Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state.

Tuberous sclerosis complex (TSC) is an autosomal dominant cancer predisposition disorder caused by heterozygous mutations in TSC1 or TSC2 genes and characterized by mTORC1 hyperactivation. TSC-associated tumors develop after loss of heterozygosity mutations and their treatment involves the use of mTORC1 inhibitors. We aimed to evaluate cellular processes regulated by mTORC1 in TSC cells with different mutations before tumor development. Flow cytometry analyses were performed to evaluate cell viability, cell cycle and autophagy in non-tumor primary TSC cells with different heterozygous mutations and in control cells without TSC mutations, before and after treatment with rapamycin (mTORC1 inhibitor). We did not observe differences in cell viability and cell cycle between the cell groups. However, autophagy was reduced in mutated cells. After rapamycin treatment, mutated cells showed a significant increase in the autophagy process (p=0.039). We did not observe differences between cells with distinct TSC mutations. Our main finding is the alteration of autophagy in non-tumor TSC cells. Previous studies in literature found autophagy alterations in tumor TSC cells or knock-out animal models. We showed that autophagy could be an important mechanism that leads to TSC tumor formation in the haploinsufficiency state. This result could guide future studies in this field.

Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

Tuberous Sclerosis Complex with rare associated findings in the gastrointestinal system: a case report and review of the literature.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a complex and heterogeneous genetic disease that has well-established clinical diagnostic criteria. These criteria do not include gastrointestinal tumors. CASE PRESENTATION: We report a 45-year-old patient with a clinical and molecular diagnosis of TSC and a family history of cancer, presenting two rare associated findings: gastrointestinal polyposis and pancreatic neuroendocrine tumor. This patient was subjected to a genetic test with 80 cancer predisposing genes. The genetic panel revealed the presence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the initiation codon. No changes were identified in the colorectal cancer and colorectal polyposis genes. DISCUSSION AND CONCLUSIONS: We describe a case of TSC that presented tumors of the gastro intestinal tract that are commonly unrelated to the disease. The patient described here emphasizes the importance of considering polyposis of the gastrointestinal tract and low grade neuroendocrine tumor as part of the TSC syndromic phenotype.

Haplotypic characterization of BRCA1 c.5266dupC, the prevailing mutation in Brazilian hereditary breast/ovarian cancer.

Specific pathogenic mutations associated with breast cancer development can vary between ethnical groups. One example is BRCA1 c.5266dupC that was first described as a founder mutation in the Ashkenazi Jewish population, but was later also found in other populations. In Brazil, this mutation corresponds to 20% of pathogenic BRCA1 variants reported. Our objective was to investigate the haplotype component of a group of Brazilian families who inherited c.5266dupC in the BRCA1 gene and to verify the ancestry contribution from European, African, and Amerindian origins. Fourteen probands carrying c.5266dupC and 16 relatives (carriers and non-carriers) were investigated. The same haplotype was observed segregating within all the families analyzed, revealing no recombinants in a region of 0.68 Mb. Ancestry analysis demonstrated that the European component was predominant among probands. The BRCA1 c.5266dupC analysis indicates that there was a founder effect in the Brazilian population.

Synchronous Periampullary Tumors in a Patient With Pancreas Divisum and Neurofibromatosis Type 1.

INTRODUCTION: In this study, we describe for the first time a Neurofibromatosis type 1 patient with pancreas divisum, multiple periampullary tumors and germline pathogenic variants in NF1 and CFTR genes. CASE REPORT: A 62-year-old female NF1 patient presented with weakness, choluria, nausea, and diffuse abdominal pain to an emergency room service. Magnetic resonance imaging revealed an abdominal mass involving the periampullary region and pancreas divisum. After surgical resection, three synchronous neoplasms were detected including two ampullary tumors (adenocarcinoma of the major ampulla and a neuroendocrine tumor of the minor ampulla) and a gastrointestinal stromal tumor (GIST). Germline multigene panel testing (MGPT) identified two pathogenic heterozygous germline variants: NF1 c.838del and CFTR c.1210-34TG[12]T[5]. CONCLUSION: This is the first report of a Neurofibromatosis type 1 patient with pancreas divisum and multiple periampullary tumors harboring pathogenic germline variants in NF1 and CFTR genes. The identification of two germline variants and a developmental anomaly in this patient may explain the unusual and more severe findings and underscores the importance of comprehensive molecular analyses in patients with complex phenotypes.

Performance of the Gail and Tyrer-Cuzick breast cancer risk assessment models in women screened in a primary care setting with the FHS-7 questionnaire.

Breast cancer (BC) risk assessment models base their estimations on different aspects of a woman's personal and familial history. The Gail and Tyrer-Cuzick models are the most commonly used, and BC risks assigned by them vary considerably especially concerning familial history. In this study, our aim was to compare the Gail and Tyrer-Cuzick models after initial screening for familial history of cancer in primary care using the FHS-7 questionnaire. We compared 846 unrelated women with at least one positive answer to any of the seven FHS-7 questions (positive group) and 892 unrelated women that answered negatively (negative group). Concordance between BC risk estimates was compared by Bland-Altman graphics. Mean BC risk estimates were higher using the Tyrer-Cuzick Model in women from the positive group, while women from the negative group had higher BC risk estimates using the Gail model. With increasing estimates, discordance also increased, mainly in the FHS-7 positive group. Our results show that in women with a familial history of cancer, the Gail model underestimates risk and the Tyrer-Cuzick seems to be more appropriate. FHS-7 can be a useful tool for the identification of women with higher breast cancer risks in the primary care setting.

Utilização da ocitocina em gado Girolando: avaliação da via vaginal como alternativa à via endovenosa / Use of oxytocin in Girolando cattle: evaluation of the vaginal rout as an alternative to intravenous rout

O objetivo deste trabalho foi testar a viabilidade da utilização da via vaginal em fêmeas bovinas visando à aplicação de ocitocina a partir de formulações específicas. A ocitocina foi utilizada associada a facilitadores de absorção e na forma injetável (para comparação). Foram produzidas sete formulações, todas com concentração de 5 UI/mL de ocitocina. O delineamento experimental foi em quadrado latino 8x8 (oito dias, oito tratamentos e oito novilhas ciclando). As administrações de ocitocina foram pela via vaginal e a ocitocina injetável pela via endovenosa, contendo 10 UI cada. Amostras de sangue (n=7) foram coletadas de cada animal, no tempo 0, anterior à administração dos tratamentos, e de três em três minutos até 18 minutos. A ocitocina foi extraída do plasma utilizando coluna cromatográfica C-18 e dosada utilizando o kit comercial Oxytocin EIA. Os resultados obtidos foram avaliados por análise estatística não paramétrica utilizando o teste Kruskal Wallis para comparação das médias. A concentração de ocitocina diferiu entre o tempo 0 e o tempo 12 minutos (p<0,05) para a formulação ocitocina em glicerina. Concluiu-se que houve absorção através da via vaginal para essa formulação. Mais estudos serão necessários para seu emprego no manejo com as fêmeas bovinas de forma efetiva.(AU)

The aim of this study was to test the feasibility of vaginal route in order to apply oxytocin in female bovines using specific formulations. The oxytocin was used in its injectable form (as a comparison standard) and associated with absorption enhancers. Seven formulations containing 5 IU/ml of oxytocin each were used. The experimental design was an 8x8 latin square (eight days, eight treatments and eight cycling heifers). The formulations were delivered in vaginal route and the injectable oxytocin was applied intravenously, all of them having 10 IU of oxytocin. Blood samples (n=7) were collected from each animal, the first at time 0, prior to the administration of the treatment, and the following every three minutes until 18 minutes. Oxytocin was extracted from plasma using the C18 Sep-Pak column and measured with the commercial kit Oxytocin EIA. The responses were evaluated using the nonparametric ANOVA and the Kruskal Wallis test was used to compare the means. Statistical difference was observed between times 0 and 12 (p<0,05) for the oxytocin plus glycerin formulation, showing that absorption did occur. Nonetheless, it does not suppress the need for further research before it can be effectively used in female bovine management.(AU)

Utilização da ocitocina em gado Girolando: avaliação da via vaginal como alternativa à via endovenosa / Use of oxytocin in Girolando cattle: evaluation of the vaginal rout as an alternative to intravenous rout

O objetivo deste trabalho foi testar a viabilidade da utilização da via vaginal em fêmeas bovinas visando à aplicação de ocitocina a partir de formulações específicas. A ocitocina foi utilizada associada a facilitadores de absorção e na forma injetável (para comparação). Foram produzidas sete formulações, todas com concentração de 5 UI/mL de ocitocina. O delineamento experimental foi em quadrado latino 8x8 (oito dias, oito tratamentos e oito novilhas ciclando). As administrações de ocitocina foram pela via vaginal e a ocitocina injetável pela via endovenosa, contendo 10 UI cada. Amostras de sangue (n=7) foram coletadas de cada animal, no tempo 0, anterior à administração dos tratamentos, e de três em três minutos até 18 minutos. A ocitocina foi extraída do plasma utilizando coluna cromatográfica C-18 e dosada utilizando o kit comercial Oxytocin EIA. Os resultados obtidos foram avaliados por análise estatística não paramétrica utilizando o teste Kruskal Wallis para comparação das médias. A concentração de ocitocina diferiu entre o tempo 0 e o tempo 12 minutos (p<0,05) para a formulação ocitocina em glicerina. Concluiu-se que houve absorção através da via vaginal para essa formulação. Mais estudos serão necessários para seu emprego no manejo com as fêmeas bovinas de forma efetiva.

The aim of this study was to test the feasibility of vaginal route in order to apply oxytocin in female bovines using specific formulations. The oxytocin was used in its injectable form (as a comparison standard) and associated with absorption enhancers. Seven formulations containing 5 IU/ml of oxytocin each were used. The experimental design was an 8x8 latin square (eight days, eight treatments and eight cycling heifers). The formulations were delivered in vaginal route and the injectable oxytocin was applied intravenously, all of them having 10 IU of oxytocin. Blood samples (n=7) were collected from each animal, the first at time 0, prior to the administration of the treatment, and the following every three minutes until 18 minutes. Oxytocin was extracted from plasma using the C18 Sep-Pak column and measured with the commercial kit Oxytocin EIA. The responses were evaluated using the nonparametric ANOVA and the Kruskal Wallis test was used to compare the means. Statistical difference was observed between times 0 and 12 (p<0,05) for the oxytocin plus glycerin formulation, showing that absorption did occur. Nonetheless, it does not suppress the need for further research before it can be effectively used in female bovine management.

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast.

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Correction: BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

[This corrects the article DOI: 10.1371/journal.pone.0187630.].

Clinical and molecular characterization of neurofibromatosis in southern Brazil.

OBJECTIVES: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil. METHODS: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification. RESULTS: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort. CONCLUSION: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.

TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.

Premenopausal breast cancer (BC) is a core tumor of Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) Syndromes, predisposition disorders caused by germline mutations in TP53 gene. In the Southern and Southeastern regions of Brazil, a specific TP53 germline mutation, c.1010G>A (p.Arg337His), was identified at a population frequency of 0.3%, the highest value ever described for a TP53 germline variation. In Brazilian BC patients, carrier frequency can vary from 0.5% to 8.7%. The current study assessed carrier frequency by genotyping TP53 c.1010G>A in 2 BC groups: 1) 315 patients unselected for age of diagnosis and family history (FH) and 2) 239 patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. One carrier was identified in group 1 (0.3%; CI 95% 0.1-1.76%) and six carriers in group 2 (2.5%; CI 95% 0.93-5.39%). The frequencies differed significantly between groups (p = 0.04). The mutation carrier frequency observed in group 2 could justify mutation testing in BC patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. Further studies in larger samples of BC patients of different ages and regions of the country are necessary to provide more definitive TP53 p.Arg337His carrier frequencies in different scenarios.

BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

BACKGROUND: Germline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC). METHODS: In this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria. RESULTS: A pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p ≤ 0.05) for 25 criteria; 14 of these had p ≤ 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer. CONCLUSIONS: This is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries.

Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by the development of multiple hamartomas in many organs and tissues. It occurs due to inactivating mutations in either of the two genes, TSC1 and TSC2, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the TSC1 and TSC2 loci has been performed in several cohorts of patients and a broad spectrum of pathogenic mutations have been described. In Brazil, there is no data regarding incidence and prevalence of tuberous sclerosis and mutations in TSC1 and TSC2. We analyzed both genes in 53 patients with high suspicion of tuberous sclerosis using multiplex-ligation dependent probe amplification and a customized next generation sequencing panel. Confirmation of all variants was done by the Sanger method. We identified 50 distinct variants in 47 (89%) of the patients. Five were large rearrangements and 45 were point mutations. The symptoms presented by our series of patients were not different between male and female individuals, except for the more common occurrence of shagreen patch in women (p = 0.028). In our series, consistent with other studies, TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis.

TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review

Abstract Tuberous sclerosis complex is an autosomal dominant disorder characterized by skin manifestations and formation of multiple tumors in different organs, mainly in the central nervous system. Tuberous sclerosis is caused by the mutation of one of two tumor suppressor genes, TSC1 or TSC2. Currently, the development of novel techniques and great advances in high-throughput genetic analysis made mutation screening of the TSC1 and TSC2 genes more widely available. Extensive studies of the TSC1 and TSC2 genes in patients with TSC worldwide have revealed a wide spectrum of mutations. Consequently, the discovery of the underlying genetic defects in TSC has furthered our understanding of this complex genetic disorder, and genotype-phenotype correlations are becoming possible, although there are still only a few clearly established correlations. This review focuses on the main symptoms and genetic alterations described in TSC patients from 13 countries in three continents, as well as on genotype-phenotype correlations established to date. The determination of genotype-phenotype correlations may contribute to the establishment of successful personalized treatment for TSC.

TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review.

Tuberous sclerosis complex is an autosomal dominant disorder characterized by skin manifestations and formation of multiple tumors in different organs, mainly in the central nervous system. Tuberous sclerosis is caused by the mutation of one of two tumor suppressor genes, TSC1 or TSC2. Currently, the development of novel techniques and great advances in high-throughput genetic analysis made mutation screening of the TSC1 and TSC2 genes more widely available. Extensive studies of the TSC1 and TSC2 genes in patients with TSC worldwide have revealed a wide spectrum of mutations. Consequently, the discovery of the underlying genetic defects in TSC has furthered our understanding of this complex genetic disorder, and genotype-phenotype correlations are becoming possible, although there are still only a few clearly established correlations. This review focuses on the main symptoms and genetic alterations described in TSC patients from 13 countries in three continents, as well as on genotype-phenotype correlations established to date. The determination of genotype-phenotype correlations may contribute to the establishment of successful personalized treatment for TSC.

Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations.

Germline mutations in BRCA1 or BRCA2 (BRCA) are responsible for 5-15% of breast (BC) and ovarian cancers (OC), predisposing to the development of early onset and often multiple primary tumors. Since mutation carriers can benefit from risk-reducing interventions, the identification of individuals with hereditary breast and ovarian cancer (HBOC) syndrome has a significant clinical impact. We assessed whether a panel assay for recurrent Hispanic BRCA mutations (HISPANEL) has an adequate breadth of coverage to be suitable as a cost effective screening tool for HBOC in a cohort of patients from Southern Brazil. A multiplex, PCR-based panel was used to genotype 232 unrelated patients for 114 germline BRCA mutations, finding deleterious mutations in 3.5% of them. This mutation prevalence is within the range detected by the HISPANEL among BC patients unselected for family history in other Latin American settings. The HISPANEL would have accounted for 27% of the BRCA mutations detected by complete sequencing in a comparison cohort (n = 193). This prevalence may be region-specific since significant differences in population structure exist in Brazil. Comprehensive analysis of BRCA in a larger set of HBOC patients from different Brazilian regions is warranted, and the results could inform customization of the HISPANEL as an affordable mutation screening tool.

Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes: a review for the pediatrician.

INTRODUCTION: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-like syndromes (LFS/LFL), both of which are caused by TP53 germline mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. OBJECTIVE: to review clinical relevant aspects of LFS/LFL by our multidisciplinary team with focus on pediatric cancer. METHODS: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li-Fraumeni syndrome, Li-Fraumeni-like syndrome and pediatric cancer; and all manuscripts published between 1990 and 2014 using these keywords were retrieved and reviewed. CONCLUSION: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and families. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidisciplinary approach should be sought for the counseling, diagnosis and management of patients and families affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and families to genetic cancer risk evaluation and management programs.

Vitamin D Status and VDR Genotype in NF1 Patients: A Case-Control Study from Southern Brazil.

Neurofibromatosis type 1 (NF1) patients are more likely to have vitamin D deficiency when compared to the general population. This study aimed to determine the levels of 25-OH-vitamin D [25(OH)D] in individuals with NF1 and disease-unaffected controls and analyze FokI and BsmI VDR gene polymorphisms in a case and in a control group. Vitamin D levels were compared between a group of 45 NF1 patients from Southern Brazil and 45 healthy controls matched by sex, skin type, and age. Genotypic and allelic frequencies of VDR gene polymorphisms were obtained from the same NF1 patients and 150 healthy controls. 25(OH)D deficiency or insufficiency was not more frequent in NF1 patients than in controls (p = 0.074). We also did not observe an association between FokI and BsmI VDR gene polymorphisms and vitamin D levels in NF1 patients, suggesting that their deficient or insufficient biochemical phenotypes are not associated with these genetic variants. The differences between the groups in genotypic and allelic frequencies for FokI and BsmI VDR gene polymorphisms were small and did not reach statistical significance. These polymorphisms are in partial linkage disequilibrium and the haplotype frequencies also did not differ in a significant way between the two groups (p = 0.613).