RESUMO
OBJECTIVES: The identification of constitutional cytogenetic abnormalities in patients with cancer may indicate loci of genes, abnormalities of which are responsible for tumor development or progression. This study was undertaken to determine whether girls with Turner's syndrome (TS) (partial or complete deletion of an X chromosome, short stature, gonadal dysgenesis) are at increased risk of neural crest-derived tumors. STUDY DESIGN: Medical records of 394 patients with TS who were followed up at Thomas Jefferson Hospital and Children's Hospital of Pittsburgh were reviewed for documentation of TS phenotype, constitutional cytogenetics, and history of neuroblastoma or related tumors. Informative cases were reviewed for tumor pathology, primary site, disease stage, associated symptoms, treatment, and outcome. RESULTS: Three patients were found to have neuroblastoma. A fourth child who died of neurofibrosarcoma was found to have extensive areas of ganglioneuroma, the benign counterpart of neuroblastoma, at autopsy. An additional four girls with TS and neuroblastoma were identified in the literature, as were two more patients with ganglioneuroma. These 10 patients ranged in age from 1 week to 16 10/12 years (median age, 3 years), and all but two of the children had localized lesions. Two of the seven children with neuroblastoma had courses complicated by opsoclonus-myoclonus, a syndrome found in fewer than 5% of all patients with neuroblastoma. CONCLUSIONS: These data strongly suggest that girls with TS are predisposed to the development of neuroblastoma and related tumors. Because these tumors are often of limited stage and may be underdiagnosed, screening of urine of patients with TS for elevated catecholamine metabolite levels may strengthen this association.
Assuntos
Neuroblastoma/complicações , Síndrome de Turner/complicações , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas/genética , Deleção Cromossômica , Transtornos Cromossômicos , Feminino , Seguimentos , Ligação Genética/genética , Humanos , Lactente , Recém-Nascido , Cariotipagem , Neuroblastoma/genética , Síndrome de Turner/genética , Cromossomo X/genéticaRESUMO
Blood samples for plasma steroid hormone determinations and molecular genotype analysis of the 21-hydroxylase gene (CYP21) were obtained from 15 infants identified through a voluntary newborn screening program. Mutations were identified on both CYP21 alleles in 12 (80%) of 15 infants; all had confirmatory plasma 17-hydroxyprogesterone concentrations > 3500 ng/dl. No patient was found to carry mutations associated with late-onset 21-hydroxylase deficiency. Newborn screening hastened diagnosis in eight infants.
Assuntos
Hiperplasia Suprarrenal Congênita , Triagem Neonatal , 17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/prevenção & controle , Alelos , Androstenodiona/sangue , Éxons/genética , Feminino , Conversão Gênica/genética , Genótipo , Humanos , Recém-Nascido , Íntrons/genética , Masculino , Mineralocorticoides/uso terapêutico , Biologia Molecular , Mutação/genética , Hibridização de Ácido Nucleico , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Progesterona/sangue , Splicing de RNA/genética , Análise de Sequência de DNA , Esteroide 21-Hidroxilase/sangue , Esteroide 21-Hidroxilase/genética , Virilismo/diagnósticoRESUMO
OBJECTIVE: We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents. METHODS: Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay. RESULTS: Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range. CONCLUSIONS: Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.
Assuntos
Hormônio Foliculoestimulante/sangue , Ensaio Imunorradiométrico/estatística & dados numéricos , Medições Luminescentes , Hormônio Luteinizante/sangue , Puberdade/sangue , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Fluorimunoensaio , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Ensaio Imunorradiométrico/métodos , Lactente , Recém-Nascido , Masculino , Puberdade/fisiologia , Puberdade Precoce/sangue , Puberdade Precoce/diagnóstico , Radioimunoensaio , Valores de Referência , Fatores SexuaisRESUMO
OBJECTIVE: We assessed the utility of spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays in the evaluation and monitoring of precocious puberty. METHODS: We evaluated serum gonadotropin values from intravenous GnRH stimulation tests in 49 girls with clinical signs suggesting central precocious puberty (CPP). Because GnRH-stimulated LH has been considered the standard for diagnosing CPP, we used it as the basis for comparison with GnRH-stimulated FSH levels and spontaneous LH and FSH measured by immunochemiluminometric assay. RESULTS: Twenty-six patients had a peak serum LH value above the +2 SD threshold for normal prepubertal female subjects (LH > 5 IU/L). The GnRH-stimulated FSH values had a narrow range and did not discriminate patients with CPP. In contrast, elevations in spontaneous LH and FSH were found to be specific for CPP. Spontaneous LH levels correlated strongly with peak stimulated LH levels in subjects with precocious puberty (r = 0.79) or in control subjects (r = 0.93, both p (0.0001). Spontaneous LH levels in excess of 0.1 IU/L detected true puberty with 94% sensitivity and 88% specificity. Random LH levels in excess of 0.3 IU/L had 100% specificity for CPP. CONCLUSIONS: The GnRH-stimulated FSH levels do not adequately differentiate children with and without CPP and have limited utility in the evaluation of precocious puberty. Spontaneous FSH levels are elevated in CPP with fair sensitivity and marked specificity. Elevated random LH, measured by third-generation assay such as immunochemiluminometric assay, is strongly correlated with and highly predictive of elevated peak GnRH-stimulated LH, and is a useful screening tool for CPP.
Assuntos
Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Puberdade Precoce/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Ensaio Imunorradiométrico/estatística & dados numéricos , Leuprolida/uso terapêutico , Medições Luminescentes , Masculino , Puberdade Precoce/sangue , Puberdade Precoce/terapia , Sensibilidade e EspecificidadeRESUMO
It is necessary not only to perform laboratory tests for the correct diagnosis of children with precocious puberty, but also to monitor laboratory tests to ensure adequacy of therapy. Careful laboratory testing is a requisite in the differentiation of central from peripheral precocious puberty. It is also required to determine whether the patient who presents with early physical changes of pubertal development with peripheral precocious puberty has evidence of pubertal hormonal secretion. The most useful single test is gonadotropin-releasing hormone (gonadorelin) stimulation of luteinizing hormone release. The same stimulation test is also indicated to verify the adequacy of suppression of gonadotropin secretion among patients with central precocious puberty who are being treated with gonadotropin-releasing hormone analogue. It is necessary to know which gonadotropin assay is being used and the range of normal levels to correctly interpret the tests.
Assuntos
Técnicas de Laboratório Clínico , Monitorização Fisiológica , Puberdade Precoce/diagnóstico , Criança , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina , Gonadotropinas Hipofisárias/metabolismo , Humanos , Hormônio Luteinizante/metabolismo , MasculinoRESUMO
Disorders of the CYP21 gene, which is located within the major histocompatibility complex on the short arm of chromosome 6, are the leading causes of congenital adrenal hyperplasia (CAH). The coding gene and a highly homologous pseudogene are tandemly arranged with the two genes for the fourth component of complement (C4A and C4B). To analyse the prevalence rates of mutations of the CYP21 genes and the segregation of the CYP21 genes with their corresponding human leucocyte antigen (HLA)-haplotypes, 21 families with one or two children with the severe form of 21-hydroxylase deficiency were studied. Mutations of the CYP21 gene on their corresponding HLA-haplotype were detected by hybridisation of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotides and solid phase direct sequencing. Our study has shown the following. (1) A single basepair mutation (A-->G or C-->G) within the second intron is the most frequent mutation leading to impaired 21-hydroxylase activity. This mutation is only detected in HLA-haplotypes associated with the salt-wasting form of CAH. (2) A large deletion of part or all of the CYP21 gene is associated with the HLA-haplotype A3, BW47, C6, DR7, DR53, DQ2 but is also observed in other HLA-haplotypes and can be detected by a simple rapid PCR restriction fragment length polymorphism method. (3) Two alleles of the coding CYP21 gene differing in a leucine codon within the first exon, (formerly described as a mutation associated with 21-hydroxylase deficiency) have been found with an equal distribution in patients with 21-hydroxylase deficiency, non-disease HLA-haplotypes and the local healthy controls.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Genes MHC da Classe II , Genes MHC Classe I , Haplótipos , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/enzimologia , Adulto , Sequência de Bases , Criança , DNA , Éxons , Feminino , Deleção de Genes , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase , PseudogenesRESUMO
BACKGROUND: Hirsutism in women is a clinical manifestation of excessive production of androgens. The source of the excess androgen may be either the ovaries or the adrenal glands, and distinguishing between these sources may be difficult. METHODS: To determine whether measurements of plasma dehydroepiandrosterone (DHEA) sulfate and ACTH stimulation tests, both widely used in the evaluation of hirsutism in women, provide useful information, we performed both tests in 22 normal women and 31 female patients with hirsutism. The hormones measured in plasma during the ACTH stimulation tests were progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, androstenedione, 11-deoxycortisol, and cortisol. RESULTS: The women with hirsutism were divided into four groups based on their individual responses to ACTH stimulation: patients with a possible 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency, those with a possible 21-hydroxylase deficiency, those with a possible 11 beta-hydroxylase deficiency, and those with no apparent defect in steroidogenesis. The results in 19 patients (61 percent) suggested subtle defects in adrenal steroidogenesis. There was no significant correlation between the basal plasma DHEA sulfate levels and the hormonal response to ACTH, nor were the basal levels of hormones predictive of the levels after ACTH stimulation. Eleven patients had significantly elevated basal levels of plasma DHEA sulfate; only 5 of these 11 had responses to ACTH suggestive of compromised steroidogenesis. Thirteen patients who had responses suggestive of defective steroidogenesis had DHEA sulfate levels within the normal range. CONCLUSIONS: A substantial proportion of women with hirsutism have mild defects in adrenal steroidogenesis, revealed by an ACTH stimulation test, that are indicative of late-onset (nonclassic) congenital adrenal hyperplasia. Measurements of basal steroid levels are not helpful in differentiating among the causes of increased androgen production in such patients and may be misleading.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hormônio Adrenocorticotrópico , Hirsutismo/diagnóstico , 17-alfa-Hidroxipregnenolona/sangue , 17-alfa-Hidroxiprogesterona , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Adulto , Androstenodiona/sangue , Cortodoxona/sangue , Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona , Diagnóstico Diferencial , Feminino , Hirsutismo/sangue , Humanos , Hidrocortisona/sangue , Hidroxiprogesteronas/sangue , Progesterona/sangueRESUMO
We describe four male patients with hypothalamic hamartomas associated with sexual precocity. Our assessment of their management suggests that resection using current microsurgical techniques is a valid treatment option if the patient has a normal pubertal endocrine makeup, if the hamartoma is pedunculated, and if the patient is young enough to require years of parenteral medical treatment. Such surgical treatment can be curative, and subsequent growth and development can be normal (patients 1 and 2). However, if the patient is near to pubertal age (patient 3) or if neurosurgical or gonadotropin releasing hormone analogue treatment is not available, the natural history (patient 4) suggests that the only undesirable effects are accelerated growth, tall stature for age, and premature sexual development during childhood, as well as the psychosocial problems that may accompany them. Adult height may be compromised, although the two patients who did not undergo a surgical procedure and did not receive gonadotropin releasing hormone analogue therapy are above the lower limits of the normal range of adult male height. Therefore, if the hamartoma is pedunculated and cessation of pubertal development is desired, resection of the hamartoma is a reasonable therapeutic option.
Assuntos
Hamartoma/complicações , Neoplasias Hipotalâmicas/complicações , Puberdade Precoce/etiologia , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Danazol/uso terapêutico , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/uso terapêutico , Hamartoma/tratamento farmacológico , Hamartoma/cirurgia , Humanos , Neoplasias Hipotalâmicas/tratamento farmacológico , Neoplasias Hipotalâmicas/cirurgia , Lactente , Leuprolida , Hormônio Luteinizante/sangue , Masculino , Testosterona/sangueRESUMO
Sellar enlargement and suprasellar extension of a pituitary mass, demonstrated by magnetic resonance imaging or computed tomographic scanning in three children with primary hypothyroidism, resolved after treatment with levothyroxine sodium. This condition, a logical consequence of the pathogenesis of primary hypothyroidism, must be considered in patients with pituitary and suprasellar masses.
Assuntos
Hipotireoidismo/complicações , Hipófise/patologia , Sela Túrcica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Hiperplasia , Hipertrofia , Imageamento por Ressonância Magnética , Masculino , Hipófise/efeitos dos fármacos , Tiroxina/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
Leuprolide acetate (D-Leu6 des-Gly-NH2(10), Pro-ethylamide9), a synthetic non-apeptide analog of naturally occurring gonadotropin releasing hormone, was used to treat 62 children with central precocious puberty. Sex steroid levels (testosterone in boys and estradiol in girls) were suppressed during treatment lasting from 3.5 to 24.9 months. Basal follicle-stimulating hormone values and both luteinizing hormone and follicle-stimulating hormone peak responses to stimulation by luteinizing hormone releasing hormone were also suppressed, although basal luteinizing hormone values did not differ. Linear growth rate and the rate of bone age advancement decreased during leuprolide therapy. Side effects were minimal. The long-term safety of this treatment has not yet been established; however, leuprolide appears to be an effective long-term therapy for central precocious puberty.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Puberdade Precoce/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/uso terapêutico , Crescimento/efeitos dos fármacos , Humanos , Lactente , Leuprolida , Hormônio Luteinizante/sangue , Masculino , Puberdade Precoce/sangueRESUMO
Familial expression of inadequate virilization of 46XY siblings is often reported as an isolated anomaly. We recently evaluated two families with 2 siblings who had a 46XY karyotype, ambiguous genitalia or micropenis, facial anomalies and mental retardation. There is no evidence of gonadotropin deficiency, defects of steroidogenesis, or androgen insensitivity. While there was a testosterone response to human chorionic gonadotropin stimulation in all 3 tested, gonadotropin levels were elevated in 2 of the infants suggestive of faulty seminiferous tubules, 1 of whom later had elevated luteinizing hormone levels. These kindreds may represent a new syndrome with either an X-linked recessive or sex-limited autosomal dominant form of inheritance, with partial testicular failure, multiple congenital anomalies, and mental retardation.
Assuntos
Sistema Nervoso Central/anormalidades , Genitália Masculina/anormalidades , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal/genética , Células Cultivadas , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/fisiopatologia , Feminino , Disgenesia Gonadal 46 XY/fisiopatologia , Humanos , Recém-Nascido , Cariotipagem , Masculino , Linhagem , Receptores Androgênicos/metabolismo , Pele/metabolismoAssuntos
Hiperplasia Suprarrenal Congênita , Hiperfunção Adrenocortical/genética , Triagem de Portadores Genéticos , Esteroide Hidroxilases/deficiência , Hiperfunção Adrenocortical/sangue , Hiperfunção Adrenocortical/etiologia , Hormônio Adrenocorticotrópico , Homozigoto , Humanos , Hidroxiprogesteronas/sangue , Progesterona/sangueRESUMO
Long-term, low-dosage androgen treatment of patients with Turner syndrome results in more rapid growth and significantly greater adult height than in control patients who receive only estrogen for pubertal development. Seventeen patients treated with oxandrolone for one year and ten treated for two years had significantly greater growth velocities during than before treatment. Mean adult height of 25 patients treated with oxandrolone, fluoxymesterone, or both was significantly taller than the height of adult patients with Turner syndrome treated with estrogen only. Excessive skeletal maturation was not generally observed.
Assuntos
Oxandrolona/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Estatura/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Esquema de Medicação , Quimioterapia Combinada , Fluoximesterona/administração & dosagem , Fluoximesterona/farmacologia , Fluoximesterona/uso terapêutico , Crescimento/efeitos dos fármacos , Humanos , Cariotipagem , Mosaicismo , Oxandrolona/administração & dosagem , Oxandrolona/farmacologia , Estudos RetrospectivosRESUMO
Pubertal gynecomastia occurred in 20 to 29 boys who were followed for 24 or more months during puberty. Mean concentrations of LH, FSH, prolactin, testosterone, and estrone and estradiol were compared. Although levels did not differ between boys who developed gynecomastia and those who did not, when compared with the stage of puberty, changes were noted between mean concentrations from samples before and when gynecomastia was first noted. A significant increase of estradiol occurred with the onset of gynecomastia, while testosterone levels did not change; thus the testosterone-estradiol ratio decreased. Prolactin concentrations fell significantly with the onset of gynecomastia. These data indicate a difference of hormonal dynamics between boys with and without gynecomastia.