasia suprarrenal congénita / Assessment of gestational age-adjusted 17-hydroxyprogesterone cut-off values for neonatal screening of congenital adrenal hyperplasia

La pesquisa neonatal de hiperplasia suprarrenal congénita se realiza mediante la determinación de 17 hidroxiprogesterona (17OHP) en gotas de sangre seca en papel de filtro. Los bebés prematuros presentan valores más elevados que los bebés de término, siendo de utilidad contar con límites de corte apropiados. Nuestro objetivo fue actualizar los valores de corte de 17OHP ajustados por edad gestacional para la metodología en uso a nivel nacional por las jurisdicciones asistidas por el "Programa Nacional de Fortalecimiento de la Detección Precoz de Enfermedades Congénitas". La 17OHP se determinó utilizando el kit comercial de enzimo-inmunoanálisis (ELISA competitivo), Elizen Neonatal 17OHP Screening (Zentech, Bélgica). Se obtuvieron límites de corte utilizando percentiles de la distribución de los valores de 17OHP para cada edad gestacional. La sensibilidad obtenida fue 100%, especificidad 98,76 %, tasa de falsos positivos 1,24 % y el valor predictivo positivo 1,12 %. Destacamos la importancia de disponer de límites de corte adecuados a la población. La armonización de los mismos permitirá resultados comparables entre los programas regionales de pesquisa neonatal (AU)

Newborn screening for congenital adrenal hyperplasia is performed by the measurement of 17-hydroxyprogesterone (17OHP) in dried blood spots on filter paper. Premature infants have higher values than full-term infants, and appropriate cutoff values are useful. Our aim was to update the cut-off values of 17OHP adjusted for gestational age for the methodology used at a national level in regions assisted by the "National Program for Strengthening the Early Detection of Congenital Diseases". 17OHP was determined using the commercial enzyme-linked immunosorbent assay (competitive ELISA) kit, Elizen Newborn 17OHP Screening (Zentech, Belgium). Cut-off values were obtained using percentiles of the distribution of 17OHP values for each gestational age. Sensitivity was 100%, specificity 98.76%, false positive rate 1.24%, and positive predictive value 1.12%. It is important to have cut-off values that are adjusted to the population. Harmonization will allow for the comparison of results among regional newborn screening programs (AU)

Cognitive functions in children with congenital adrenal hyperplasia

ABSTRACT Objective There is controversy regarding cognitive function in patients with congenital adrenal hyperplasia (CAH). This study is aimed at the assessment of cognitive functions in children with CAH, and their relation to hydrocortisone (HC) therapy and testosterone levels. Subjects and methods Thirty children with CAH due to 21 hydroxylase deficiency were compared with twenty age- and sex-matched healthy controls. HC daily and cumulative doses were calculated, the socioeconomic standard was assessed, and free testosterone was measured. Cognitive function assessment was performed using the Wechsler Intelligence Scale - Revised for Children and Adults (WISC), the Benton Visual Retention Test, and the Wisconsin Card Sorting Test (WCST). Results The mean age (SD) of patients was 10.22 (3.17) years [11 males (36.7%), 19 females (63.3%)]. Mean (SD) HC dose was 15.78 (4.36) mg/m 2 /day. Mean (SD) cumulative HC dose 44,689. 9 (26,892.02) mg. Patients had significantly lower scores in all domains of the WISC test, performed significantly worse in some components of the Benton Visual Retention Test, as well as in the Wisconsin Card Sorting Test. There was no significant difference in cognitive performance when patients were subdivided according to daily HC dose (< 10, 10 - 15, > 15 mg/m 2 /day). A positive correlation existed between cumulative HC dose and worse results of the Benton test. No correlation existed between free testosterone and any of the three tests. Conclusion Patients with CAH are at risk of some cognitive impairment. Hydrocortisone therapy may be implicated. This study highlights the need to assess cognitive functions in CAH.

Puntos de corte de 17-hidroxiprogesterona en la detección de Hiperplasia Suprarrenal Congénita / Cut offs levels of 17-hydroxyprogesterone in screening of Congenital Adrenal Hyperplasia / Pontos de corte da 17-hidroxiprogesterona na detecção de Hiperplasia Adrenal Congênita

El presente estudio investiga la utilidad de determinar puntos de corte ajustados según la edad gestacional y el peso al nacer de neonatos (2-100 días) en la cuantificación de 17-hidroxiprogesterona en muestras de sangre seca en papel de filtro. Se analizaron los resultados de 6.266 determinaciones realizadas en el marco del Programa Nacional de Fortalecimiento de la Detección Precoz de Enfermedades Congénitas. Los datos se dividieron en cuatro grupos; Grupo 1: recién nacido pretérmino con bajo peso; Grupo 2: recién nacido pretérmino con peso normal; Grupo 3: recién nacido a término con bajo peso y Grupo 4: recién nacido a término con peso normal. Se establecieron puntos de corte diferentes a partir del cálculo del percentilo 99 de la distribución de frecuencias. Basado en este análisis se realizó la comparación de la tasa de resultados falsos positivos que se obtuvieron según el punto de corte establecido por el fabricante y los obtenidos en el estudio. Los nuevos puntos de corte obtenidos fueron: 217,72 nmol/L, 102,14 nmol/L, 61,62 nmol/L y 82,38 nmol/L para los grupos 1, 2, 3 y 4 respectivamente. Se evidenció una tasa total de falsos positivos del 1% con los nuevos puntos de corte, significativamente menor a la tasa del 6,2% obtenida al utilizar el punto de corte del fabricante. Esto puso en evidencia que el uso de puntos de corte adecuadamente establecidos para la población en estudio reduce significativamente las complicaciones derivadas de las repeticiones de análisis y eventualmente la tasa de recitaciones, lo cual es una importante contribución a la Salud Pública.

The present work studies the usefulness of determining adjusted cut-offs for the quantification of 17-hydroxyprogesterone in dried blood samples on filter paper, taking into account the gestational age and weight of the neonates. The results of 6266 determinations made within the framework of the National Program of Strengthening Early Detection of Congenital Disease were analysed. Data were divided into groups, Group 1: early established from the calculation of the 99 percentiles of the frequency distribution. New cutoff points were: 217.72 nmol/L, 102.14 nmol/L, 61.62 nmol/L and 82.38 nmol/L for groups 1, 2, 3 and 4 respectively. It showed a total rate of 1% false positives with the new cut-off points, which was significantly lower than the rate of 6.2% obtained using the manufacturer's cutoff. This revealed that the use of properly established cut-offs for the study of population reduces significantly the complications derived fromn analysis repetitions and eventually the recitation rate, which is an important contribution to Public Health.

O presente estudo investiga a utilidade de determinar pontos de corte estabelecidos conforme a idade gestacional e o peso ao nascer de neonatos (2-100 dias) na quantificação da 17-hidroxiprogesterona em amostras de sangue seco em papel filtro. Foram analisados os resultados de 6.266 determinações feitas no âmbito do Programa Nacional de Fortalecimento da Detecção Precoce de Doenças Congênitas. Os dados foram divididos em quatro grupos; Grupo 1: recém-nascido pré-termo com baixo peso, Grupo 2: recém-nascido pré-termo com peso normal, Grupo 3: recém-nascido a termo com baixo peso e Grupo 4: recém-nascido a termo com peso normal e foram estabelecidos pontos de corte diferentes a partir do cálculo do percentil 99 da distribuição de frequências. Com base nesta análise foi realizada a comparação da taxa de resultados falsos positivos obtidos conforme o ponto de corte estabelecido pelo fabricante e os obtidos no estudo. Os novos pontos de corte obtidos foram: 217,72 nmol/L, 102,14 nmol/L, 61,62 nmol/L e 82,38 nmol/L para os grupos 1, 2, 3 e 4, respectivamente. Tornou-se evidente uma taxa total de 1% de falsos positivos, com os novos pontos de corte significativamente menor do que a taxa de 6,2% obtida utilizando o ponto de corte do fabricante. Isto revelou que o uso de pontos de corte de forma adequada estabelecidos para a população em estudo reduz significativamente as complicações decorrentes das repetições de análises e eventualmente a taxa de repetição de novos encontros, o que é uma importante contribuição para a saúde pública.

Valores elevados de leptina e LDL-colesterol em pacientes com hiperplasia adrenal congênita bem controlados / Elevated levels of leptin and LDL-cholesterol in patients with well controlled congenital adrenal hyperplasia

OBJETIVO: O objetivo deste estudo foi avaliar pacientes com HAC clássica antes e após tratamento com glicocorticoides e/ou mineralocorticoides e comparar o perfil metabólico entre o grupo bem controlado (BC) e mal controlado (MC). SUJEITOS E MÉTODOS: Foram selecionados pacientes recém-diagnosticados e pacientes em acompanhamento por HAC, forma clássica, em uso regular ou não de glicocorticoides/mineralocorticoides do Serviço de Genética do Hupes-UFBA, atendidos de março/2004 a maio/2006. Todos os pacientes foram submetidos a avaliação clínica detalhada e exames laboratoriais (glicemia, sódio e potássio, colesterol total, HDL, LDL, triglicerídeos, ácido úrico, leptina, 17-hidroxiprogesterona, testosterona total, peptídeo C e insulina). Os pacientes com valores normais de andrógenos foram classificados como bem controlados (BC) e os com valores elevados de andrógenos em uso ou não de glicocorticoides/mineralocorticoides foram classificados como mal controlados (MC). RESULTADOS: Foram estudados 41 pacientes com HAC: 11 no grupo BC e 30 no grupo MC. Leptina e LDL colesterol estavam mais elevados no grupo BC que no MC (p < 0,05). Valores de ácido úrico eram menores no grupo BC quando comparados com MC (p < 0,05). CONCLUSÃO: O controle adequado da HAC com glicocorticoides parece seguro, pois está associado a alterações discretas no perfil lipídico e da leptina. Não observamos outras alterações metabólicas associadas ao uso de glicocorticoides. O motivo para o menor valor de ácido úrico encontrado nos pacientes com HAC bem controlada não é conhecido e deve ser mais bem estudado.

OBJECTIVE: The objective of this study was to evaluate patients with classic CAH before and after treatment with glucocorticoids/mineralocorticoid and compare the metabolic profile of the well controlled (WC) and poorly controlled (PC) group. SUBJECTS AND METHODS: We selected newly diagnosed patients and patients monitored for CAH, classical form, regularly using or not glucocorticoids/mineralocorticoid in the Genetics Service Hupes-UFBA, seen from March/2004 to May/2006. All patients underwent detailed clinical evaluation and laboratory tests (glucose, sodium and potassium; total cholesterol, HDL, LDL, triglycerides and uric acid; leptin, 17-hydroxyprogesterone, total testosterone, C peptide, and insulin). Patients with normal androgens were classified as well controlled (WC), and those with high levels of androgens either using or not glucocorticoids/mineralocorticoids were classified as poorly controlled (PC). RESULTS: We studied 41 patients with CAH: 11 in the WC group and 30 in PC group. Leptin and LDL cholesterol levels were higher in WC than in the PC group (p < 0.05). Uric acid values ​​were lower in WC compared with the PC group (p < 0.05). CONCLUSION: Adequate control of CAH with steroids seems safe, as it is associated with only mild changes in lipid profile and leptin values. No other metabolic abnormality was associated with glucocorticoid use. The reason for lower uric acid levels found in WC CAH patients is unknown and should be further studied.

Resultados de la pesquisa de hiperplasia adrenal congénita en recién nacidos / Results of screening on congenital adrenal hyperplasia in newborns

Se realizó un estudio retrospectivo, lineal, de carácter evaluativo de la marcha del programa desde su implantación en noviembre de 2005 hasta abril de 2007 en cuanto a parámetros de calidad: edad del recién nacido en el momento de la toma de la muestra, tiempo que demoró esta en llegar al laboratorio, calidad de las muestras, cantidad de muestras no útiles y número de resultados elevados, de los municipios a los que se le ofertan los servicios del laboratorio SUMA del Hospital Docente Ginecoobstétrico Ramón González Coro. Fueron analizadas un total de 7 780 muestras de sangre seca sobre papel de filtro de recién nacidos, de las cuales, el 62,2 por ciento se realizaron al 5to. día, con un promedio de 7 días entre la toma y la recepción en el laboratorio, con muy buena calidad, 80 muestras no útiles con una cobertura del 99,98 por ciento y un total de 43 resultados elevados, ademßs se analizaron varios factores que influyen en los niveles de 17OH-Progesterona cuantificados en el UMELISA 17OH-Progesterona Neonatal como son: peso al nacer, género, edad del recién nacido en la fecha de la toma de la muestra, edad gestacional (por ciclo menstrual o fecha de última menstruación) en el momento del parto, número de fetos y forma del parto, se detectó que hay incremento en los niveles de 17OH-Progesterona en los bajo peso al nacer, prematuros, en los partos por cesárea y embarazos con más de 1 feto

An evaluative, linear and retrospective study was conducted on the underway of the program from its implementation from November, 2005 to April, 2007 related to the following quality parameters: newborn's age at the sample take moment, time elapsed from its arrival to laboratory, samples quality, number of non-useful samples and number of high results, figure of municipalities receiving the SUMA laboratory services from the Ramón González Coro Gynecology and Obstetrics Teaching Hospital. A total of 7 780 newborns dry blood samples were analyzed using filter paper and the 62.2 percent was carried out at fifth day over an average of 7 days between take and the reception in laboratory with a very good quality, there were 80 non-useful samples with a coverage of 99.98 percent and a total of 43 high results and also we analyzed some factors influencing in levels of 17OH-Progesterone quantified in the UMELISA 17OH-progesterone Neonatal including: birth weight, gender, newborn age and date of take sample, gestational age (by menstrual cycle or date of last menstruation) at labor moment, quantity of fetus and the type of labor, noting an increase in levels of 17OH-progesterone in those with a low-birth weight, prematures and in cases of cesarean section and pregnancy of more than one fetus

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil / Seis novos casos confirmam o perfil clínico molecular de deficiência combinada de 17 alfa-hidroxilase/17,20-liase no Brasil

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50 percent and 32 percent of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

Em 2004, segundo Costa-Santos e cols., p.W406R e p.R362C correspondiam a 50 por cento e 32 por cento dos alelos mutantes do gene CYP17A1, respectivamente, em 24 pacientes de 19 famílias brasileiras com deficiência da 17α-hidroxilase. Apresentamos os dados clνnicos e moleculares de seis pacientes de três famílias consanguíneas brasileiras com deficiência da 17α-hidroxilase. Todas as pacientes apresentavam hipogonadismo, amenorreia e hipertensão ao diagnóstico. Duas irmãs tinham cariótipo 46,XY, ambas com gônadas palpáveis na região inguinal. Todas tinham hipogonadismo hipergonadotrófico, com nível aumentado de ACTH (> 104 ng/mL), atividade de renina plasmática suprimida, baixos níveis de potássio (< 2,8 mEq/L) e progesterona aumentada (> 4,4 ng/mL). Três delas, incluindo duas irmãs, apresentaram homozigose para a mutação p.W406R e as outras três (duas irmãs e uma prima) foram homozigotas para a mutação p.R362C. A recorrência das mutações p.W406R e p.R362C no gene CYP17A1 aqui relatada em famílias adicionais confirma que essas são as mais frequentes causadoras do fenótipo completo da deficiência combinada de 17α-hidroxilase/17,20-liase em pacientes brasileiros.

Pesquisa de tecido prostático em pacientes 46, XX portadoras da forma clássica de hiperplasia congênita das suprarrenais / Search of prostatic tissue in 46, XX congenital adrenal hyperplasia

OBJETIVOS: Verificar a ocorrência de tecido prostático em pacientes portadoras da forma clássica de hiperplasia congênita das suprarrenais, com cariótipo 46,XX e analisar a sensibilidade e a especificidade do antígeno prostático específico (PSA) das pacientes com hiperplasia congênita das suprarrenais em relação à detecção de tecido prostático na ressonância magnética (RNM) de região pélvica. MÉTODOS: Foram estudadas 52 crianças e adolescentes, sendo 32 meninas portadoras da forma clássica de hiperplasia congênita das suprarrenais, 10 meninas e 10 meninos sem hiperplasia congênita das suprarrenais. A RNM da região pélvica e a coleta de PSA, diidrotestosterona e testosterona foram realizadas em todos os pacientes. Para analisar a capacidade de discriminação do antígeno prostático-específico, foi utilizada a curva ROC (receiver operating characteristic curve). RESULTADOS: Cinco das 32 pacientes portadoras de hiperplasia congênita das suprarrenais apresentaram tecido prostático na RNM de região pélvica. Para concentração de antígeno prostático-específico de 0,1 ng/mL, obteve-se sensibilidade de 100 por cento e especificidade de 88,9 por cento para a detecção de tecido prostático. CONCLUSÕES: A ocorrência de tecido prostático nas pacientes portadoras de hiperplasia congênita das suprarrenais estudadas foi de 15,6 por cento. O antígeno prostático-específico mostrou ser valioso marcador de tecido prostático nestas pacientes.

OBJECTIVES: To describe the presence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia (CAH); to evaluate the sensitivity and specificity of prostatic specific antigen (PSA) measured in congenital adrenal hyperplasia patients with regard to the detection of prostatic tissue in pelvic MRI. METHODS: We studied 52 children and adolescents, 32 with the classical form of congenital adrenal hyperplasia, 10 boys and 10 girls without CAH. Pelvic MRI was performed in all patients to detect prostatic tissue. Prostate specific antigen, testosterone and dihydrotestosterone were measured in all patients. We used Receiver Operating Characteristic Curve for PSA discrimination capacity. RESULTS: Five girls with congenital adrenal hyperplasia showed image of prostatic tissue on pelvic MRI. Prostate specific antigen showed sensitivity and specificity of 100 percent and 88.9 percent, respectively, taking 0.1 ng/mL as the cutoff level. CONCLUSIONS: The incidence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia was 15.6 percent. PSA demonstrated to be a good marker of prostatic tissue in these patients and should be used to screen patients to be submitted to image studies.

Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening / Heterozigose para mutação no gene CYP21A2 considerada como deficiência de 21-hidroxilase na triagem neonatal

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90 percent of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.2 nmol/L, normal < 40) upon neonatal screening who was treated as having CAH up to the age of 8 months. He was brought to us for molecular diagnosis. Medication was gradually suspended and serum 17-OHP dosages mantained normal. The p.V281L mutation was found in compound heterozygous status with a group of nucleotide alterations located at the 3' end intron 4 and 5' end exon 5 corresponding to the splice site acceptor region. Molecular studies continued in order to exclude the possibility of a nonclassical 21-OHD form. The group of three nucleotide changes was demonstrated to be a normal variant since they failed to interfere with the normal splicing process upon minigene studies.

A deficiência de 21-hidroxilase (21-OHD) é uma doença autossômica recessiva que contribui com mais de 90 por cento dos casos de hiperplasia congênita da adrenal. O teste de dosagem de 17-hidroxiprogesterona (17-OHP) por radioimunoensaio em amostras de sangue colhidas em papel de filtro tem sido o método mais usado nos programas de triagem neonatal. No entanto, essa triagem pode apresentar alto número de falso-positivos pelo fato de os recém-nascidos prematuros apresentarem dosagens mais elevadas deste esteróide. Apresentamos aqui os estudos moleculares de uma criança, sexo masculino, nascida pré-termo (IG = 30 sem; peso = 1.390 g) que apresentava valores elevados de 17-OHP sérica (91,2 nmol/L, normal < 40) na triagem neonatal e que foi tratada como portadora da forma clássica da 21-OHD até a idade de 8 meses quando nos foi encaminhada para diagnóstico molecular. A terapia foi, então, gradativamente descontinuada, sendo que as concentrações séricas de 17-OHP se mantiveram normais. A mutação p.V281L foi encontrada em heterozigose composta com um grupo de alterações no terminal 3' do íntron 4 e no terminal 5' do éxon 5 correspondendo à região do sítio aceptor de splicing. A análise do gene CYP21A2 prosseguiu para se excluir a possibilidade de a criança ser afetada com a forma não-clássica de 21-OHD. Pela análise de minigene ficou demonstrado que o grupo de três trocas nucleotídicas não afeta o processo normal de transcrição. Concluindo, a criança é apenas heterozigota da mutação p.V281L sem necessidade de tratamento.

Hiperplasia suprarrenal no clásica, características clínicas y genéticas / Clinical and genetic features of non classical adrenal hyperplasia

Background: The non classical form of congenital adrenal hyperplasia (NCAH) is increasingly recognized inhyperandrogenic patients, with variable phenotypic expression. Aim: To determine the clinical, hormonal, andgenetic characteristics of a group of patients with NCAH. Patients and methods: The medical records of 57NCAH patients were retrospectively reviewed. The diagnosis was established by basal or post-ACTH-stimulation 17-hydroxyprogesterone (17-OHP) levels >7 ng/mL and > 15 ng/mL, respectively. Patients with post-ACTH 17-OHP levels between 10-15 ng/mL, and with one identified allele o without genetic tests, were consideredas heterozygous. Genotyping for 10 mutations was performed by PCR. Results: The average age of diagnosis was 12.4 +/- 0.9 years. Six patients were male. Pubarche and hirsutism were the clinical signs more frequently described in patients below 10 years of age (25/29) and over 10 years of age (11/24), respectively. A basal 17-OHP > 7 ng/mL was observed in 36 patients; the post ACTH 17-OHP was between 10-15 and > 15 ng/mL in 5 and 17 patients, respectively. Genotype analyses were performed in 38 patients. V281L was carried on approximately 68.4 percent of all alleles and 29 percent of patients carried severe mutations. Only one of five possible carrier patients, was diagnosed as NCAH after the genetic test (V281L/ In2splice). Conclusions: Males with NCAH were apparently sub-diagnosed. Pubarche and hirsutism were the more frequently reported signs. The genetic test is complementary in the diagnosis of NCAH. One third of the patients carried a classic mutation and could have an increased risk to have siblings with Classical CAH.

Triagem neonatal para hiperplasia adrenal congênita: experiência do estado do Rio de Janeiro / Congenital adrenal hyperplasia newborn screening: Rio de Janeiro experience

OBJETIVO: Descrever a distribuição das concentrações de 17OH Progesterona (17OHP) na triagem neonatal para pesquisa de Hiperplasia Adrenal Congênita por deficiência da 21hidroxilase (HAC-D21OH). CASUíSTICA E MÉTODO: Análise da 17OHP por método imunofluorimétrico em 76.360 amostras de sangue colhido em papel filtro no período de junho de 1992 a dezembro de 2000 no Estado do Rio de Janeiro. O valor de corte foi definido em 10ng/mL e os casos com resultados acima deste valor eram chamados para nova coleta. RESULTADOS: Foram reconvocados 38 casos para nova coleta, sendo confirmados 11 casos com a forma clássica da HAC-D21OH (4 do sexo masculino, 6 feminino e 1 indeterminado), com valores de 17OHP na primeira amostra variando de 25 a 254,5ng/mL (média de 133ng/mL) e na segunda amostra de 45,86 a 360ng/mL (média de 218,84ng/mL). Os pacientes com a forma perdedora de sal apresentaram concentrações mais elevadas que os com a forma virilizante simples, tanto na primeira amostra (média de 169,21 contra 27,46ng/mL) quanto na segunda (média de 227,16 versus 110,95ng/mL). As concentrções de 17OHP nos 27 casos não confirmados (falso-positivos) variaram de 10,27 a 27,50ng/mL (média de 14,80ng/mL) na primeira amostra e de 2,39 a 32,39ng/mL (média 10,07ng/mL) na segunda amostra. Oito mantiveram concentrações de 17OHP moderadamente elevadas, sendo que normalizaram no decorrer do primeiro ano de vida em 7 casos, e em 1 paciente, apesar de assintomático, manteve valores elevados de 17OHP durante o acompanhamento de oito anos, com teste de estímulo com ACTH compatível com a forma não clássica da HCA-D21OH. CONCLUSÃO: A dosagem da 17OHP foi um método eficaz para a triagem da HAC-D21OH sendo capaz de discriminar as crianças normais daquelas acometidas pela forma clássica da doença.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia [CAH] is an autosomal recessive disorder caused by any of the enzymatic steps requied to synthesize adrenal hormones. Depending on the enzymatic step that is deficient, there may be clinical and laboratory finding. The aim was to evaluate the epidemiology and clinical finding of CAH. The clinical and laboratory characteristics of 68 patients with CAH who were managed in the pediatric Endocrinology unit of Imam Reza Hospital during 7 years were recorded in this study; the clinical and epidemiological characteristics of congenital adrenal hyperplasia were evaluated in 68 patients admitted Imam Reza Hospital in Mashed, also one patient has been followed in endocrine and metabolism pediatric clinic in this time, during 6 years retrospectively and I year prospectively. Parental consanguinity rate among families of patients was higher than the general population in Mashad [73.8% vs 30%]. In 44.6% of patients the history of disease were positive in sibling. 52.2% of patients were males and 47.8% females. 21- Hydroxylase deficiency was present in 60 patients [88.2%], salt - losing form in 40 [66.7%] and simple virilizing form in 20 [33.3%] of them. 11- beta hydroxylase deficiency was present is [10.3%]. Also one case of 3- beta OHSD was reported. The median chronological age at diagnsis in sall- losing form were 75 and 85 days in boys and girls; in simple virilizing form were 46 and 43 months in boys and girls. 14 of girls were considered to be male before diagnosis was established. This study underscores the necessity for prospective neonatal screening, so that the benefits of early diagnosis and treatment can be realized. In addition the incidence of CAH is expected to be high due to a high rate of consanguinity in our population, here genetic counseling before marriage is beneficial in our population

Adrenocorticotropin stimulation test in congenital adrenal hyperplasia: comparison between standard and low dose test.

The aim of the study was to compare the response between the standard and low dose adrenocorticotropin (ACTH) test for patients with congenital adrenal hyperplasia (CAH). The authors employed a 2-by-2 crossover design and enrolled 16 patients, 14 girls and 2 boys, aged between 1.4 months and 15 years. Steroid treatment was stopped 24 hours before each test was conducted. The standard ACTH (250 microg) test was performed followed by the low dose test (1 microg) in eight patients; the other eight underwent the low dose ACTH test first followed by the standard one. The cortisol and 17-hydroxyprogesterone (17-OHP) levels in each patient varied unpredictably between the two tests. The cortisol responses to the low dose ACTH at 30 and 60 minutes were lower than at time zero; in contrast to the 60-minute peak cortisol response to the standard dose. The serum 17-OHP in all specimens was more than 10,000 ng/dl (300 nmol/L), with the peak response at 60 minutes in both groups. Both the low dose and standard dose ACTH test indicated adrenal insufficiency and the high 17-OHP levels were diagnostic of 21- hydroxylase (21-OH) deficiency. If the low dose ACTH test becomes the "standard" ACTH test, the diagnosis of 21-OH deficiency would probably not be missed.

Monitoring congenital adrenal hyperplasia using blood spot 17-hydroxyprogesterone assay.

Blood spots taken by finger prick collected on filter paper cards can provide an option to venous blood extraction in monitoring 17-OHP levels in children with Congenital Adrenal Hyperplasia (CAH). This study was done to evaluate the usefulness of blood spot 17-OHP in monitoring disease control in pre-pubertal children with CAH, to correlate it with simultaneously extracted venous 17-OHP levels, and to compare blood spot levels of children with CAH with that of normal non-virilized children. Nine pre-pubertal children with CAH (1 male; 8 females) were enrolled in the study. Age, sex, growth velocity, height age and bone age were determined. Simultaneous venous and blood spot specimens were taken between 0800 and 0900 hours. Nine pre-pubertal, age- and sex-matched normal non-virilized children served as controls. COAT-A-COUNT was used to measure venous 17-OHP levels, and AutoDELFIA Neonatal 17alpha-OH-progesterone was employed for blood spot specimens. Mean age of patients with CAH was 42.78 months (SD= 21.45214). Four had simple virilizing form and five were salt-losers. Venous 17-OHP levels ranged from 7.5 to 800nmol/l. Blood spot 17-OHP levels ranged from < or =0.5000nmol/l to 355.5nmol/l. There was a strong positive correlation between the venous and blood spot determination, with a correlation coefficient gamma= 0.947 (p < 0.001). All of the children in the control group had a blood spot 17-OHP level < or =0.5000nmol/l. Taking blood spot 17-hydroxyprogesterone levels is a simple, acceptable, convenient, and less costly alternative to venous 17-OHP determination in monitoring treatment response of children with CAH. The decision to make treatment modification, however, should be made on random blood spot 17-OHP interpretation in conjunction with clinical history and evaluation of growth parameters.

Effect of gender, birth weight and gestational age on serum 17-hydroxyprogesterone concentration and distribution among neonates in Saudi Arabia.

Blood samples from 813 newborns were spotted on to filter paper and the 17-hydroxyprogesterone concentration was measured using the Delfia (R) fluorometric immunoassay. The median, mean, and standard deviation (SD) for the total population were 20, 21 and (11) nmol/L respectively. Males had significantly higher levels than females with median, mean and (SD) of 22, 22 and (12) nmol/L. Similarly, low birth weight babies were found to have significantly higher levels than normal birth weight babies with median, mean and (SD) of 21, 24 (12) nmol/L. Preterm babies were also found to have significantly higher levels than full term babies, with median, mean and (SD) of 25, 29 (16) nmol/L. As experienced elsewhere, those factors should be taken into consideration when considering a cut-off point in any neonatal screening program for congenital adrenal hyperplasia.

O espectro clínico e laboratorial da forma näo clássica de hiperplasia adrenal congênita por deficiência da 21-hidroxilase / The clinical and laboratorial spectrum of the non-classic way of congenital adrenal hyperplasia by 21-hydroxilase deficiency

Foram estudadas 9 pacientes portadoras da forma nao clássica de hiperplasia adrenal congênita por deficiência de 2l-hidroxilase (2l-FNC). O diagnóstico baseou-se na resposta da 17-hidroxiprogesterona (l7-OHP) 60 minutos após estímulo com 250 ug de ACTH sintético por via EV. Em relaçao à reserva de glicocorticóide, observamos somente uma paciente com resposta deficiente de cortisol ao estímulo com ACTH. A concentraçao basal de 17-OHP foi altamente variável, tanto em relaçao a mesma paciente como entre as pacientes. Em duas delas, observamos concentraçao basal de 17-OHP normal, após estímulo com ACTH, observamos uma hiperresposta de 17-OHP, compatível com o diagnóstico de 2l-FNC. As pacientes foram subdivididas em três grupos de acordo com o diagnóstico clínico: Grupo I: Pubarca precoce (n= 1); Grupo II: Hirsutismo com ciclos menstruais regulares e ovulatórios (n= 4); e Grupo III: Hirsutismo com alteraçao menstrual (n= 3). Nao observamos qualquer diferença entre os três grupos tanto em relaçao à reserva de glicocorticóide adrenal e a concentraçao de 17-OHP, basal ou pós-estímulo, nem com relaçao à parâmetros clínicos, como obesidade, menarca ou idade de início do hirsutismo nas pacientes dos grupos II e III, sugerindo que a manifestaçao clínica da 2l -FNC esteja na dependência de fatores extra-adrenais, excetuando-se a pubarca precoce.

Aspectos clínicos e laboratorias da forma näo clássica de hiperplasia adrenal congênita por deficiência da 21-hidroxilase / The clinical and laboratorial aspects of adrenal hyperplasia congenital nonclassical form for 21-hydroxylase deficiency

Os autores apresentam os aspectos clínicos e bioquímicos de ll pacientes com a forma nao clássica da deficiência de 21 -hidroxilase. Os fenótipos variaram desde a ausência de sintomas a um amplo espectro de manifestaçoes clínicas (pubarca precoce, hirsutismo, irregularidade menstrual, infertilidade e clitorimegalia). O diagnóstico foi firmado através da dosagem plasmática da l7OHP basal elevada quando comparada ao grupo controle (média ñ EPM) (697 ñ 267 vs 70 ñ 8 ng/dl) e sua resposta exagerada ao estímulo com ACTH exógeno (4.198 ñ 494 vs 164 ñ 21 ng/dl). As concentraçoes basais de cortisol (ll ñ 1,4 ug/dl foram semelhantes às do grupo controle (12 ñ O,7 ug/dl), porém com resposta subnormal após ACTH (20ñ 1,2 vs 30 ñ 1,5 ug/dl). Em condiçoes basais a concentraçao plasmática de ACTH foi normal (28 ñ 5 vs 22 ñ 2 pg/ml) indicando um estado de equilíbrio entre esta deficiência parcial da síntese de cortisol e a secreçao hipofisária de ACTH. Os níveis de andrógenos variaram desde normais até elevados para sexo e idade. A androstenediona esteve aumentada em todos os pacientes.

Congenital adrenal hyperplasia among peripubertal girls with hyperandrogenism.

Fifteen girls with severe hyperandrogenism were investigated by us during the last 6 years. Thirteen of these were cases of untreated congenital adrenal hyperplasia (CAH) and 2 were cases of tumoral (one sertoli leydig cell tumor of the ovary and one adrenal adenoma) hyperandrogenism. Here we present the clinical profile and laboratory data of those with congenital adrenal hyperplasia. All the girls had masculinization of genitalia (clitoromegaly alone 5, clitoromegaly with varying degree of posterior labial fusion 8). Eleven cases had hirsutism and 9 had short stature. Two patients underwent unilateral adrenelectomy with diagnosis of adrenal adenoma. Hormonal profile confirmed the diagnosis of CAH with 21 hydroxylase deficiency (elevated 17 OHP levels with exaggerated 17 OHP response to ACTH) in 12 cases and 3 beta hydroxy steroid dehydrogenase deficiency (elevated DHEAS and 17 pregnenelone levels and exaggerated DHEAS and 17 pregnenelone response to ACTH) in one case.