Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Objective: Only few large families with multiple endocrine neoplasia type 1 (MEN1) have been documented. Here, we aimed to investigate the clinical features of a seven-generation Brazilian pedigree. which included 715 at-risk family members. Design: Genealogical and geographic analysis was used to identify the MEN1 pedigree. Clinical and genetic approach was applied to characterize the phenotypic and genotypic features of the family members. Results: Our genetic data indicated that a founding mutation in the MEN1 gene has occurred in this extended Brazilian family. Fifty family members were diagnosed with MEN1. Very high frequencies of functioning and non-functioning MEN1-related tumors were documented and the prevalence of prolactinoma (29.6%) was similar to that previously described in prolactinoma-variant Burin (32%). In addition, bone mineral density analysis revealed severe osteoporosis (T,-2.87 +/- 0.32) of compact bone (distal radius) in hyperparathyroidism (HPT)/MEN1 patients. while marked bone mineral loss in the lumbar spine (T,-1.95 +/- 0.39). with most cancellous bone, and femoral neck (mixed composition: T,-1.48 +/- 0.27) were also present. Conclusions: In this study, we described clinically and genetically the fifth largest MEN1 family in the literature. Our data confirm previous findings suggesting that prevalence of MEN1-related tumors in large families may differ from reports combining cumulative data of small families. Furthermore. we were able to evaluate the bone status in HPT/MEN1 cases, a subject that has been incompletely approached in the literature. We discussed the bone loss pattern found in our MEN1 patients comparing with that of patients with sporadic primary HPT.

Early-Onset, Progressive, Frequent, Extensive, and Severe Bone Mineral and Renal Complications in Multiple Endocrine Neoplasia Type 1-Associated Primary Hyperparathyroidism

Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT However studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking In this cross sectional study performed in a tertiary academic hospital 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual energy X ray absorptiometry (DXA) scanning of the proximal one third of the distal radius (1/3DR) femoral neck, total hip, and lumbar spine (LS) The mean age of the patients was 389 +/- 145 years Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77 8%) In the younger group (<50 years of age) demineralization in the 1/3DR was more frequent more severe and occurred earlier (40% Z-score 1 81 +/- 0 26) The older group (>50 years of age) had a higher frequency of bone demineralization at all sites (p < 005) and a larger number of affected bone sites (p < 0001), and BMD was more severely compromised in the 1/3DR (p = 007) and LS (p= 002) BMD values were lower in symptomatic (88 9%) than in asymptomatic HPT patients (p < 006) Patients with long standing HPT (>10 years) and gastnnoma/HPT presented significantly lower 1/3DR BMD values Urolithiasis occurred earlier (<30 years) and more frequently (75%) and was associated with related renal comorbidities (50%) and renal insufficiency in the older group (33%) Bone mineral- and urolithiasis-related renal complications in HPT/MEN1 are early onset frequent extensive severe and progressive These data should be considered in the individualized clinical/surgical management of patients with MEN1 associated HPT (C) 2010 American Society for Bone and Mineral Research

Bone mineral density analysis in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 after total parathyroidectomy

P>Objective Limited data have been reported on the effect of parathyroidectomy (PTx) on bone mineral density (BMD) in the setting of patients with hyperparathyroidism (HPT) associated with multiple endocrine neoplasia type 1 (MEN1). This study investigates the impact of total PTx on BMD in patients with HPT/MEN1. Design and patients A case series study was performed in a tertiary academic hospital. A total of 16 HPT/MEN1 patients from six families harbouring MEN1 germline mutations were subjected to total PTx followed by parathyroid auto-implant in the forearm. Measurements Bone mineral density values were assessed using dual-energy X-ray absorptiometry. Results Before PTx, reduced BMD (Z-score <-2 center dot 0) was highly prevalent in the proximal one-third of the distal radius (1/3 DR) (50%), lumbar spine (LS) (43 center dot 7%), ultradistal radius (UDR) (43 center dot 7%), femoral neck (FN) (25%) and total femur (TF) (18 center dot 7%) in the patients. Fifteen months after PTx, we observed a BMD improvement in the LS (from 0 center dot 843 to 0 center dot 909 g/cm2; +8 center dot 4%, P = 0 center dot 001), FN (from 0 center dot 745 to 0 center dot 798 g/cm2; +7 center dot 7%, P = 0 center dot 0001) and TF (from 0 center dot 818 to 0 center dot 874 g/cm2; +6 center dot 9%, P < 0 center dot 0001). No significant change was noticed in the 1/3 DR and UDR after PTx. Conclusions This data confirmed BMD recovery in the LS and FN after PTx in HPT/MEN1 patients. We also documented a significant BMD increase in the TF and no change in both the 1/3 DR and UDR BMD after PTx. Our data suggest that LS and proximal femur are the most informative sites to evaluate the short-term BMD outcome after PTx in HPT/MEN1 subjects.

HLA-G polymorphisms in women with squamous intraepithelial lesions harboring human papillomavirus

Human papillomavirus (HPV) infection is etiologically associated with low-(LSIL) and high-grade squamous intraepithelial lesions (HSIL) and with cervical cancer. The progression or regression of the lesions may depend, among other factors, on the host heritable immune response. Because human leukocyte antigen (HLA)-G molecules are involved in the modulation of innate and adaptive immune responses, and because no previous studies have evaluated HLA-G polymorphism in patients with SIL, we conducted a study to assess the association between HLA-G polymorphisms and cervical lesions harboring HPV infection. Cervico-vaginal scrapings and blood samples were collected from 125 women with SIL (68 LSIL and 57 HSIL) and from 94 healthy women without HPV infection and cytological abnormalities. HPV type and HLA-G polymorphisms in exons 2, 3 and 8 (14 bp insertion/deletion) were evaluated by PCR methodology, and digested with restriction endonucleases. The Genepop software and the EM and PHASE algorithms were used for statistical analysis. A significant protective association was observed between the presence of the G*0103 allele and SIL and between the G0101/G0104 genotype and HSIL in the group of patients compared to control. The presence of the G0104/+14 bp and G0104/-14 bp haplotypes conferred susceptibility to SIL compared to control. In addition, patients possessing the G0104/+14 bp haplotype and harboring HPV-16 and -18 co-infections were particularly associated with HSIL. These findings suggest that HLA-G polymorphisms may be associated with HPV infection and SIL, consequently representing a profile of predisposition to cervical cancer. Modern Pathology (2009) 22, 1075-1082; doi: 10.1038/modpathol.2009.67; published online 1 May 2009

Emerging concepts in colorectal neoplasia

An understanding of the mechanisms that explain the initiation and early evolution of colorectal cancer should facilitate the development of new approaches to effective prevention and intervention. This review highlights deficiencies in the current model for colorectal neoplasia in which APC mutation is placed at the point of initiation. Other genes implicated in the regulation of apoptosis and DNA repair may underlie the early development of colorectal cancer. Inactivation of these genes may occur not by mutation or loss but through silencing mediated by methylation of the gene's promoter region. hMLH1 and MGMT are examples of DNA repair genes that are silenced by methylation. Loss of expression of hMLH1 and MGMT protein has been demonstrated immunohistochemically in serrated polyps. Multiple lines of evidence point to a serrated pathway of neoplasia that is driven by inhibition of apoptosis and the subsequent inactivation of DNA repair genes by promoter methylation. The earliest lesions in this pathway are aberrant crypt foci (ACF). These may develop Into hyperplastic polyps or transform while still of microscopic size into admixed polyps, serrated adenomas, or traditional adenomas. Cancers developing from these lesions may show high- or low-level microsatellite instability (MSI-H and MSI-L, respectively) or may be microsatellite stable (MSS). The suggested clinical model for this alternative pathway is the condition hyperplastic polyposis. If colorectal cancer is a heterogeneous disease comprising discrete subsets that evolve through different pathways, it is evident that these subsets will need to be studied individually in the future.

Familial adult renal neoplasia

Our understanding of the molecular mechanisms underlying the tumorigenesis of renal cell carcinoma (RCC) has partially come from studies of RCC related familial cancer syndromes such as von Hippel-Lindau (VHL) disease and hereditary papillary RCC (HPRC). These studies have led to the identification of RCC related genes, which, besides allowing accurate diagnosis of these diseases, have been found mutated or abnormally expressed in the sporadic counterparts of these familial renal tumours. To date, a number of renal tumour related syndromes have been described. We review recent advances in this field and discuss a genetic approach to managing familial cases of renal tumours occasionally encountered by cancer geneticists and urologists.

A Utilização de Endopróteses na Síndrome da Veia Cava Superior por Neoplasia do Pulmão

Apresentam-se seis casos de síndrome da veia cava superior causado por neoplasia do pulmão e que foram tratados por endopróteses colocadas por via percutânea. Descreve-se a técnica e avaliam-se os resultados. Num caso ocorreu trombose aguda da endoprótese que foi tratada por uroquinase. Não se registaram outras complicações. Um doente faleceu 1 mês depois por progressão da doença. Os restantes mantinham-se sem queixas de síndrome da veia cava superior durante mais do que 6 meses. Conclui-se que a colocação de endopróteses é uma técnica pouco invasiva, eficaz e com melhoria imediata no síndrome da veia cava superior.

Circulation of human papillomavirus (HPV) genotypes in women from Córdoba, Argentina, with squamous intraepithelial lesions

Human papillomavirus (HPV) can induce a wide spectrum of squamous intraepithelial lesions (SIL) of varying severity. The aim of the present study was to establish the frequency of HPV infection and identify the genotypes circulating in women from Córdoba, Argentina, in relation to age and cytology. A total of 186 women, between 18 and 65 years old, with antecedents of SIL, underwent a pelvic examination and had cervical cells collected for cytology and HPV DNA detection. Ninety-six samples (51.6%) were positive for HPV detection, and sixty-three (65.6%) of them showed the presence of at least one HR-HPV. Low- and high-grade SIL showed significant association in patients younger than 35 years of age. We found 18 different genotypes, with a greater presence of HR-HPV. Genotypes 16 and 6 were the most frequent. Seven (7.3%) multiple infections, 85.7% of which had at least one HR-HPV, were detected. The detection of a large number of different HPV genotypes is a warning sign. It is thus necessary to strengthen the monitoring of the circulation of high-risk genotypes, currently less prevalent in intraepithelial lesions, as a control measure for the possible impact of the implementation of vaccines against genotypes 16 and 18.

Utilidade da Broncofibroscopia no Diagnóstico de Neoplasia do Pulmão em Doentes com Pneumonia Arrastada

A broncofibroscopia (BF) é frequentemente efectuada em doentes com pneumonias de evolução arrastada com o objectivo de excluir patologia endobrónquica de etiologia neoplásica. Dado que a resolução radiográfica das pneumonias da comunidade é variável, sendo dependente de vários factores (agente etiológico, idade, doenças associadas) a decisão para efectuar uma BF é muitas vezes empírica. Com o objectivo de descrever a nossa experiência neste problema estudámos retrospectivamente 123 doentes com o diagnóstico de pneumonia da comunidade baseado em critérios clínicos e radiográficos e que, apesar da antibioferapia considerada adequada, não apresentavam melhoria radiográfica significativa ao fim de pelo menos 2 semanas. Obtivemós um diagnóstico histológico de neoplasia maligna do pulmão em 7 doentes (5,6° o), sendo todos do sexo masculino, com idade superior a 55 anos efuínadores de pelo menos 40 U.M.A. A análise comparativa com os restantes doentes mostrou diferenças com significado~estatístico em relação à idade e ao consumo tabágico. O tempo de evolução da doença,valores médios de hemoglobina, leucocitos, VS, existência ou não de alterações da função renal ou hepática não foram significativamente diferentes nos dois grupos. Concluimos que a BF deve ser efectuada precocemente nos doentes pertencentes ao grupo de risco identificado (fumadores, com mais de 55 anos) não se justificando a sua realização nos restantes doentes antes das 4 a 8 semanas de evolução, a menos que estejam presentes critérios clínicos objectivos tais como progressão da doença ou agravamento do estado geral.

Mutational Analysis of Portuguese Families with Multiple Endocrine Neoplasia Type 1 Reveals Large Germline Deletions

OBJECTIVE: To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation-carriers. PATIENTS, DESIGN AND RESULTS: Six unrelated MEN1 families were studied for MEN1 gene mutations by single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the coding region and exon-intron boundaries of the MEN1 gene. These methods identified 4 different heterozygous mutations in four families: two mutations are novel (mt 1539 delG and mt 655 ims 11 bp) and two have been previously observed (mt 735 del 46p and mt 1656 del C) all resulting in a premature stop codon. In the remaining two families, in whom no mutations or abnormal MEN1 transcripts were detected, segregation studies of the 5' intragenic marker D11S4946 and codon 418 polymorphism in exon 9 revealed two large germline deletions of the MEN1 gene. Southern blot and tumour loss of heterozygosity analysis confirmed and refined the limits of these deletions, which spanned the MEN1 gene at least from: exon 7 to the 3' untranslated region, in one family, and the 5' polymorphic site D11S4946 to exon 9 (obliterating the initiation codon), in the other family. Twenty-six mutant-gene carriers were identified, 6 of which were asymptomatic. CONCLUSIONS: These results emphasize the importance of the detection of MEN1 germline deletions in patients who do not have mutations of the coding region. Important clues indicating the presence of such deletions may be obtained by segregation studies using the intragenic polymorphisms D11S4946 and at codon 418. The detection of these mutations will help in the genetic counselling of clinical management of the MEN1 families in Portugal.

Hidatidose policística: cisto hidático calcificado, simulando neoplasia mesentérica, descoberto acidentalmente

É descrito um caso de hidatidose abdominal, sem comprometimento hepático, em paciente do Estado do Acre. O cisto, já em degeneração e parcialmente calcificado, foi descoberto, por acaso, mediante estudo radiológico da coluna vertebral feito para avaliação de hérnia de disco, detectada algum tempo antes. Embora as imagens sugerissem uma neoplasia do mesentério, o achado de acúleos rostelares no conteúdo pastoso da hidátide, removida cirurgicamente, permitiu reconhecer-se a natureza parasitária da lesão.

Nódulo pulmonar esquistossomótico simulando neoplasia: relato de caso

Paciente sadio em que, ao exame de rotina, foi detectado nódulo pulmonar esquistossomótico com verme adulto, 25 anos após o tratamento específico com oxamniquine® e distante da região endêmica. O nódulo simulava clinicamente neoplasia.

Esquistossomose mansônica simulando neoplasia da bexiga

Paciente de 36 anos de idade, proveniente de zona endêmica foi admitido com episódios de hematúria macroscópica total e disúria terminal. A citoscopia mostrou um tumor exofítico na parede anterior da bexiga, sugestivo de câncer. A biópsia revelou esquistossomose mansônica. Ressecção transuretral confirmou o diagnóstico. O paciente foi clinicamente tratado com oxamniquine, obtendo cura. O caso apresentado nesse trabalho enfatiza que nem todos os tumores de bexiga com hematúria microscópica são cânceres de bexiga.