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Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION

Severe aplastic anemia (SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation (HCT). Haploidentical donor transplantation with post-transplantation cyclophosphamide (haplo-PTCy) is an option for patients lacking an HLA-matched donor. We analyzed 87 patients who underwent haplo-PTCy between 2010 and 2019. The median patient age was 14 years (range, 1 to 69 years), most were heavily transfused, and all received previous immunosuppression (25% without antithymocyte globulin). Almost two-thirds (63%) received standard fludarabine (Flu)/cyclophosphamide (Cy) 29/total body irradiation (TBI) 200 cGy conditioning, and the remaining patients received an augmented conditioning: Flu/Cy29/TBI 300-400 (16%), Flu/Cy50/TBI 200 (10%), or Flu/Cy50/TBI 400 (10%). All patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. Most grafts (93%) were bone marrow (BM). The median duration of follow-up was 2 years and 2 months. The median time to neutrophil recovery was 17 days. Primary graft failure occurred in 15% of the patients, and secondary or poor graft function occurred in 5%. The incidences of grade II-IV acute GVHD was 14%, and that of chronic GVHD was 9%. Two-year overall survival and event-free survival (EFS) were 79% and 70%, respectively. EFS was higher for patients who received augmented Flu/Cy/TBI (hazard ratio [HR], .28; P = .02), and those who received higher BM CD34 cell doses (3.2 × 10E6/kg) (HR, .29; P = .004). The presence of donor-specific antibodies before HSCT was associated with lower EFS (HR, 3.92; P = .01). Graft failure (HR, 7.20; P.0001) was associated with an elevated risk of death. Cytomegalovirus reactivation was frequent (62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimens and BM grafts with higher CD34 cell doses.

The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by the inadequate production of at least one of the hematopoietic lineages, leading to the development of both isolated cytopenia (anemia, neutropenia, or thrombocytopenia) or pancytopenia. Different biological mechanisms justify the pathophysiological changes found in the IBMFS, emphasizing the repair pathways in Fanconi anemia (FA), maintenance of telomeres in congenital dyskeratosis, and ribosome biogenesis in Shwachman Diamond syndrome (SSD) and Blackfan Diamond anemia. These disorders are generally associated with the presence of congenital malformations and an increased risk of cancer, mainly hematological, gynecological, and head and neck neoplasms. Although the diagnosis occurs typically in childhood, adult patients, mostly below 40 years of age with signs and symptoms suggestive of IBMFS, should be investigated. Currently, hematopoietic stem cell transplantation (HSCT) is the only curative option for hematological complications related to IBMFS. It is essential to highlight that these patients must be monitored throughout their lives to prevent or detect early treatable neoplasia.

Neurofibromatosis type 1 (NF1) is a chronic and progressive autosomal dominant genetic and sporadic disease characterized by cutaneous and neurological abnormalities. Plexiform neurofibroma (PN), a significant cause of clinical complications in NF-1, is a benign tumor of the peripheral nerve sheath that involves multiple nerve fascicles. Although there is an important number of patients who are affected by NF1 in Brazil, there is little data on the behavior of the disease in the national literature as well as in other low- and middle-income countries.We performed a retrospective analysis of 491 patients with NF1 followed at two reference centers in Brazil.Approximately 38% of patients had PNs, resulting in reduced life quality. The median patient age with PNs was 30 years (range: 6 to 83 years). Head and neck, and extremity were the main affected locations with 35.8 and 30.6%, respectively. PNs were classified as asymptomatic in 25.1% of patients, while 52.5% presented symptomatic and inoperable tumors. The most common manifestations related to PNs were disfigurement and orthopedic involvement. Twenty patients developed neoplasms and ten (50%) presented with malignant peripheral nerve sheath tumors (MPNST). The prevalence of MPNST in our study was 2.9%.Patients with NF1 experience clinically significant morbidity, especially when it is associated with PN. Though there are many patients affected by NF1 in Brazil and other low- and middle-income countries, there is little data available in the corresponding literature. Our results are comparable to the previous results reported from higher-income countries and international registries.

The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation. RESUMO O Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes foi elaborado com a participação de nutricionistas, médicos nutrólogos e médicos hematologistas pediátricos de 10 centros brasileiros que são referência em transplante de células-tronco hematopoiéticas. O objetivo foi salientar a importância do estado nutricional e da composição corporal durante o tratamento, bem como as principais características relacionadas à avaliação nutricional do paciente. As intenções, ao se estabelecer o consenso, foram aprimorar e padronizar a terapia nutricional durante o transplante de células-tronco hematopoiéticas. O consenso foi aprovado pela Sociedade Brasileira de Transplante de Médula Óssea.

HSCT is performed in Brazil since the 70’s, most of them in public centers. Transplant numbers are regularly reported by most centers to the Brazilian Transplant Registry/ Brazilian Solid Organ Association (ABTO/RBT), Latin American Bone Marrow Transplant Group/ Worldwide Network for Blood and Marrow Transplantation (LABMT/WBMT), but transplant outcomes are not available in our country. The objective of this work is to understand HSCT activity and outcomes of Brazilian children. Methods The Brazilian Society of Bone Marrow Transplant and Cellular Therapy (SBTMO) has developed the initiative to collaborate with the Center for International Blood and Marrow Transplant Research (CIBMTR) to receive back deidentified aggregate nationwide data reported by Brazilian transplant centers. This was approved by the national central IRB in 2019 (Conep CAAE: 65575317.5.1001.0071, principal investigator Dr. Nelson Hamerschlak) as a research project, including data from 2008 through 2027. This is the first report of the Brazilian Pediatric Hematopoietic Stem Cell Transplant activity prepared by the SBTMO Data Managers Working Group with the data reported to the CIBMTR and returned to the country as an enhanced Data Back to Center file. Results Between 2008 and 2019, 16 of the 19 institutions reporting to the CIBMTR also reported pediatric transplants. A total of 1,929 transplants were reported in children younger than 18 years of age and, different from the adult experience, most of them are allogeneic transplants. Within the past three years, the number of allogeneic transplants from unrelated and mismatched donors have increased and are now performed more often than transplants from matched sibling donors. Unrelated cord blood grafts were rarely used. Marrow was the preferred graft source for all allogeneic transplants. Acute leukemias and severe aplastic anemia were the most common indications for HSCT. Infections were the first cause of death within 100 days post HSCT. The 2-year overall survival after HSCT with HLA-identical sibling, unrelated donors and mismatched related donors for acute lymphoblastic leukemia was 56%, 60% and 37% (p = 0.2) and for acute myelogenous leukemia, 57%, 55% and 62% (p = 0.8), respectively. Pediatric myelodysplastic syndrome and chronic myelogenous leukemia had overall survival over 80%. Severe aplastic anemia was the most common non-malignant HSCT indication and the results with matched related and unrelated transplants are excellent, > 85% survival. In conclusion, this is the first report on transplant outcomes in Brazilian children. The collaboration with the CIBMTR may be a feasible way for Latin American countries to know their transplant outcomes using a mature registry structure with several tools already in place to enhance the collaboration. We would like to acknowledge Dr Nelson Hamerschlak, principal investigator of the National protocol, Dr. Marcelo Pasquini, for his help with the collaboration between CIBMTR and SBTMO, the Brazilian institutions reporting their data, the Data Manager Working Group and the Pediatric Working Group of the SBTMO and SOBOPE.

Carlos Romualdo Barbosa Gama,1 Manoel Antônio Gonçalves Pombo,1 Carlos Pereira Nunes,1 Gustavo Falcão Gama,1 Spyros GE Mezitis,2 Mendel Suchmacher Neto,3 Oscar Roberto Guimarães,1 Mauro Geller,1,4 Lisa Oliveira,4 Adenilson de Souza da Fonseca,1 Aline Sitnoveter,1 Gerson Goldwasser,3 Karin Soares Cunha,5 Luiz Guilherme Darrigo Junior6 1UNIFESO Medical School, Rio de Janeiro, Brazil; 2New York-Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA; 3Santa Casa de Misericórdia do Rio de Janeiro, Rio de Janeiro, Brazil; 4Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; 5Pathology Department, Faculdade de Medicina - Universidade Federal Fluminense (UFF), Niterói, Brazil; 6Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, BrazilCorrespondence: Mauro Geller Av. Ataulfo de Paiva, 135 sl. 1104, Rio de Janeiro, RJ 22440-901, BrazilTel +55 21 3875-6660Fax + 55 21 2259-3395Email maurogeller@gmail.comPurpose: Urinary antiseptics including methenamine and methylene blue are used in the symptomatic treatment of urinary tract infections (UTIs).Patients and Methods: This was a prospective, double-blind, randomized, double-dummy safety and efficacy study of 2 urinary antiseptic combinations in the symptomatic treatment of recurrent cystitis: methenamine 120mg + methylene blue 20mg (Group A) versus acriflavine 15mg + methenamine 250mg + methylene blue 20mg + Atropa belladonna L. 15mg (Group B). All subjects underwent pretreatment urine culture and antibiotic sensitivity tests prior to 3-day oral treatment with study drug, followed by 3 days of antibiotic therapy (based on urine culture) + study drug treatment. Efficacy was evaluated using the Urinary Tract Infection Symptoms Assessment Questionnaire (UTISA). The primary endpoint was the percentage of patients presenting improvement in cystitis manifestations on the UTISA domain “Urination Regularity” at Visit 2. The primary safety variable was the incidence of treatment-related adverse events.Results: A total of 144 subjects were randomized per group and 272 completed the study. Primary endpoint analysis demonstrates homogeneity between treatment groups, with 69.4% and 72.2% subjects, respectively, showing improvement in the score of the urinary regularity UTISA domain after 3 days of treatment (p= 0.87). At Visit 2, incidence of treatment-related adverse events was higher in Group B (Group A: n= 11, Group B: n= 31, p= 0.0057).Conclusion: Both treatments were effective in reducing UTI symptoms assessed by UTISA questionnaire after 3 days of treatment. The two regimens were comparable in incidence of adverse events, but the combination of methenamine + methylene blue resulted in fewer treatment-related adverse effects.Keywords: urinary tract infection; UTI, urinary antiseptics, UTISA, methenamine, methylene blue

Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.

Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system and, despite the standard therapy; the patients’ prognoses remain dismal. The miRNA expression profiles have been associated with patient prognosis, suggesting that they may be helpful for tumor diagnosis and classification as well as predictive of tumor response to treatment. We described the microRNA expression profile of 29 primary GBM samples (9 pediatric GBMs) and 11 non-neoplastic white matter samples as controls (WM) by microarray analysis and we performed functional in vitro assays on these 2 most differentially expressed miRNAs. Hierarchical clustering analysis showed 3 distinct miRNA profiles, two of them in the GBM samples and a group consisting only of cerebral white matter. When adult and pediatric GBMs were compared to WM, 37 human miRNAs were found to be differentially expressed, with miR-10b-5p being the most overexpressed and miR-630 the most underexpressed. The overexpression of miR-630 was associated with reduced cell proliferation and invasion in the U87 GBM cell line, whereas the inhibition of miR-10b-5p reduced cell proliferation and colony formation in the U251 GBM cell line, suggesting that these miRNAs may act as tumor-suppressive and oncogenic miRNAs, respectively. The present study highlights the distinct epigenetic profiling of adult and pediatric GBMs and underscores the biological importance of mir-10b-5p and miR-630 for the pathobiology of these lethal tumors.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH HEMOGLOBINOPATHIES

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA AND INHERITED BONE MARROW FAILURE SYNDROMES

Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs. In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data. Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway. In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1. A primeira parte desta diretriz abordou o diagnóstico diferencial das neurofibromatoses (NF): neurofibromatose do tipo 1 (NF1), neurofibromatose do tipo 2 (NF2) e schwannomatose (SCH). As NF compartilham algumas características, como a origem neural dos tumores e sinais cutâneos, e afetam cerca de 80 mil brasileiros. O aumento do conhecimento científico sobre as NF tem permitido melhor manejo clínico e redução da morbidade das complicações, resultando em melhor qualidade de vida para os pacientes com NF. A maioria dos médicos é capaz de realizar o diagnóstico das NF, mas a variedade de manifestações clínicas e a dificuldade de se prever o surgimento e a gravidade de complicações, torna o manejo da NF um desafio para o clínico e envolve diferentes especialistas para o tratamento adequado e aconselhamento genético, especialmente a NF2 e a SCH. O presente texto sugere algumas orientações para o acompanhamento dos portadores de NF, com ênfase na NF1.

Optic pathway gliomas represent 5% of pediatric brain tumors and are typically low-grade lesions. Because of their unpredictable clinical course, adequate treatment approaches have been controversial, involving surveillance, surgery, chemotherapy, and radiotherapy. In this study, we use volumetric imaging to compare evolution of optic chiasmatic-hypothalamic gliomas (OCHG) treated with and without chemotherapy, analyzing tumor volume variation during the overall period. A total of 45 brain MRI were retrospectively analyzed for 14 patients with OCHG. Volumetric assessment of the lesions was performed by a neuroradiologist, using software DISPLAY. OCHG patients were allocated into two groups: group 1 (n = 8) who underwent chemotherapy and group 2 (n = 6) who did not receive chemotherapy. Outcome analysis was performed comparing tumor volume evolution of these two groups. The results showed a reduction of 4.4% of the volume of the lesions for group 1 after the end of chemotherapy, with an increase of 5.3% in volume in the late follow-up examination. For group 2, we found a slight reduction (5%) of the overall volume of the lesions, both with no statistical significance (p > 0.05). From the limited series analyzed in this study, no significant differences were observed in relation to the volume change of lesions treated or not treated with chemotherapy. Larger prospective clinical trials are needed to better evaluate the effect of chemotherapy and radiological response of OCHG.

OBJETIVO: Realizar uma revisão da literatura sobre neurofibromatose tipo 1 (NF1) em crianças e adolescentes, enfatizando as manifestações clínicas. FONTES DE DADOS: Artigos publicados, indexados na base de dados Medline e publicados entre 1998 a 2007, buscados pelos seguintes termos: "neurofibromatosis type 1", "neurofibroma", "von Recklinghausen" e "optic pathway gliomas". SÍNTESE DOS DADOS: A NF1 é uma doença genética autossômica dominante, crônica e progressiva, com incidência de 1/2.000 a 1/7.800 nascidos vivos. Tem sido observada em diferentes partes do mundo, em todas as raças e nos dois sexos. Metade dos casos representa mutações novas. A taxa de mutação para o gene NF1 é de 1/10.000, a qual se deve ao fato do gene ser grande e possuir estrutura interna atípica, que predispõe a deleções e mutações. O diagnóstico presuntivo da NF1 é feito por critérios clínicos. As três principais manifestações - neurofibromas, manchas café-com-leite e nódulos de Lisch - ocorrem em mais de 90% dos pacientes até a puberdade. CONCLUSÕES: Os cuidados com os pacientes com NF1 devem antecipar as principais complicações e oferecer um tratamento precoce. No aconselhamento genético, é importante informar pais e familiares a respeito do panorama geral da doença e suas possíveis complicações, enfatizando que a maioria dos pacientes apresenta vida saudável e produtiva. OBJECTIVE: To review clinical and diagnostic features of neurofibromatosis type 1 (NF1) in children and adolescents. DATA SOURCES: Articles published from 1998 to 2007 and retrieved by the words "neurofibromatosis type 1"; "neurofibroma", "von Recklinghausen" and "optic pathway gliomas" in Medline database. DATA SYNTHESIS: NF1 is a chronic and progressive autosomal dominant disorder with an incidence of 1/2,000 to 1/7,800 live births. There is no racial, geographic or gender preference. Half of the cases represent new mutations, and the mutation rate for NF1 gene is 1/10.000. The high mutation rate of NF1 may reflect the fact that the gene is large and/or that it has an unusual internal structure, predisposing it to deletions and other mutations. The presuntive diagnosis of NF1 is made on clinical basis. The three main features - neurofibromas, café-au-lait spots and Lisch nodules - are present in more than 90% of all affected patients until puberty. CONCLUSIONS: The mainstay of care for patients with NF1 is anticipatory guidance and early detection and treatment of disease complications. Counseling of patients and their families should provide a realistic overview of possible clinical complications, while emphasizing that most individuals with NF1 have healthy and productive lives.

Fever, skin rash, headache, and thrombocytopenia are considered hallmarks of dengue infection. However, these symptoms are frequently observed in infectious and non-infectious complications of hematopoietic stem cell transplant recipients and oncohematological patients. Thus, laboratory confirmation of dengue is relevant for prompt intervention and proper management of dengue in endemic and non-endemic regions. Because no prospective study of dengue has been conducted in these populations, the actual morbidity and mortality of dengue is unknown. In the present series, we describe five cases of dengue in patients living in endemic areas, emphasizing the prolonged course of the disease and the occurrence of prolonged viremia.

Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management. Neurofibromatoses (NF) constituem um grupo de doenças genéticas com predisposição ao crescimento de múltiplos tumores: tipo 1 (NF1), tipo 2 (NF2) e schwannomatose (SCH). Estas doenças têm em comum a origem neural dos tumores e os sinais cutâneos. Afetam cerca de 80 mil brasileiros. O maior conhecimento científico sobre as NF tem permitido melhor manejo clínico, redução da morbidade das complicações e melhor qualidade de vida. Na maioria dos casos, os especialistas em neurologia, dermatologia, genética clínica, oncologia e medicina interna estão capacitados a realizar o diagnóstico diferencial e identificar suas principais complicações. Devido à sua variabilidade fenotípica, curso progressivo, multiplicidade de órgãos acometidos e evolução imprevisível, as NF frequentemente necessitam de especialistas em NF para o acompanhamento. A Parte 1 deste texto oferece orientações para o diagnóstico de cada tipo de NF e discute os diagnósticos diferenciais com outras doenças. A Parte 2 oferecerá orientações em relação ao manejo clínico das NF.

CONTEXT: Neurofibromatosis type 1 (NF-1) is the most prevalent autosomal dominant genetic disorder among humans. Moyamoya disease is a cerebral vasculopathy that is only rarely observed in association with NF-1, particularly in the pediatric age range. The present study reports an occurrence of this association in an infant. CASE REPORT: An eight-month-old female presented convulsive seizures with clonic movements. The patient suffered an ischemic stroke with hemiparesis. Magnetic resonance imaging revealed radiological findings compatible with moyamoya disease. The diagnosis of NF-1 was made at the age of 20 months. CONCLUSION: Despite the rarity of this association in childhood, children with focal neurological symptoms and a diagnosis of NF-1 deserve to be investigated for moyamoya syndrome.

Type 1 neurofibromatosis (NF-1) is a multisystem genetic disease with significant cutaneous manifestations such as cafe-au-lait spots, freckles and neurofibromas. The incidence of NF-1 is about 1 : 2 500 new births; it affects equally all races and both sexes. Estimates show that there are currently in Brazil about 80 000 cases; worldwide, there are about 1.5 million cases of NF-1. A diagnosis of NF-1, according to criteria established by the “National Institutes of Health” (NIH) in 1987 and updated in 1990, depend on a careful clinical examination of the patient, his or her parents and siblings, and a detailed family medical history; at times, laboratory exams are needed. The plexiform neurofibroma (PN), also named plexiform neuroma, pachydermatocele or neurofibromatous elephantiasis, has been classified as a benign tumor of peripheral nerve sheath involving multiple nerve fascicles. It is a highly vascularized, slow-growing and locally invasive non-metastatic tumor. PNs are one of the important complications of NF-1; it may occur in infancy and rarely after adolescence. Although frequent in patients with NF-1, PNs are not pathognomonic of NF-1. The most common site is the trunk (43%), followed by the head and neck (42%) and limbs (15%). PNs may give rise to malignant peripheral nerve sheath tumors (MPNST) that in the past were referred to as neurofibrosarcomas or malignant schwannomas; these are the main cause of death and the most common malignancies in this group of patients. NF-2 is characterized by bilateral vestibular schwannomas, rarely with cutaneous manifestations. Typical lesions are schwannomas that may be present in the acoustic nerve or in other cranial nerves (nerve V, and sometimes nerve X) and meningiomas. CASE STUDY

Introdução: A neurofibromatose tipo 1 (NF1) é uma doença genética, autossômica dominante, que se caracteriza principalmente por alterações neurocutâneas, mas com acometimento multissistêmico. Embora as manifestações clínicas da NF1 estejam bem documentadas, os aspectos nutricionais começaram a ser estudados recentemente. Estudo anterior realizado com adultos com NF1 levantou hipóteses de alterações do gasto energético total (GET) e uma possível relação dessa variável com características do consumo alimentar e composição corporal. Objetivo: Estudar o gasto energético de repouso (GER) e o GET em indivíduos com NF1, e suas relações com a composição corporal, força muscular e o consumo alimentar. Casuística e métodos: Uma amostra de 26 indivíduos com NF1 (14 homens e 12 mulheres) com idades entre 18 e 45 anos foram comparados com 26 voluntários controles pareados por idade, sexo, índice de massa corporal (IMC) e nível de atividade física. Foram aferidos: peso, estatura e perímetros de braço e cintura. A composição corporal foi avaliada por meio da absorciometria de raios X de dupla energia (DXA). A densitometria do corpo inteiro, coluna e fêmur também forneceu a massa óssea e densidade mineral óssea (DMO) nessas regiões. O GER e o GET foram avaliados por meio da calorimetria indireta. A força muscular foi avaliada pelo teste de preensão manual usando um dinamômetro, e calculada como força muscular máxima (Fmax) e força por unidade de área (Farea). Avaliou-se a ingestão alimentar por meio de um recordatório 24 horas e dois registros alimentares, totalizando três dias não consecutivos. Foram avaliados os seguintes constituintes da dieta: energia, proteína, lipídeos, colesterol, carboidrato, fibras, cálcio, magnésio, manganês, fósforo, ferro, sódio, potássio, cobre, zinco, tiamina, riboflavina, piridoxina, niacina, vitamina C, vitamina D, vitamina A e ácidos graxos saturados, monoinsaturados e poli-insaturados, ácido linolênico e ácido linoleico. O percentual de gordura também foi avaliado por bioimpedância elétrica e por dobras cutâneas, e os resultados comparados com a avaliação por DXA (padrão-ouro). Equações preditivas de GER e GET foram também comparadas com a calorimetria indireta, também considerada o padrão-ouro. Resultados: A idade média foi de 34,31 ± 6,05 e 32,92 ± 6,14 anos de idade nos grupos NF1 e controle, respectivamente (P=0,316). A estatura foi menor nos indivíduos com NF1 (P=0,003). Não houve diferenças no peso, IMC, perímetro da cintura, massa gorda, percentual de gordura e índice de gordura corporal. A massa magra apendicular ajustada pelo IMC foi menor no grupo NF1 (P=0,048). A massa óssea também foi menor no grupo NF1 (P=0,046) assim como a DMO do corpo total e da coluna (P=0,036 e P=0,015, respectivamente). Indivíduos com NF1 também apresentaram redução da Fmax (P=0,035) e da Farea (P=0,028). O GER ajustado por peso (P=0,046), massa magra (P=0,013) e massa magra apendicular (P=0,004) foi maior, enquanto o quociente respiratório (QR) (P=0,008) foi menor na NF1. Os indivíduos com a doença oxidaram mais lipídios e menos carboidratos que o grupo controle (P=0,011 e P=0,029, respectivamente). Não houve diferenças no consumo alimentar de energia e macronutrientes. Dentre os micronutrientes, os indivíduos com NF1 consumiram menos cálcio, ferro e vitamina A, assim como consumiram mais sódio, ácidos graxos poli-insaturados e ácido linoleico. Na estratificação por sexo, as alterações observadas em gasto energético, composição corporal e força muscular aconteceram somente nas mulheres com NF1 comparadas ao grupo controle. Não houve diferença nesses aspectos entre os homens. Os valores de GER e GET se correlacionaram negativamente com o percentual de gordura, e positivamente com as variáveis antropométricas (peso, estatura, IMC e perímetro da cintura, superfície corporal), com as variáveis de composição corporal (massa magra, massa apendicular e massa magra apendicular ajustada por IMC), com as variáveis ósseas (massa óssea e DMO do corpo total), com as variáveis de força (Fmax e Farea). Não houve correlação de GER e GET com massa gorda, índice de gordura corporal e com variáveis do consumo alimentar (energia e macronutrientes). A análise de regressão demonstrou que a massa magra foi a variável que mais influenciou o GER na NF1. Na comparação de métodos, todas as equações preditivas usando dobras cutâneas subestimaram o percentual de gordura e apenas a equação de Sun e colaboradores usando a bioimpedância elétrica se aproximou mais do percentual de gordura avaliado na DXA. Todas as oito equações de GER subestimaram essa variável quando comparados com a calorimetria indireta, e somente a equação de 35 kcal/kg/dia aproximou-se do GET desse estudo. Conclusões: Os indivíduos com NF1 apresentam GER ajustado por peso ou massa magra ou massa magra apendicular aumentado comparado ao grupo controle. Os voluntários com NF1 nessa pesquisa apresentam menor massa magra apendicular ajustada por IMC e menor força muscular máxima, o que pode indicar uma sarcopenia precoce nessa população. As mulheres com NF1 respondem diferente a essas alterações. Os resultados dessa pesquisa permitem concluir que os indivíduos com NF1 apresentam alterações no metabolismo energético. Os mecanismos dessas alterações no GER e na utilização de substratos energéticos, como lipídios e carboidratos, precisam ser investigados em estudos futuros. Introduction: Neurofibromatosis type 1 (NF1) is a genetic disease, autosomal dominant, which is mainly characterized by neurocutaneous changes, but may also have multisystemic involvement. Although the clinical manifestations of NF1 are well documented, nutritional aspects have begun to be studied recently. A previous study with NF1 adults raised hypothesis of changes in total energy expenditure (TEE) and a possible relationship with food consumption and body composition. Objective: To study the resting energy expenditure (REE) and TEE in individuals with NF1 and their relationships with body composition, muscle strength and dietary intake. Methods: A sample of 26 individuals with NF1 (14 men and 12 women) aged 18-45 years old were compared to 26 control volunteers matched for age, sex, body mass index (BMI), and physical activity level. Weight, height and circumferences (arm and waist) were measured. Body composition was assessed by dual energy X-ray absorptiometry (DXA). The densitometry of the whole body, spine and femur also provided bone mass and bone mineral density (BMD) in these regions. REE and TEE were evaluated by indirect calorimetry. The muscle strength was evaluated by the handgrip test using a dynamometer, and calculated as maximum muscle strength (Fmax) and per unit area (Farea). Food intake were evaluated through one day 24hrecall and two days food records (three nonconsecutive days).The following diet constituents were investigated: energy, protein, lipid, cholesterol, carbohydrates, fiber, calcium, magnesium, manganese, phosphorus, iron, sodium, potassium, copper, zinc, thiamine, riboflavin, pyridoxine, niacin, vitamin C, vitamin D, vitamin A, and saturated, monounsaturated and polyunsaturated fatty acids, linoleic acid and linolenic acid. The body fat percentage were also evaluated by bioelectrical impedance and skinfolds thickness, and the results were compared to DXA (gold standard method). Predictive equations of REE and TEE were compared to indirect calorimetry, also considered the gold standard method for this evaluation. Results: The mean age was 34.31 ± 6.05 and 32.92 ± 6.14 years old in the NF1 and control groups, respectively (P=0.316). Stature was lower in individuals with NF1 (P=0.003). There were no differences in weight, BMI, waist circumference, fat mass, body fat percentage and body fat index. Appendicular lean mass adjusted by BMI was lower in the NF1 group (P=0.048). Bone mass was also lower in the NF1 group (P=0.046) as well as total body and spine BMD (P=0.036 and P=0.015, respectively). Individuals with NF1 also presented reduction of Fmax (P=0.035) and Farea (P=0.028). The adjusted REE by weight (P=0.046), lean mass (P=0.013) and appendicular lean mass (P=0.004) was higher, while the respiratory quotient (QR) (P=0.008) was lower in NF1. Individuals with NF1 oxidized more lipids and less carbohydrates than control group (P=0.011 and P=0.029, respectively). There were no differences in energy and macronutrients intake. Among micronutrients, individuals with NF1 consumed less calcium, iron and vitamin A, as well as consumed more sodium, polyunsaturated fatty acids and linoleic acid. In gender stratification, the observed changes in energy expenditure, body composition and muscle strength occurred only in women with NF1 compared to the control group. There was no difference in these aspects among men. The values of REE and TEE correlated negatively with body fat percentage, and positively with anthropometric variables (weight, height, BMI, waist circumference and body surface), with body composition variables (lean mass, appendicular lean mass), with the bone variables (bone mass and total body BMD), with the strength variables (Fmax and Farea). There was no correlation of REE and TEE with fat mass, body fat index and food intake variables (energy and macronutrients). Regression analysis showed that lean mass was the variable that most influenced REE in NF1. In the methods comparison, all predictive equations using skinfolds underestimated the percentage of fat in NF1 individuals, and only the equation of Sun and collaborators using the bioelectrical impedance approached more than the body fat percentage evaluated by DXA. All eight equations of REE underestimated this value compared to indirect calorimetry, and only the equation using 35kcal/kg/day approached the TEE of this study. Conclusions: Individuals with NF1 have an increased REE adjusted by weight or lean mass or appendicular lean mass compared to the control group. The NF1 group in this study have lower lean mass adjusted for BMI and lower maximal muscle strength, which may indicate early sarcopenia in this population. Women with NF1 respond differently to these changes. The results of this study allow us to conclude that individuals with NF1 present alterations in energy metabolism. The mechanisms of these changes in REE and the use of energy substrates, such as lipids and carbohydrates, need to be investigated in further studies.