Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

[Thyroid and pregnancy]. / Tireóide e gravidez.

Pregnancy is associated with an increased requirement of hormone secretion by the thyroid, within the first weeks after conception. To this greater demand to occurs, pregnancy induces a series of physiological changes that affect thyroid function and, consequently, the tests of glandular function. For normal pregnant women living in areas with a sufficient supply of iodine, this challenge regarding the adjustment of thyroid hormone releases to this new state of equilibrium and its maintenance until the end of pregnancy it meets no difficulties. However, among women with impaired thyroid function due to some thyroid disease or among women residing in areas with an insufficient iodine supply, this does not occur. The management of thyroid dysfunction during gestation requires special considerations, since both hypothyroidism and hyperthyroidism can lead to maternal and fetal complications. In addition, thyroid nodules are detected at reasonable frequency among pregnant women, a fact that requires a differential diagnosis between benign and malignant growths during the pregnancy itself.

Tireóide e gravidez / Thyroid and pregnancy

A gravidez está associada com a necessidade aumentada de secreção hormonal pela tireóide desde as primeiras semanas após a concepção. Para que esta maior demanda ocorra, a gestação induz uma série de alterações fisiológicas que afetam a função tireoidiana e, portanto, os testes de avaliação da função glandular. Para as mulheres grávidas normais que vivem em áreas suficientes em iodo, este desafio em ajustar a liberação de hormônios tireoidianos para o novo estado de equilíbrio e manter até o término da gestação, geralmente, ocorre sem dificuldades. Entretanto, em mulheres com a capacidade funcional da tireóide prejudicada por alguma doença tireoidiana ou naquelas que residem em áreas de insuficiência iódica, isso não ocorre. O manejo de disfunções tireoidianas durante a gestação requer considerações especiais, pois tanto o hipotireoidismo quanto o hipertireoidismo podem levar a complicações maternas e fetais. Além disso, nódulos tireoidianos são detectados, com certa freqüência, em gestantes, o que pode gerar a necessidade do diagnóstico diferencial entre benignos e malignos ainda durante a gestação.

Pregnancy is associated with an increased requirement of hormone secretion by the thyroid, within the first weeks after conception. To this greater demand to occurs, pregnancy induces a series of physiological changes that affect thyroid function and, consequently, the tests of glandular function. For normal pregnant women living in areas with a sufficient supply of iodine, this challenge regarding the adjustment of thyroid hormone releases to this new state of equilibrium and its maintenance until the end of pregnancy it meets no difficulties. However, among women with impaired thyroid function due to some thyroid disease or among women residing in areas with an insufficient iodine supply, this does not occur. The management of thyroid dysfunction during gestation requires special considerations, since both hypothyroidism and hyperthyroidism can lead to maternal and fetal complications. In addition, thyroid nodules are detected at reasonable frequency among pregnant women, a fact that requires a differential diagnosis between benign and malignant growths during the pregnancy itself.

Cystic fibrosis and neonatal screening.

The clinical and diagnostic aspects of cystic fibrosis have been extensively reviewed, with an emphasis on neonatal screening. This systematic literature review involved a search for relevant contributions in the PubMed and SciELO databases. The first references to cystic fibrosis date to the Middle Ages. Cystic fibrosis is the most frequent autosomal recessive hereditary disease among Caucasians (1:2,000 to 3,500). More than 1,000 mutations lead to the disease, the most common being "F508, with 70% prevalence among Canadian, Northern European, and American Caucasians and 23 to 55% prevalence among Brazilians. The basic defect is in chloride ion secretion. Cystic fibrosis screening has long been controversial, and after almost three decades, there are few nationwide programs (most are regional or local). However, the U.S. Centers for Disease Control and Prevention (CDC) has concluded that screening for cystic fibrosis is justified. The lack of a specific screening test and the ethnic heterogeneity of the Brazilian population pose challenges for neonatal screening.

Cystic fibrosis and neonatal screening / Fibrose cística e a triagem neonatal

The clinical and diagnostic aspects of cystic fibrosis have been extensively reviewed, with an emphasis on neonatal screening. This systematic literature review involved a search for relevant contributions in the PubMed and SciELO databases. The first references to cystic fibrosis date to the Middle Ages. Cystic fibrosis is the most frequent autosomal recessive hereditary disease among Caucasians (1:2,000 to 3,500). More than 1,000 mutations lead to the disease, the most common being "F508, with 70 percent prevalence among Canadian, Northern European, and American Caucasians and 23 to 55 percent prevalence among Brazilians. The basic defect is in chloride ion secretion. Cystic fibrosis screening has long been controversial, and after almost three decades, there are few nationwide programs (most are regional or local). However, the U.S. Centers for Disease Control and Prevention (CDC) has concluded that screening for cystic fibrosis is justified. The lack of a specific screening test and the ethnic heterogeneity of the Brazilian population pose challenges for neonatal screening.

Aspectos clínicos e diagnósticos da fibrose cística são revistos de modo abrangente, com ênfase na triagem neonatal. Esta revisão sistematizada da literatura envolveu busca de contribuições relevantes nos bancos de dados PubMed e SciELO. Referências sobre fibrose cística existem desde a Idade Média. É a doença hereditária autossômica recessiva mais freqüente em caucasianos (1:2.000 a 3.500). Mais de mil mutações levam à doença, a mais comum: "F508 (prevalência: 70 por cento em caucasianos canadenses, americanos e norte-europeus; de 23 a 55 por cento em brasileiros). O defeito básico ocorre na secreção do íon cloro. Sua triagem é assunto polêmico e apesar de estar disponível há quase três décadas, por meio de diferentes protocolos, poucos programas de abrangência nacional existem. Entretanto, o Centers for Disease Control and Prevention, dos Estados Unidos, afirma que o rastreamento neonatal para fibrose cística é justificado. A falta de um teste específico e a heterogeneidade étnica da população brasileira dificultam sua triagem neonatal.

Pituitary-gonadal hormones and interleukin patterns in leprosy.

The functional status of pituitary-gonadal hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous (LL/BL) and tuberculoid (TT/BT) poles of leprosy were investigated. Gonadotropins [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and C-reactive protein (CRP) concentrations and erythrocyte sedimentation rate (ESR) were significantly higher in LL/BL leprosy patients than in controls and were not different from controls in TT/BT patients. LH and FSH were positively correlated with IL-1beta, IL-6 and TNF-alpha, and CRP concentrations and ESR. Testosterone plasma levels were significantly decreased in LL/BL patients and not different in TT/BT patients compared with controls. In addition, testosterone levels were inversely correlated with IL-6 and TNF-alpha. Prolactin plasma levels of both LL/BL and TT/BT patients were not different when compared with those of controls. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. The significant correlations between gonadotropins and testosterone and cytokines in leprosy patients suggest that cytokines may have a direct influence at testicular level and may be of pathogenetic significance in leprosy and in other inflammatory states involving reproductive dysfunction.

Polymorphisms in the RET proto-oncogene and the phenotypic presentation of familial medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) occurs in a sporadic or as an autosomal dominant hereditary form. Inherited forms of MTC are related to mutations in the RET proto-oncogene. We screened genomic DNA from 11 patients with MTC for mutations in exons 10, 11, 13, 14, 15, and 16 of the RET proto-oncogene. Subsequently, we also evaluated a family of 1 patient with presumed diagnosis of sporadic MTC. Three patients with MEN2A from two unrelated families presented mutations in exon 11 (C634Y and C634R). A heterozygous mutation in exon 14 (V804M) was identified in the patient with the presumed sporadic MTC. We also observed two different polymorphisms: S904S in exon 15 (2 patients) and L769L in exon 13 (4 patients). The L769L polymorphism has been associated with earlier onset of sporadic MTC. On the other hand, mutations in exon 14 are associated with MTC of later onset and lower aggressiveness. Indeed, the carrier of the V804M mutation associated with L769L polymorphism presented MTC at 32 years of age, in contrast to her asymptomatic mother, who had only the V804M mutation and had MTC diagnosed by fine-needle aspiration biopsy at 60 years of age. In conclusion, the present study confirms the need for genetic screening to differentiate sporadic and hereditary forms of MTC. In addition, the genetic study allows the identification of asymptomatic carriers of hereditary forms of MTC. Finally, we speculated that the L769L polymorphism of the RET proto-oncogene may be related to earlier age of onset in the patient with the V804M mutation.

Adrenocortical hormones and interleukin patterns in leprosy.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous and tuberculoid poles of leprosy were investigated. Interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha plasma levels, C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates (ESR) were significantly higher in LL/BL (lepromatous) leprosy patients than in control subjects. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulphate (DHEA-S) plasma levels were significantly lower in leprosy patients than in sex-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6, TNF-alpha, and CRP concentrations. This finding may be of pathogenetic significance in this disease and in other inflammatory states.

Carcinoma medular de tireóide: da definiçäo às bases moleculares / Medullary thyroid carcinoma: from definition to genetic bases

O carcinoma medular de tireóide (CMT) é um tumor maligno raro com origem nas células parafoliculares da tireóide, tendo como principal produto secretório a calcitonina. Representa 3 a 10 por cento de todos os tumores tireoidianos e é responsável por um grande número de mortes em portadores de câncer de tireóide. Em 75-90 por cento dos pacientes, o CMT ocorre de forma esporádica e, nos demais casos, é uma doença hereditária autossômica dominante com alto grau de penetrância e variabilidade de expressäo, podendo fazer parte de 3 síndromes distintas: neoplasia endócrina múltipla (NEM) 2A, NEM 2B ou CMT familiar. As diferentes formas clínicas do CMT, principalmente as hereditárias, estäo relacionadas com mutações no proto-oncogene RET, as quais resultam em ativaçäo constitutiva do receptor de membrana tirosina-quinase RET. A distinçäo entre estas formas é de extrema relevância clínica por causa das diferenças apresentadas entre elas em termos de prognóstico e pela necessidade de um rastreamento familiar, aconselhamento genético e seguimento das formas hereditárias. A eficiência do rastreamento genético, pela pesquisa de mutações no proto-oncogene RET, está bem estabelecida no diagnóstico e na identificaçäo de portadores assintomáticos das formas hereditárias de CMT, permitindo uma intervençäo cirúrgica precoce e efetiva, reduzindo a morbidade e a mortalidade associadas a esta doença.

Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in paracoccidioidomycosis were investigated in a prospective study. Patients were evaluated before treatment and 1 and 6 months after receiving antifungal therapy. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha plasma levels, C-reactive protein (CRP) concentrations, and erythrocyte sedimentation rate (ESR) were significantly higher in untreated patients than in control subjects. After 6 months of treatment, levels of the 3 cytokines, CRP concentrations, and the ESR decreased significantly. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) plasma levels were significantly lower in patients than in sex- and age-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6 plasma levels. This finding may be of pathogenetic significance in this disease and in other inflammatory states.

Adrenocortical hormones and interleukin patterns in leprosy

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous and tuberculoid poles of leprosy were investigated. Interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha plasma levels, C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates (ESR) were significantly higher in LL/BL (lepromatous) leprosy patients than in control subjects. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulphate (DHEA-S) plasma levels were significantly lower in leprosy patients than in sex-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6, TNF-alpha, and CRP concentrations. This finding may be of pathogenetic significance in this disease and in other inflammatory states.