Programa Científico e Anais do 5th SIDEP. by Faculdade de Medicina

5th International Symposium on Primary Immunodeficiencies Belo Horizonte Brasil

ProGrAMA cientĂfico

ANAIS

5 International Symposium on Primary Immunodeficiencies th

Expediente

Faculdade de Medicina da UFMG Assessoria de Comunicação Social Coordenação

Gilberto Boaventura Projeto gráfico e Diagramação

Juliana Guimarães Atendimento Publicitário

Desirée Suzuki Fotografia

Miguel Aun

SuMÁrIo APRESENTAÇÃO.......................................................................................................................4 PALAVRA DO PRESIDENTE......................................................................................................6 Mapa da Faculdade de Medicina...............................................................................................8 Programação..............................................................................................................................10 Anais..........................................................................................................................................15 ÍNDICE DE AUTORES..............................................................................................................29

APrESENtAÇÃo Depois do sucesso das quatro edições anteriores em São Paulo (2005, 2009 e 2011) e em Recife (2013), a Faculdade de Medicina da UFMG realizará, de 20 a 23 de maio de 2015, em parceria com o Laboratório de Investigação Médica em Dermatologia e Imunodeficiências (LIM-56)/Departamento de Dermatologia e do Departamento de Patologia da Faculdade de Medicina da Universidade de São Paulo, o 5 International Symposium on Primary Immunodeficiencies – SIDEP. Esse evento já integra o calendário internacional de atividades sobre imunodeficiências primárias, reunindo imunologistas de grande relevância no âmbito nacional e internacional, com a contribuição de renomados imunologistas clínicos e pesquisadores da Europa e dos Estados Unidos. Em 2015, o SIDEP abordará tanto os aspectos práticos do diagnóstico e tratamento das imunodeficiências primárias, como os principais avanços de pesquisa ocorridos neste campo. Na programação estão conferências, sessões de revisões, apresentações de trabalhos selecionados e de trabalhos inscritos sob a forma de apresentação oral e pôster. Suas primeiras edições contaram com a presença de participantes de diversas especialidades médicas (imunologia, pediatria, alergologia, pneumologia, infectologia, gastroenterologia, otorrinolaringologia, dermatologia e clínica médica) e de outros profissionais de saúde (enfermeiros, biólogos, biomédicos).

cobid O SIDEP constitui também o evento científico oficial do Consórcio Brasileiro de Centros de Referência e de Treinamento em Imunodeficiências Primárias/ CoBID (www.cobid.com.br). Criado em 2012 com o apoio do Ministério da Saúde, o CoBID reúne centros localizados em 15 estados e no Distrito Federal, prestando assistência a mais de 5.000 pacientes portadores de Imunodeficiências Primárias. No 5th SIDEP haverá sessão específica do CoBID, com apresentação das casuísticas dos centros participantes, discussão de projetos colaborativos e ações educacionais.

Pré-Simpósio Curso teórico-prático sobre técnicas e aplicação do diagnóstico laboratorial das imunodeficiências primárias Curso téorico-prático sobre uso de imunoglobulinas.

PALAVrA do PrESIdENtE caros colegas, É com grande prazer que os recebemos na Faculdade de Medicina da UFMG, em Belo Horizonte, para o 5º Simpósio Internacional de Imunodeficiências Primárias (SIDEP). Realizado a cada dois anos, o SIDEP chega à sua 5ª edição consolidado no calendário internacional de eventos sobre imunodeficiências primárias, reunindo imunologistas de grande relevância no âmbito nacional e internacional, com a contribuição de renomados imunologistas clínicos e pesquisadores da Europa e dos Estados Unidos. O simpósio aborda tanto os aspectos práticos do diagnóstico e tratamento das imunodeficiências primárias como os principais avanços de pesquisa ocorridos neste campo. São conferências com palestrantes nacionais e estrangeiros, que falam dos últimos avanços em pesquisas e sessões de revisões sobre imunodeficiências primárias e os respectivos manejos. Os temas livres inscritos serão apresentados durante o evento, tanto sob a forma de apresentação oral, quanto pôster, discutidos com a comissão examinadora composta pelos principais imunologistas brasileiros e internacionais, permitindo diálogo científico e interação de alto nível. O SIDEP constitui também o evento científico oficial do Consórcio Brasileiro de Centros de Referência e de Treinamento em Imunodeficiências Primárias (CoBID). Criado em 2012 com o apoio do Ministério da Saúde, o CoBID reúne centros localizados em 15 estados e no Distrito Federal, prestando assistência a mais de cinco mil pacientes portadores de Imunodeficiências

Primárias. No 5º SIDEP haverá sessão específica do CoBID, voltada para a apresentação das casuísticas dos centros participantes, discussão de projetos colaborativos e ações educacionais. Cordialmente,

Jorge Andrade Pinto Presidente do 5º SIDEP

Professor Titular de Pediatria da Faculdade de Medicina-UFMG, Coordenador do Serviço de Imunologia Clínica do Hospital das Clínicas-UFMG

Alberto José da Silva Duarte Presidente de Honra do 5º SIDEP Professor Titular de Patologia da Faculdade de Medicina da USP e Chefe do Laboratório Central do HC FMUSP

Mapa da Faculdade de Medicina 5

3 4

ENTRADA

4 Salão Nobre (1) Sala Amílcar Vianna (2)

Exposição de Pôsteres (3) Sanitários (4) Rampa de acesso aos expositores e coffe break (5)

Programação Curso Pré-Simpósio I 20 de maio de 2015 | Sala Amílcar Vianna (62) Técnicas laboratoriais avançadas para estudo das Imunodeficiências Primárias 8h30 9h15 10h 10h30 11h15 12h 14h 14h45 15h15 15h45 às 17h15 15h45

As imunodeficiências primárias: cenário nacional Prof. Jorge Pinto – UFMG

Avanços no diagnóstico laboratorial das imunodeficiências primárias Prof. João Bosco de Oliveira Filho – IMIP

Intervalo Imunodeficiências humorais Profª. Maria Marluce Vilela – UNICAMP

Imunodeficiências combinadas Prof. Dewton Moraes Vasconcelos – FMUSP

Intervalo para almoço Defeitos da imunidade inata Prof. Pérsio Rocho Jr. – FMUSP-RP

Transplante de medula óssea em PIDs Drª. Juliana Folloni – USP/ Hospital Albert Einstein, SP

Intervalo Princípios práticos de citometria de fluxo para o diagnóstico de IDPs (grupo selecionado de até 15 pessoas) Profª. Silvana Elói-Santos e Dra. Maria Luiza Silva - UFMG

Caso clínico 1 -

Dra. Thalita Dias - UFMG

16h15

Caso clínico 2 -

Dr. Gustavo Fusaro - UFMG

16h45

Caso clínico 3 -

Drª Juliana Nunes - UFMG

17h15

Roteiro para avaliação laboratorial do paciente com suspeita de IDP Drª. Luciana Cunha - UFMG

Curso Pré-Simpósio II 20 de maio de 2015 | Ambulatórios (CTR-DIP) Curso teórico-prático sobre uso de imunoglobulinas 8h30

Composição, Origem, Obtenção de Imunoglobulinas Humanas e Importância do seu Uso nas Imunodeficiências Primárias, Secundárias e Doenças Autoimunes Profª. Myrthes A.M.Toledo Barros – FMUSP

9h15

Cuidados na Administração de Gamaglobulinas – o que deve ser controlado antes, durante e após a infusão; aplicação de medicação pré-infusão Enfermeiras Maria do Carmo Tavares e Annelisa Lage – PBH/UFMG

10h 10h30

Intervalo Apresentação das diferentes gamaglobulinas para uso endovenoso e subcutâneo (composição, diluição, presença de açúcares, custos, doses usuais, etc) Farmacêuticas Helga Namie Murakami (FMUSP) e Betânia Ferreira (CTR-DIP/PBH)

11h15 12h 14h 14h45 15h30 16h15 18h às 19h

Aplicação de Gama Subcutânea – cuidados e controles

Prof. José Marcos Cunha -- UFRJ

Intervalo para almoço Visita ao Hospital dia do CTR-DIP/PBH-UFMG Enfermeiras Maria do Carmo Tavares e Annelisa Lage – PBH/UFMG

Estação Prática 1 – Reações adversas e Anafilaxia – reconhecer e tratar Drª. Juliana Nunes e Drª. Fernanda Minafra – PBH/UFMG

Estação Prática 2 -- Aplicação de Gama Subcutânea Enfermeiras Maria do Carmo Tavares e Annelisa Lage – PBH/UFMG

Avaliação do curso - com café de encerramento

Assembléia Geral do CoBID 13

Simpósio 21, 22 e 23 de maio de 2015 | Salão Nobre 21 de maio 8h30 às 8h40 8h40 às 9h20

Opening remarks Jorge Pinto (UFMG), Alberto Duarte (USP), Tarcizo Nunes (UFMG)

Opening lecture: Novel innate immunity defects Steven Holland (National Institutes of Health - NIH - USA) Chairperson: Dirceu Greco (UFMG)

Oral abstracts (2 abstracts 10’/each) Abstract 002: Association of a heterozygous STAT4 mutation with susceptibility to Pacaroccidioidomycosis

9h20 às 9h40

Marques, L.F.S.; Marques, C.O.; Khan, T.A.; Cavalcanti, R.S.; Junior, E.B.; Feriotti, C.; Costa, T.; Bustamante, J.; Casanova, J.L.; Mendes, R.P.; Calich V.L.G.; Torgerson, T.; Ochs, H.D.; Neto, C.A. (Instituto de Ciências Biomédicas, Laboratório Imunologia Humana)

Abstract 013: Histopathological aspects of acute-form paracoccidioidomycosis in IL-12BR1 deficient patients

Vasconcelos, D.M.; Campeas, A.E.; Ferrão, M.S.; Brasil, R.A.; Pagliari, C.; Sotto, M.N.; Duarte, M.I.S. (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo) Moderator: Dirceu Greco (UFMG)

9h40 às 10h20 10h20 às 10h40 10h40 às 11h20 11h20 às 12h 12h10 às 13h15 13h15 às 14h 14h às 14h40

Educational session: The use of flow cytometry to diagnose and understand primary immunodeficiencies Thomas Fleisher (National Institutes of Health - NIH - USA) Chairperson: Silvana Elói-Santos (UFMG)

Coffee break

Lecture: Wiskott Aldrich Syndrome and X-linked thrombocytopenia: clinical presentation, molecular characteristics, therapeutic options Hans Ochs (Seattle Children´s Hospital, USA) Chairperson: Persio Rocho Jr (USP-RP)

Educational session: Use of Next Generation Sequencing to screen for PIDD

Sergio Rosenzweig (National Institutes of Health - NIH - USA) Chairperson: João Bosco Oliveira (IMIP)

Satellite Symposium (Baxter): Subcutaneous immunoglobulin therapy for PIDD John Sleasman (Duke University, USA) Chairperson: Jorge Pinto (UFMG)

Guided poster session Educational session: Hemophagocytic Lymphohistiocytosis and Other Hemophagocytic Disorders Elie Haddad (University of Montreal - UM - Canada) Chairperson: Alberto Duarte (USP)

Oral abstracts (2 abstracts 10’/each) 14h40 às 15h

Abstract 010: Phenotypical features and ability to induce lymphocyte proliferation of monocyte derived dendritic cell in Chronic Mucocutaneous Candidiasis

Rigato,P.O.; Dias, A.S.; Oshiro, T.; Vasconcelos, D.M.; Duarte, A.J.S. (Laboratory of Dermatology and Immunodeficiencies (LIM56), Faculdade de Medicina, Universidade de São Paulo & Center of Immunology, Instituto Adolfo Lutz, Brazil)

Abstract 029: Assessment chemotaxis and p38 MAPK signaling pathway activated by TLR2 and TLR4 in neutrophils of patients with common variable immunodeficiency Pinto, P.C.G.; Andrade, M.V.M.; Batista, S.A.; Nunes, J.B.S.; Vargas, F.R.; Pinto, J.A. (UFMG) Moderator: Alberto Duarte (USP)

15h às 15h40 15h40 às 16h 16h às 16h40

Lecture: Chromosome 22q11.2 Deletion Syndrome: DiGeorge Syndrome/Velocardiofacial Syndrome Kathleen Sullivan (Children´s Hospital of Philadelphia - CHOP - USA) Chairperson: -

Coffee break

Mistery case Dewton Vasconcelos (FM-USP, Brazil) and Elie Haddad (UM, Canada)

22 de maio

8h30 às 9h10

Lecture: Monogenic disorders associated with immunodysregulation Thomas Fleisher (National Institutes of Health - NIH - USA) Chairperson: Dewton Vasconcelos (USP)

Oral abstracts (2 abstracts 10’/each) 9h10 às 9h30

Abstract 030: Common Variable Immunodeficiency: a phenotypic approach at a single-center cohort Nunes, J.B.S; Cunha L.A.O.; Greco D.B; Pinto, J.A. (Division of Immunology, Hospital das Clínicas, Federal University)

Abstract 006: Identification by exome sequencing of a novel homozygous variant in RLTPR in a family with EBV+ smoothmuscle-tumours Linhares, N.D.; Hauck, F.; Schober, T.; Bahia, M.; Klein, C.; Pena, S.D.J. (Universidade Federal de Minas Gerais) Moderator: Dewton Vasconcelos (USP)

9h30 às 10h10 10h10 às 10h30 10h30 às 11h10 11h10 às 11h50

Lecture: Newborn Screening for SCID and other PIDD John Sleasman (Duke University - USA) Chairperson: Jorge Pinto (UFMG)

Coffee break

Lecture: Hematopoietic stem cell transplantation (HSCT) in PIDD Elie Haddad (University of Montreal - Canada) Chairperson: Juliana Folloni (USP)

Educational session: ALPS and ALPS-related disorders

João Bosco Oliveira (IMIP, Brazil) Chairperson: Alberto Duarte (USP)

11h50 às 13h15 13h15 às 14h 14h às 14h40

Satellite Symposium (Novartis): Auto-inflammatory syndromes Maria Vitória Quintero (Belo Horizonte - Brazil); João Bosco Oliveira (IMIP - Brazil) Moderator: Jorge Pinto (UFMG)

Guided poster session Lecture: Infectious diseases management in PIDD Steven Holland (National Institutes of Health - NIH - USA) Chairperson: Myrthes Toledo Barros (USP)

Educational session: X-LP&EBV infection

14h40 às 15h10

Hirokazu Kanegane (Tokyo University - Japan)

15h10 às 15h30

Coffee break

15h30 às 16h10 16h10 às 17h

Chairperson: Maria Marluce Vilela (UNICAMP)

Lecture: IFN-G/IL-12 axis defects Sergio Rosenzweig (National Institutes of Health - NIH - USA) Chairperson: Luciana Cunha (UFMG)

Panel Discussion: Pre &Post HSCT management Kate Sullivan (CHOP, USA); Elie Haddad (UM - Canada) and Juliana Folloni (USP/ Hospital Albert Einstein - SP) Moderator: José Marcos Cunha (UFRJ)

23 de maio

8h30 às 9h10

Lecture: Update on CVID Kathleen Sullivan (Children´s Hospital of Philadelphia - CHOP - USA) Chairperson: Maria Marluce Vilela (UNICAMP)

Oral abstracts (2 abstracts 10’/each) 9h10 às 9h30

Abstract 005: Molecular characterization and clinical aspects of Bruton’s Tirosine Kinase deficient patients in a single center in Brazil Cunha, L.A.O.; Silva, M.L.; Oliveira, J.B.; Pinto, J.A. (Universidade Federal de Minas Gerais; IMIP)

Abstract 027: BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients Teocchi, M.A.; Ramalho, V.D.; Abramczuk, B.M. ; Vilela, M.M.S. (UNICAMP) Moderator: Maria Marluce Vilela (UNICAMP)

9h30 às 10h30 10h40 16

Panel discussion: PID Consortium Initiatives Jorge Pinto (UFMG - Brazil); Kate Sullivan (CHOP - USA) and Elie Haddad (UM - Canada)

Closing session Jorge Pinto (UFMG - Brazil); Alberto Duarte (USP)

ANAIS

001

Neutrophils from CD40L-Deficient Patients Present Defective Fungicidal Activity that Can be Improved by Recombinant Human IFN-y Marques, C.O.; Schimke L.F.; Khan T.A.; Iqbal A.; Feriotti C.; Costa T.Aa.; Weber C.W.; Ferreira J.F.; Di Gesu R.S.We.; Carvalho, C.B.T.; Calich V.L.G.; Barbuto J.A.Ma.; Torgerson T.R.; Ochs H.D.; Neto, C.A. Sao Paulo University

002

Association of a heterozygous STAT4 mutation with susceptibility to Pacaroccidioidomycosis Marques, L.F.S.; Marques, C.O.; Khan, T.A.; Cavalcanti, R.S.; Junior, E.B.; Feriotti, C.; Costa, T.; Bustamante, J.; Casanova, J.L.; Mendes, R.P.; Calich V.L.G.; Torgerson, T.; Ochs, H.D.; Neto, C.A. Instituto de Ciências Biomédicas, Laboratório Imunologia Humana

003

Bone Marrow Transplantation in a Wiskott-Aldrich patient Cruz, L.P.B.; Cunha, L.A.O.; Nunes, J.B.; Vieira, A.K.; Santos, F.G.M.S.; Pinto, J.A Universidade Federal de Minas Gerais

Introduction: The CD40L-CD40 interaction plays a central role in the interaction between T and B, and T and dendritc cells. However, multiple other functions of the CD40L-CD40 dyad, including regulation of myelopoiesis by T-cell and the presence of platelet-derived soluble CD40L (sCD40L) in serum have been revealed. In accordance, patients with CD40L deficiency may have intermittent neutropenia and are susceptible to a wide range of opportunistic infections even when neutrophil counts are normal suggesting defective neutrophil function and macrophage/dendritic cell defects. Objective: To determine whether neutrophils from CD40L-deficient patients exhibit defective function. Material and Methods: Killing of Paracoccidioides brasiliensis by neutrophils from CD40L-deficient patients and controls was assessed as well as their ability to phagocytose and trigger the respiratory burst. In addition, neutrophils were evaluated for the expression of NADPH oxidase components (gp91-, p22-, p40-, p47-, and p67-phox), TLR receptors expression (TLR1, 2, 4, and 6), maturation markers expression (CD15, CD11b, CD11c, CD18, and CD16), and for their ability to activate TLR pathways by measuring CD62L shedding. Results: Neutrophils from patients with CD40L deficiency showed defective fungicidal activity. While patients´ neutrophils phagocytosed normally, they demonstrated significant reduction in the oxidative burst in response to PMA and P. brasiliensis. Expression of NADPH components and maturation markers revealed reduced levels of p40phox and CD16, respectively. In vitro incubation with sCD40L did not improve the patients´ defective fungicidal activity, while recombinant human IFN-γ significantly improved this function. Conclusions: Absence of CD40L-CD40 interaction impairs neutrophil function which may contribute to the susceptibility to opportunistic infections in CD40L-deficient patients. The restoration of fungicidal activity by exogenous IFN-γ may indicate a potential new clinical use of this cytokine for the control or prevention of opportunistic infections in patients with CD40L deficiency.

Introduction: Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin America caused by the fungus P. brasiliensis and manifests with granulomatous lesions in lungs, lymphnodes, skin, bones and other organs. Only less than 1% of the individuals infected with P. brasiliensis develop the disease. This suggest a genetic predisposition leading to susceptibility to PCM in some individuals. However, to date PCM has been associated only in two patients with well-defined primary immunodeficiency (PID). Objectives: To investigate a Brazilian female patient (index patient) and her father who developed acute PCM disease in their 20s in order to find an underlying genetic defect leading to susceptibility to PCM. Methods: Whole exome sequencing of the index patient was performed in order to select candidate genes for susceptibility to PCM. Candidate genes were confirmed by Sanger Sequencing in the patient and her parents and functional studies performed by flow cytometry to confirm the impact of the variation on protein function. Results: Whole-exome sequencing identified the heterozygous mutation p. Glu651Val in the signal transducer and activator of transcription 4 (STAT4) gene. This mutation affects a conserved amino acid located in the Src Holology 2 (SH2) domain near residues critical for binding to the phosphotyrosine residue on the receptor. Bioinformatic computational analysis by Mutation Taster predicted that this mutation is disease causing. The mutation was confirmed by sanger sequencing and was not found to be a single-nucleotide polymorphism (SNP) in dbSNP. The father of the patient also carries the variation in STAT4. Functional analysis showed reduced phosphorylation of STAT4 in patient’s and father’s lymphocytes as well as reduced IFN-γ production in response to IL12 when compared to healthy controls. Conclusions: Our data suggest that STAT4 deficiency is a new primary immunodeficiency disease leading to susceptibility to Paracoccidioidomycosis.

Introduction: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by eczema, thrombocytopenia and T and B cell immunodeficiency. The patients have an increased susceptibility to pyogenic and opportunistic infections secondary to a poor antibody response. A mutation in WAS gene abolish the production of WAS P protein causing the symptoms. Although the prognosis of WAS has improved considerably in the last years after an aggressive anti-infective therapy, the cure is only possible through bone marrow transplantation (BMT). Case Report: This paper reports the clinical diagnosis, molecular diagnostics and the outcome of BMT performed in a 24-month-old male child with Wiskott-Aldrich. The patient was referred to the Immunology Division of Clinical Hospital of the Federal University of Minas Gerais at the age 12-month after a sepsis event in 2010 requiring ICU admission and invasive respiratory support given the gravity of the situation. The WAS diagnosis was made in our Center in April 2011. Laboratory Data: The molecular diagnosis was possible after sending the patient’s blood sample to Dr. Ochs and Dr. Troy from Seattle Immunology Diagnostic Laboratory. A nonsense mutation (c.100C>T) was identified in the WAS gene. This results in a premature termination codon at position 34 (p.R34X) which is expected to cause the absence of WAS p expression. After the diagnosis, human venous immunoglobulin every 21 days and anti-infective agents such fluconazole and Sulfamethoxazole-trimethoprim were prescribed. Treatment: At the age of 24-months-old, the child has been treated by BMT from his HLA-matched, 9-years-old sister. The recipient was prepared with a course of bussulfan (16mg/Kg) and fludarabin (160mg/m2) followed by methotrexate to prevent graft-versus-host disease (GVHD). The donor engraftment, an absolute neutrophil count of 500/microL, and untransfused platelet count of >20000/microL were observed at day 21 after transplantation. Two and a half years after the transplantation the patient has shown no evidence of GVHD and has a complete immune reconstitution with immunoglobulin recovery. Conclusion: This case illustrates the benefits of BMT in a patient with WAS. Although this is the first case of BMT in WAS in our Center, the excellent outcome will make the hematologists and immunologists more confident and less reluctant to perform transplant in WAS patients and in other immunodeficiency.

Introduction:Revesz syndrome (RS) is a rare severe phenotypic variant of dyskeratosis congenita and its effects are similar to that of Hoyeraal-Hreidarsson. This genetic disease thought to be caused by short telomeres and the patients have presented with heterozygous mutations in TINF2 gene which is located on chromosome 14q12. Clinically this syndrome is characterized by growth retardation of prenatal onset, cerebellar hypoplasia with ataxia, cerebral calcifications, microcephaly, significant developmental delay, bilateral exudative retinopathy, fine sparse hair, bone marrow failure and immunodeficiency. Case Report: TA 13-month-old male child with the clinical symptoms compatible with Revesz syndrome was referred to the Immunology Division of Clinical Hospital of the Federal University of Minas Gerais after numerous episodes of bacterial infections, failure to thrive, delayed psychomotor development and thrombocytopenia. He was born at 36 weeks of gestation with intrauterine growth retardation and had several events of pneumonia, otitis, sinusitis and candidiasis. Clinically the child was extremely underweight for his age and showed an important psychomotor delayed, paleness of the skin, petechias in the shoulders, microcephaly, sparce scalp hair, tongue leukoplakia and candidiasis. Retinal detachment and exudative retinopathy were observed. Laboratory Data: TInvestigations demonstrated anaemia (Hb 10.7g/dL), thrombocytopenia (platelets 12.000/L), average value of immunoglobulin, normal range of T cells, very low B and NK cells and shortened telomere lengths. The MRI of the brain showed microcalcifications and marked hypoplasia of cerebellar vermis and hemispheres. The child progressed with bone marrow failure requiring platelets and blood transfusion besides decreased levels of immunoglobulin. Treatment: After the clinical diagnosis human venous immunoglobulin every 21 days and antibiotics were prescribed. The patient underwent a bone marrow transplantation with a match sibling donor but died three months later secondary to a cytomegalovirus pneumonia. Conclusion: Revesz syndrome and Hoyeraal Hreidarsson previously thought to be distinct disorders are now recognized to be part of the phenotypic spectrum of dyskeratosis congenital. The bone marrow transplantation is the only long term cure for this disease but has poor outcomes in this group.

Introduction: Primary Immunodeficiency diseases have recently been recognized as a global public health problem affecting at least one in every 250 individuals. However, the care of these patients remains neglected particularly in countries with poor socioeconomic conditions. The X-linked agammaglobulinemia is considered the prototype of Primary Immunodeficiency. Material and Methods: Clinical, molecular and laboratorial data of seventeen boys diagnosed as Brutons Tirosine Kinase deficient patients, ten from four family clusters and seven sporadic cases, followed at a single center in a Brazilian State (Minas Gerais) were analyzed. We studied the genetic profile of the patients, the need of hospitalization before and after the diagnosis, the presence of infections and tolerance to the immunoglobulin reposition. Results: The study found seventeen patients with Btk mutation in follow up at the primary Immunodeficency Service. The most frequent infections are respiratory tract infections, followed by gastrointestinal manifestations. Before the diagnosis, 94% of patients had needed hospitalization and after the diagnosis and instauration of treatment only 35% needed hospitalization. The treatment with immunoglobulin replacement was well tolerated, with only one patient presenting reaction requiring medication before infusion. Different types of genes abnormalities were detected in patients, premature stop codons, initiation codon variant, deletions, insertions, frameshift deletion, intronic variant, missense variants. Five new mutations were found. One patient presented BTK expression at flow cytometry and mutation described as pathogenic. Discussion: The genetic testing is important to genetic counselling especially in patients who present BTK at flow cytometry, but the history and clinical presentation are suggestive of X-linked agammaglobulinemia. The diagnosis and correct treatment contribute to a decrease in the need of hospitalization.

Identification by exome sequencing of a novel homozygous variant in RLTPR in a family with EBV+ smooth-muscletumours Linhares, N.D.1*; Hauck, F.2*; Schober, T.2*; Bahia, M.3; Klein, C.2#; Pena, S.D.J.1#. *# contributed equally to this work. 1. Laboratório de Genômica Clínica, Faculdade de Medicina, UFMG, Belo Horizonte, MG, Brazil. 2. Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig Maximilians University, Munich, Germany. 3. Divisão de Gastroenterologia Pediátrica, HC-UFMG, Belo Horizonte, MG, Brazil. Introduction: Epstein-Barr virus (EBV)-associated smooth muscle tumors (SMT) are rare proliferative disorders which manifest predominantly in patients with acquired immunodeficiencies, such as uncontrolled HIV infection or immunosuppressive treatment after solid organ transplantation. In ten sporadic cases it has been associated with primary immunodeficiencies (PID). Objectives: We study the molecular pathogenesis of a family with two brothers with EBV+ SMT. They did not present other major infectious complications and no organ-specific autoimmunity. Material and methods: We have performed whole-exome sequencing of the two brothers and their healthy consanguineous parents. We have collaborated with a group from Ludwig Maximilians University in the characterization of the immunologic defects in our family. This group has studied a family from Middle East with the same EBV+ SMT. Results: Whole-exome analysis testing for autosomal recessive model of inheritance identified in the two brothers a novel homozygous splice site variant in RLTPR gene. Analysis of RLTPR cDNA and Western Blot experiments, performed in Germany, revealed that their variant cause the skipping of exon 11 of RLTPR and defective protein expression. The RLTPR protein is involved with T cell-dependent autoimmunity. It had been demonstrated that in the mouse, the protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. Indeed, further studies conducted in Germany with patient´s T cells showed defective CD28 cosignaling as illustrated by defective CD28-mediated T cell activation, proliferation and cytokine secretion. Conclusions: We thus propose the variant in RLTPR may be causative of the new PID in the studied family and that it should be investigated in other similar cases.

004

Clinical e laboratory diagnose of Revesz syndrome: case report Cruz, L.P.B.; Nunes, J.B.; Dias, T.R.; Cunha, L.A.O.; Vieira, A.K.; Pinto, J.A. Universidade Federal de Minas Gerais

005

Molecular characterization and clinical aspects of Bruton’s Tirosine Kinase deficient patients in a single center in Brazil Cunha, L.A.O.; Silva, M.L.; Oliveira, J.B.; Pinto, J.A. Universidade Federal de Minas Gerais; IMIP

006

Identification by exome sequencing of a novel homozygous variant in RLTPR in a family with EBV+ smooth-muscletumours Linhares, N.D.*; Hauck, F.*; Schober, T.*; Bahia, M.; Klein, C.#; Pena, S.D.J.#.

Universidade Federal de Minas Gerais

007

A case of severe neutropenia evolving to myelodysplasia Silva, C.S.M.; Santos, J.P.; Cancela, C.S.P.; Cunha, L.A.O.; Condack, C.E. HC - Universidade Federal de Minas Gerais

008

Can we use determination of Stat-1 phosphorylation in blood mononuclear cells assessed by flow cytometry to suggest gain of function mutations of STAT1 in Chronic Mucocutaneous Candidiasis patients? Kossakowski, V.B.1; Rigato, P.O.1,2; Dias, A.D.1; Duarte, A.J.S.1; Vasconcelos, D.M.1. 1. Laboratório de Investigação Médica 56 FMUSP, 2. Centro de Imunologia do Instituto Adolfo Lutz

009

NKG2 receptors expression on natural killer cells (NK) and CD8 T cell in patients with extensive warts caused by human papillomavirus (HPV) Oliveira,T.C.1; Rigato, P.O.1,2; Dias, A.S.1; Kossakowski, V.B.1; Duarte, A.J.S.1; Vasconcelos, D.M.1. 1 Laboratory of Dermatology and Immunodeficiencies – LIM56, Faculdade de Medicina da Universidade de São Paulo, 2 Center of Immunology of Institute Adolfo Lutz, São Paulo

Introduction: Congenital Neutropenia encompasses a group of genetic diseases with various clinical presentations that vary according to the levels of circulating neutrophils. We describe a case of a patient with severe congenital neutropenia that evolved to pancytopenia and multiple hospital admissions due to severe infections. Case report: LKSOS, admitted at the ambulatory of primary immunodeficiency diseases at the age of six months with a history of previous omphalitis in the second week of life, associated with neutropenia, which persisted during a second hospital admission at the age of two months, due to a severe skin infection and gingivitis. She was assessed at our clinic, where neutropenia was confirmed. A year later, she progressed with pancytopenia, which was later diagnosed as a possible case of Myelodysplasia. Since her second year of life, she has been admitted at the pediatric ward for 18 times with persistent pancytopenia and various episodes of severe infections. Laboratory data:CBC at first admission: WBC 3600 cells/mm³: Neut: 468 cells/mm³; Lymph: 2556 cells/mm³; Mono: 576 cells/mm³; HGB: 13.7g/dL, platelets: 379,000/ mm³. First assessment at the immunology clinic: VDRL neg; IgG and IgM for rubella – neg; IgM and IgG for CMV – positive; IgM and IgG for toxoplasmosis – neg; CH-100: 174; HIV: neg.; Anti-A and Anti-B isohaemaglutinin neg. Lymph cells immunophenotyping: T CD3+ 32,49%; B CD 19+ 53,29%; T CD3+CD4+ 20,62; T CD3+CD8+ 11,04%; CD 16+ 4,88%; CD 56+ 4,88%; NK 4,88; NKT 0,23%; CD4/CD8 ratio: 1,87; serum IgG: 2239 mg/dL, serum IgM: 1150 mg/dL; serum IgA: 419 mg/dL. Dihydrorhodamine Flow Cytometric Test: Neutrophilic oxidation after in vitro stimulation. Bone Marrow Aspiration showed a hypercelular bone marrow and important signs of dysplasia, suggesting myelodysplastic syndrome. BCR-ABL fusion gene negative. Treatment and Clinical Outcome: LKSOS is receiving clinical support due to her pancytopenia. A bone marrow transplant is being considered, but so far she has no full compatible donor. Conclusions: We describe a case of a patient with severe congenital neutropenia with no genetic diagnose so far. At the moment, there is no available donor for a bone marrow transplant.

Introduction: Chronic Mucocutaneous Candidiasis is a rare congenital disorder characterized by recurrent and persistent skin, nail and mucosal membrane infections caused mainly by Candida albicans. Mutations in the STAT1 encoding gene can generate loss or gain of function of the active protein changing the polarization of Th response and are among several genetic disorders associated to increased susceptibility to infections by C. albicans. Genomic sequencing of STAT 1 is the gold standard method to identify these mutations; however recently, a flow cytometry method was incorporated to search for STAT1 GOF in CMC patients. Patients with CMC carrying STAT-1 gain of function mutations present more serious clinical complications and might be treated by hematopoietic stem cell transplantation. Objective: To evaluate the phosphorylation of STAT1 in peripheral blood mononuclear cells (PBMC) of CMC patients and healthy individuals. Material and methods: Peripheral blood mononuclear cells were stimulated with or without IFN-α or IFN-γ in the presence or absence of the inhibitor staurosporine and then stained to CD3, CD4, CD14, CD19 and phosphorylated Stat-1 proteins. Results: We analyzed the expression of phosphorylated STAT1 in CD3+CD4+, CD19+ and CD14+ in nine CMC patients and nine healthy individuals. The analysis of the data suggested that the functional assay can be used to screen STAT1 gain of function carefully checking each clinical case, as shown in a patient with known STAT1 GOF confirmed by genetic sequencing. We identified another CMC patient suspected to carry mutations with GOF in STAT1 that must be confirmed by genetic sequencing. Conclusions: The assay searching to GOF of STAT1 by flow cytometry should be used to screen STAT-1 mutations in CMC patients in laboratories that have only immunological methods such as cell culture and flow cytometry facilities.

Introduction: At some point of life, persons of the general population may develop benign warts induced by human papillomavirus (HPV). There are more than 100 genotypes of HPV classified by their tropism and oncogenic potential. The immune response to HPV is related to innate and adaptive cellular immunity, including cytotoxic T cells and natural killer (NK) cells. In some patients the warts are severe or recalcitrant, and some immune defects are identified. Among genetic and immune defects related to extensive warts caused by HPV there were: polymorphisms and mutations in EVER1 and EVER2 (epidermodysplasia verruciformis), gain-of-function (GOF) mutation in CXCR4 gene, leading to WHIM (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis syndrome), DOCK8 (autosomal recessive hyper-IgE syndrome); idiopathic CD4 lymphopenia; GATA 2; STK4, MagT1 and RHOH, among others. The function and phenotype of NK cells are not well characterized in these syndromes. Several NKG2 receptors have activatory or inhibitory potential and are proteins expressed by NK cells and subsets of CD8+ T cells and until now were not determined in disseminated verrucosis. Objective: To evaluate the expression of NKG2A, NKG2C and NKG2D in peripheral blood NK subsets and CD8 T cells from patients with disseminated warts with unknown causes and healthy individuals. Materials and methods: Whole blood collected with EDTA were stained for CD3, CD8, CD16, CD19, CD56, CD95, NKG2A, NKG2C, NKG2D molecules in a flow cytometry 9-colour panel. The data were analyzed in FlowJo and plotted in GraphPad Prism softwares. Results: There were no differences between frequencies of CD3-CD19-CD56-CD16bright and CD3-CD19-CD56+CD16low among patients and healthy individuals. Considering the two populations of NK cells, there were no differences among the percentages of NK cell subsets expressing NKG2A, NKG2C, NKG2D and CD95 between patients and healthy individuals. We also evaluated levels of NKG2 receptors in NK subsets and CD8 T cells; the amounts of these proteins are similar in the cells from the groups analyzed. Conclusions: The analyzed data showed no significant differences in NK cell subtypes or NKG2 receptors between patients and healthy controls, however more patients and controls must be included in this study to better characterize the phenotype and functionality of NK cells in the context of disseminated verrucosis. Also further functional characterization must be conducted to elucidate the role of NK cells in these syndromes that results in disseminated warts caused by HPV. According to the preliminary data, the NKG2 receptors were not modulated differently in blood peripheral NK and CD8 T cells.

Introduction: Chronic mucocutaneous candidiasis (CMC) is a complex group of disorders with persistent or recurrent infection by Candida albicans. The defects on communication between dendritic cell (DC) or T cell can impair Th17 and Th1 immune response and their effectors functions allowing the establishment of infection by Candida. Methods: The moDC from healthy individuals (n=9) and CMC patients (n=9) from the ADEE-3003 outclinic from the Hospital das Clinicas of USP generated in vitro were phenotypically analyzed. MoDC generated by adherence and cultured with IL-4 and GM-CSF in vitro received or not IL-1, TNF-, IL-6 or heat inactivated C. albicans; 48 hours later the expression of CD14, HLA-DR, CD11c, CD1a, CD40, CD80, CD83, CD86, CD207, CD206, CD209, CCR6, CCR7, CCR9, TLR2, TLR4, TLR6, Dectin-1, and Dectin-2 were analyzed. Proliferation of T and B cells was analyzed by CFSE assay. Results: Activation assessed by percentage of CD11+HLA-DRhigh was higher in moDCs cultured with C. albicans from healthy than CMC individuals. There was no difference concerning the modulation of chemokines and TLR receptors between moDCs cultured or not with C. albicans on CMC or healthy subjects. The pattern recognition receptors were modulated by C. albicans, as expected on both groups. MoDCs from CMC cultured with C. albicans poorly induced proliferation of B and T cells, however there were no differences between the percentage of proliferating lymphocytes from CMC and healthy individuals. Conclusions: Our results pointed to differences concerning activation markers and functionality of moDCs from CMC patients in comparison to healthy individuals. This data suggested that some CMC patients present defects on maturation of antigen presenting cells that could affect the immune response to C. albicans. Gene expression related to innate response after fungal recognizing will be evaluated in these MoDC to better characterize if the susceptibility of C. albicans to generate chronic mucosal persistence could be derived from antigen presenting cells.

Human leukocyte antigen class I (HLA-I) deficiency is a rare disease with remarkable clinical and biological heterogeneity. It presents a 90–99% reduction in the expression of HLA-I molecules. This syndrome is caused by defects in TAP-1, TAP-2 and Tapasin (MIM 604571). Although asymptomatic cases have been described, HLA-I deficiencies are usually characterized by chronic bacterial infections of the upper and lower airways, and also necrotizing granulomatous skin lesions. Treatment is addressed to controlling infections. Early and prolonged use of antibiotics should be performed at the first sign of infection. Some patients have benefited from immunoglobulin therapy. The lack of adequate treatments for the cure of disease associated with the fact we do not have any effective therapy for the necrotizing granulomatous lesions of the skin, directed us to look for the treatment of these recalcitrant and disabling injuries. Considering the necessity of developing new skin substitutes for the treatment of major tissue loss in patients with deficiencies of MHC class I, we propose the in vivo use of biological dressings made of denuded amniotic membranes as a substrate for the growth of a epidermal layer formed by keratinocytes of the patients, allowing the growth of epithelia from the recalcitrant wounds of granulomatous lesions presented by people with MHC class I deficiency.

We report the case of a 28-year-old man, admitted in 2008 to the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Sao Paulo, Brazil. His symptoms had started 3 years earlier with a history of pulmonary disease showing fair-pleural expansive lesions with bilateral fistula, intermittent fever, consumptive syndrome, hepatosplenomegaly, and generalized lymphadenopathy. At admission, he was emaciated and prostrated and physical examination showed mandibular stiffness to the lateral region of the neck and bilateral cervical lymphadenopathy. Laboratory findings showed signs of inflammation, with an ESR of 77 mm/h, C-reactive protein 257 mg/L, alfa1 acid glycoprotein 402 mg/dL and ferritin 1,623 ng/mL. Radiologic exams showed extensive pneumonia with pleural lesions and a significant decrease of the right upper thorax, hepatosplenomegaly and supra-aortic lymphadenopathy, as well. Immunophenotyping revealed a reduced number of CD8 T-cell subsets, CD19+ B-cells, and low activity of NK cells. Dihydrorhodamine assay showed a 90.5% reduction activity. He received empirically one year of claritromicin and cotrimoxazole for a chronic non laboratory identified actinomyces infection. A diagnosis of histiocytosis was previously suspected without laboratory confirmation. New pulmonary biopsies were obtained and a revision of the old ones was performed in HC-FMUSP. Histologic and immunohistochemistry results were compatible with the pulmonary form of Erdheim-Chester disease (ERD): CD1A (-); CD68 (histiocytes)(+); PSA (-); S-100 Protein (-) and AE-1/AE-3 (epithelium) (+). An impaired expression of CD212 was found, with mutation of the gene confirmed by capillary sequencing. Treatment for ERD was established and his clinical condition improved remarkably.

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Phenotypical features and ability to induce lymphocyte proliferation of monocyte derived dendritic cell in Chronic Mucocutaneous Candidiasis Rigato,P.O.1,2; Dias, A.S.1; Oshiro, T.1; Vasconcelos, D.M.1*; Duarte, A.J.S.1*. 1. Laboratory of Dermatology and Immunodeficiencies (LIM56), Faculdade de Medicina, Universidade de São Paulo 2. Center of Immunology, Instituto Adolfo Lutz, Brazil. * Senior authors

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Development of a biologic dressing for the treatment of skin ulcers associated to HLA class I deficiency Paggiaro, A.O.; Issac, C.; Ribeiro, R.L.; Vasconcelos, D.M. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

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Erdheim-Chester non-Langerhans cell histiocytosis in a patient with mutation of the IL-12RB1 gene – a case report Carneiro, L.E.P.; Brito, T.; Gryschek, R.C.B.; Orii, N.M.; Oliveira, J.B.; Duarte, A.J.S.; Vasconcelos, D.M. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

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Histopathological aspects of acuteform paracoccidioidomycosis in IL12BR1 deficient patients Vasconcelos, D.M.; Campeas, A.E.; Ferrão, M.S.; Brasil, R.A.; Pagliari, C.; Sotto, M.N.; Duarte, M.I.S. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

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Griscelli syndrome type 2: a report of two cases Vervloet, L.A.; Pelegrine, H.A.F.; Silva, G.R.P. Universidade Federal do Espirito Santo (UFES)

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Hereditary autoinflammatory syndromes: a report of one case Vervloet, L.A. Universidade Federal do Espirito Santo (UFES)

Paracoccidioidomycosis (PCM) is caused by the dimorphic fungus Paracoccidioides brasiliensis and presents two clinical forms: acute form (AF) and chronic form (CF). We have previously described that AF PCM could be related to CD212 deficiency. Two patients, one 18 yo male (1) and other 11 yo female (2) presented long-lasting fever and abdominal (and/or leg) pain with disseminated lymphadenopathy and hepatosplenomegaly. The biopsy of lymphnodes showed AF-PCM. Patient 1 had a history of BCGitis and disseminated salmonellosis. Patient 2 presented later pulmonary and pleural mycobacteriosis. The histological evaluation of lymphnodes showed typical granulomas with several fungal forms. Immunohistochemistry showed a palisade of CD4+ T cells and just a few in the central area. Conversely, CD8+ T cells were much less representative. Immunostaining for macrophages showed large numbers of cells. The staining for cytokines showed almost no staining for IL-4. Moreover, the staining for TNF-b and for IFN-g was scarcely distributed. Conversely, IL-17 was clearly evident as well as TGF-b around granulomas. There is an interesting clinical-pathological relationship between the clinical features, the evolution of the PCM after therapy and the histopathological aspects. These points are important to support the idea of therapy with IFN-g in case of a possible relapse of the infectious disease.

Introduction: Griscelli syndrome (GS) is a rare autosomal recessive disorder. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. Case reports: We describe two cases with GS type 2 which had different outcome. Infants were boys with aged of 2 and 5 years with no consanguineous parents. The GS diagnosis was confirmed by clinical manifestations and the microscopic examination of the hair showed irregular agglomerations of pigment in the hair shafts. A peripheral blood smear of patient was negative in view of large inclusions nucleated blood cells.The clinical and biological signs were typical and complete in the first case. The boy had silvery hair, eyebrows and eyelashes. The skin had hypopigmentation when compared to parents, who had black hair with brown skin. He was admitted to the hospital with fever, hepatosplenomegaly, and pancytopenia and evolved into haemophagocytic syndrome and death before we could send to the bone marrow transplant. The second case is currently being monitored at the University Hospital. He has a history of severe infections and presented three sepsis. During the infectious episodes, had pancytopenia and/or an important neutropenia but with good evolution. The severe infections wasn”t associated with the occurrence of haemophagocytic syndrome. The boy has blond hair. He is currently waiting a bone marrow transplant. The brother is HLA compatible. A transplant from a histocompatible donor offers the best chances of long-term survival for GS patients. Conclusions: The phenotypic appearance characteristics, especially the pigment disorder of the patient’s hair are emphasized so that it is quite possible to suspect the diagnosis at the bedside. The diagnosis before serious complications, such a haemophagocytic syndrome, may increase the chance of survival and the possibility of performing marrow transplant.

Introduction: The hereditary autoinflammatory syndromes (AIS) are caused by monogenic defects of innate immunity and are classified as primary immunodeficiencies. The clinical picture of these syndromes is characterized by recurrent or persistent inflammatory symptoms affecting various organs and body systems, and the AIS must be distinguished from infectious diseases, autoimmune conditions, and other primary immunodeficiencies. Clinical History: A male patient, 17 years old, was referred to the Hospital Universitário Cassiano Antônio Moraes (HUCAM) in February 2014, with a history that since 9 years old had began recurrent fever associated with erysipelas-like erythema, arthritis in large joints of the lower limbs, 3-4 time for year. He needed 9 previous hospitalizations and there aren’t consanguineous parents in his history. The fever is high (38.5-40 °C) and resolves spontaneously within 6 to 96 hours, accompanied by malaise and incapacitating pain. Sometimes, he had chest pain and the episodes lasts an average of 3 to 4 days. Before hospitalization, the patient had surgery of varicose veins in the legs although there was no thrombosis displayed on the doppler. Laboratory data: Leukocytosis, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) few high. IgA with p25-50, IgG with p50-90 but IgM below the 3rd percentile. Normal Antinuclear Antibody Test, Antineutrophil Cytoplasmic Antibody and C3 and C4. All negative blood cultures. Treatment: The patient had clinical response to colchicines. Conclusions: The case is a probable Familial Mediterranean fever (FMF).

Although Primary Immunodeficiency Diseases (PIDs) have been classically considered as diseases of infants and children, increasing numbers of affected adults have been identified. Here we describe the experience of a specialized dermatology ambulatory in an university hospital in São Paulo, Brazil, with both adult and pediatric PID patients. HCFMUSP is the biggest public hospital of the country and represents the main national reference center for rare and complex diseases. In our outpatient unit the most common diagnoses are: Symptomatic IgA deficiency-63 patients; Hereditary angioedema-68 pts; CVID-56 patients; CMC-38; Transient hypogammaglobulinemia-17; Idiopathic CD4 lymphocytopenia-17; Complement deficiencies (excluding HAE)-15; Phagocyte G6PD deficiency-18; MSMD-16; IgM deficiency-10; CGD-11 patients, among many other diseases. Of these patients 44 died, mainly due to septic episodes and neoplasias. The distributions are as follows: Males: 209; Females: 213; 204 children and adolescents; 233 adults; As a whole there are more than 1600 patients in follow-up nowadays, with 437 patients with well defined PIDD. Our casuistry shows an extreme diversity of different cases, with several rare diagnoses. Due to the fact that we are located in the dermatology department our patients present mainly dermatological manifestations, such as HAE, CMC, XP, EVER, Netherton etc. Primary immunodeficiencies as a whole comprise an important health problem considering that their frequency is comparable to hematological cancer or cystic fibrosis, for example. Our specialized unit has a specific set of different diseases not commonly found in other primary immunodeficiencies ambulatories.

Introduction: Periodic fever syndromes are characterized by short and recurrent attacks of fever and severe localized inflammation that occur periodically or irregularly and that are not explained by usual childhood infections. These attacks undergo spontaneous remission without antibiotic, anti-inflammatory, or immunosuppressive treatment. Between attacks, patients feel well and regain their normal daily functions until the next episode occurs. Clinical History: An eight years old girl who presents a periodic fever, that onset before the age of one; during approximately three days, median maximum temperature of 40°C, associated with abdominal pain, vomiting, and recently cervical pain. In the begging, the episodes occurred on a biweekly frequency, and nowadays it happens every two months. Before establishment of fever periodicity, she was submitted to a several infectious screenings, and even antibiotics treatment. The events do not prejudice her growth and development, but brings on elevated scholar absenteeism. In an outpatient investigation, it was questioned the hypothesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. However, lately, her younger brother initiated to present the same symptoms. This fact suggests another group of diseases, Monogenic Periodic Fevers, andalso response to periodic fever disease, which are caused by mutations of genes involved in regulation of the inflammatory response, namely, familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD). Consequently, a molecular investigation for this patient was required. Laboratory Data: The complementary exams findings include increased acute phase reactant C Reactive Protein (CRP) on the fever attacks periods, which returns to the reference values in the end of the event. Treatment: Periodic fever attacks present a good answer to symptomatic medications and recently Colchicine was added to the therapeutic intervention. Conclusions: A differential diagnosis between genetically positive and negative patients with periodic fever could be prejudiced because of clinical manifestations are largely overlapping. This is particularly true in pediatric patients, since the PFAPA syndrome could be rather frequent as Hereditary Periodic Fever.

Introduction: The syndrome of hyper-IgE syndrome or Job syndrome or Burckley syndrome, is a rare primary immunodeficiency characterized by defective phagocytic manifesting recurrent infections, mainly Staphylococcal associated with eczema severe atopic, musculoskeletal disorders, pathological fractures, scoliosis and levels high IgE (> 2.000UI / ml). Among the immunological characteristics, we can find defects in neutrophil chemotaxis, decreased production of interferon gamma, eosinophilia mutation and STAT 3.Most cases are sporadic, but there are cases with patterns of autosomal dominant or recessive inheritance. The diagnosis is clinical using the criteria of Grimbacher.The treatment is the same of the bacterial and fungal infections. Some consensus oriented prophylaxis of infections with antibiotics. Objective: Report the case of patient with severe atopic eczema carrier of Hiper IgE syndrome as criteria for Grimbacher. Case Report: TIFS 2 years and 9 months and history of atopic eczema since 3 months of age and history of intrauterine growth retarded neonatal sepsis associated with severe skin lesions, three hospitalizations for pneumonia and hospitalization due infected with abscesses dermatitis. Physical examination showed coarse facies, prominent forehead, broad nasal bridge,hyperextensible joints of knees and severe atopic eczema refractory to treatments. In evaluating additional research showed anti-HIV antibody negative,eosinophilia persistent (4080 cells / mm 3) and IgE> 2.000UI / ml. Conclusions: Given the difficulty for the molecular diagnosis of the syndrome hyperIgE, we report a probable case of the disease evaluated according to the criteria of Grimbacher be used in our service. Reiterates the importance of investigating immunodeficiency in children with severe atopic eczema associated with recurrent infections.

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Primary Immunodeciency Disorders (PID) in a specialized dermatology outpatient unt in São Paulo, Brazil Vasconcelos, D.M.; Ferreira, M.D.; Barros, N.C.; Bezerra, T.A.; Bertolini, D.L.; Muniz Jr. R.; Carneiro, L.E.P.; Duarte, A.J.S. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

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Differential Diagnosis of Periodic Fevers: A case report Azevedo, L.P.; Cunha, L.A.O.; Oliveira, F.A.; Vaz, G.H.M.; Junior, W.F.F. Hospital da Polícia Militar de Minas Gerais

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Severe atopic eczema and recurrent infections - diagnosis of the Job syndrome according to Grimbacher criteria Pinto, P.C.G.; Souza, T.M. Hospital Universitário, Universidade Federal de Juiz de Fora

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Recurrent penumonias and bronchiectasis associated a common variable immunodeficiency Pinto, P.C.G.; Duarte, M.C.; Souza, T.M. Hospital Universitario, Universidade Federal de Juiz de Fora

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Trombocytopenic purpura associated with common variable immunodeficiency and bronchiectasis Pinto, P.C.G.; Hallack Neto, A.E.; Macedo, I.T.; Guedes, LMA; Gontijo, F.P. Hospital Universitario, Universidade Federal de Juiz de Fora

Common variable immunodeficiency

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Pinto, P.C.G.; Guedes, L.M.A; Macedo, I.T.; Gontijo, F.P. Hospital Universitário, Universidade Federal de Juiz de Fora

Introduction: Commom variable immunodeficiency (CVID) is the second more commom cause of Immunodeficiency. Its prevalence is about 1 for each 10 000 a 50 000 persons. Both genders can be affected and it can be associated a several phenotypes such a recurrent infections,autoimmunity,enteropathy,neoplasms, polyclonal lymphocytic infiltration. The main recurrent infections are those that achieve lungs,paranasal sinuses and gastrointestinal . About 60% of the cases of CVID are associated a bronchiectasis. The diagnosis is based on recurrents infections, reduction of IgG, IgA and /or IgM below 2 standards-desviation for age, patients with over 4 years old and exclusion of the others causes of hypogammaglobulinemia. Objective: The objective is to report the case of a patient who was diagnosed with CVID associated a recurrent pulmonary infections and bronchiectasis. Case Report: GOA ,16 years old, 6 previous pneumonias. The first one was when she was 6 years old. She was hospitalized in two of those episodes and she also presented important weight loss. When she was 15 years old, the investigation was started. Sweat test and anti HIV were negative. Low levels of Immunoglobulins were found (IgG= 20,1 mg/dl; IgM=32,2 mg/dl; IgA=7,2 mg/dl; IgE=1,1 mg/dl). The lymphocyte immunophenotyping was normal for her age (CD3=2939mm3, CD4=693mm3, CD8=2011mm3, CD19=876mm3). Tomografy of the chest presented suggestive areas of severe chronic bronchiectasis. After the exclusion of others hypogammaglobulinemias causes and the diagnostic of CVID being confirmed, the treatment was iniciated using intravenous imunoglobulin 400 mg/kg/day and antimicrobial prophylaxis with azitrhomicin. After initiation of treatment, the child didn’ t have others infections and had satisfactory weight. Currently she is being monitorized In a immunology ambulatory. Conclusion: We want to emphasize the delay in diagnosing of primary immunodeficiency and the importance of excluding CVID in patients that presents recurrent pneumonias, mainly when its associated a bronchiectasis.

Introduction: Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency (PID) and consist of hypogammaglobulinaemia, recurrent infections and other prevalent alterations in humoral immunity. CVID is associated to infections, pulmonary involvement and its complications like the bronchiectasis. Objective: Describe a case of patient with CVID who started with thrombocytopenia and evolved with bronchiectasis. Case Report: Boy with 13 years old diagnosed with thrombocytopenic purpura and a normal myelogram. He presented low levels of immunoglobulins (A = 7 mg / dl, M = 14,2mg / dl and G = 140 mg / dl). Immunophenotyping of lymphocytes was altered with CD19 = 7.9% (81cells / mm3); CD4 = 56.5% (574cells / mm3) and CD8 = 12.3% (125cells / mm3). The research of vaccine antibodies (tetanus, mumps) was negative and didn’t produce antibodies against the pneumococcal vaccine. In his personal history was report of pneumonia at age 12 and chicken pox infection with prolonged evolution and secondary bacterial infection. A tomography of the chest showed signs of diffuse bronchiectasis. After excluding other causes of hypogammaglobulinemia and the diagnosis of CVID was initiated monthly treatment with intravenous immunoglobulin and physiotherapy. Conclusion: Reiterate the importance of diagnosis of bronchiectasis in patients with CVID, even under a single episode of pneumonia in evolution. These patients may have few signs and symptoms of respiratory and progress to complications, such as bronchiectasis, even in the presence of adequate monitoring. Furthermore, we emphasize the importance of investigating the causes of thrombocytopenic purpura associated with autoimmunity by some patients with CVID.

Introduction: The CVID is the second most common primary immunodeficiency. The prevalence of CIVD in the world is approximately 1:25,000. The age of presentation of ICV has peaks in the first decade if life and the beginning of the third decade. Both sexes are affected. Diagnostic criteria according to ESID/PAGID are: - recurrent infections; -age more 4 years; -reduced levels of IgG; decrease of IgA and/or IgM; exclusion of the other causes of hypogammaglobulinemia; no isohemaglutininas and response to the vaccine. Five clinical phenotypes are described: only infections, autoimmunity, polyclonal lymphocytic infiltration, malignancy and enteropathy. The treatament of patients with CVI is performed with the use of an infusion of immunoglobulin. Objective: To report a patient with CVI associated with infections/ infestations recurrent and splenomegaly. Case description: H.S.M.A, male, 8 years old, eight pneumonia, low weight gain, infestation by Giardia lamblia and splenomegaly (physical examination and ultrasound). Tests: HIV ELISA negative. IgG=614mg/dl; IgM=19mg/dl; IgA=24mg/dl; CD4=24 (742mm3); CD8=70% (2150/mm3) and CD19=247/mm3. Lymphocyte B total=9.2%. Discussion: the CVI can be associated with some phenotypes, such as the occurrence of infections/infestations recurrent and splenomegaly. The levels of immunoglobulins are below the 3 percentile for age, the percentage of b lymphocytes in the minimum threstold, CD8 high. Conclusions: TReiterate the importance of the diagnosis of primary immunodeficiency in patients with infections/infestations recurrent splenomegaly and in this case the CVI by important prevalence.

Introduction: Neutropenia is defined in the literature as absolute neutrophil counts in peripheral blood of less than 1500 cells/mm3 in more than one year old and less than 2000cells/mm3 in children in the first year old of life. Neutropenia is classified as mild, moderate or severe, and may be congenital or acquired, persistent or not. Kostmann syndrome is a severe neutropenia, the incidence varies1-2 cases/ 100.000 – 1.000.000 and attends with severe recurrent infections early. Case description: JBL, white, male was admitted three times with recurrent pneumonia, otitis, anemia, neutropenia, eosinophilia and monocytose in peripheral blood and cord lock maturation phase pro-myelocytic to the bone marrow. Used G-CSF. At 11 months od age showed severe pneumonia without clinical response and death. Discussion: Recurrent infection in this child began early, as happen in monocytosis, lymphocytosis and eosinophilias associated with maturation arrest of marrow in the series promyelocytic suggest the diagnosis of syndrome Kostmann. Beside the proper treatment of infections is indicated using G-CSF. Conclusions: Kostmann syndrome should be considerate in the differential diagnosis of severe persistent neutropenia in children, among the prophylaxis and treatment of infections associated with the use of G-CSF members of appropriate monitoring of the patients.

We report a case of a 4-year-old girl who presented with recurrent episodes of persistent fever, splenomegaly and hepatomegaly since the two years of age. The child was referred to us from her hometown physician located in Amazon rain forest, after being treated empirically for leishmaniasis and malaria, prevalent tropical diseases in the area. There was no response to the empiric treatments. Other infectious diseases, malignancies and collagen vascular diseases were extensively ruled out. She had two episodes of aseptic meningitis at the age of 2. The neurodevelopment was normal, without evidence of long term deficits. There were no signs of hearing or visual loss, lymphadenopathy, conjunctivitis, arthritis, joint deformities, rashes or other skin lesions. During flares, the most frequent clinical findings were moderate abdominal pain, headache, asthenia and back pain. Laboratory findings include anemia, leukopenia, thrombocytopenia, and increased acute phase reactants (ESR and CRP). Flares recur periodically and the fever attacks occur typically between 3:00PM and 4:00PM. Initial immunological assessment showed normal levels of immunoglobulins and lymphocytes subpopulations. Gene sequencing for genetic defects associated with autoinflammatory syndromes were considered for the genes MEVF, NOD2, PSTPIP1, MVK, NLRP3 and TNFRSF1A. The genetic variants found in MEVF (c.G605A:p.R202Q) and NLRP3 (c.C2107A:p.Q703K) are of uncertain clinical significance and could represent benign polymorphisms or play a role in the pathogenesis of this disease. She responded well to corticosteroids and recently cyclosporin was added to the therapeutic intervention.“Mutation negative” patients with characteristic clinical features of autoinflammatory diseases have been described and somatic mosaicism in some genes were found. In these cases the disease severity seems to be milder than in patients with germline mutations. Subcloning or deep sequencing is required to establish genetic diagnosis in Sanger sequencing “mutation negative” NOMID patient, for example. We consider the hypothesis of an immune dysregulatory disorder with autoinflammatory phenotype for a girl with signs and symptoms of systemic inflammation without evidence for infections or malignancies and with an underlying mutation in the MEVF gene.

Defects on interferon-gamma/interleukin-12 (IFN-γ/IL-12) Axis is a primary immnunodeficiency characterized clinically by Bacillus Calmette-Guerin (BCG) or other poorly pathogenic mycobacteria disease, disseminated tuberculosis, systemic and/or persistent non-typhi Salmonella infection, or severe herpesvirus infection. The IFN-γ/IL-12 pathway plays a central role in controlling mycobacterial infections. IFN-γ is necessary for the killing of mycobacteria and certain other intracellular microrganism. We report a case of a 4-month-old girl, BCG vaccinated, who developed a tumoral lesion on the site of BCG vaccine and right axillary lymphadenitis, without other signs of severe disease. Chest X-ray and hemogram were normal. Moreover, there were a family history of two male cousins that died early in life, one of them with an adverse effect following immunization with BCG vaccine. First line tuberculostatic drugs were initiated and the lesion partially regressed. Forty-five days after drug suspension, a new granuloma formation had reappeared in the same local, as well as the regional lymphadenitis. An excisional biopsy of the lymph node showed caseous necrosis and Mycobacterium bovis with an isoniazid and rifampicin resistance pattern was isolated. Standard screening measures of cellular and humoral immune function were initially normal and well-defined mmunodeficiencies (e.g. severe combined immunodeficiencies) were ruled out. As the patient’s clinical condition did not improve even during aggressive anti-microbial therapy (quadruple treatment – isoniazid, rifampicin, ethambutol, streptomycin), therapy with subcutaneous IFN-gamma was introduced. After a trial of 2 months, we observed a dramatic resolution of the lesion. Molecular investigation identified a mutation in the gene encoding the beta 1 chain of IL-12 receptor. Genetic mutations on IFN-γ receptors, IL-12 subunits, IL-12 receptors and Signal Transducer and Activator of Transcription-1 (STAT-1) have been described as autossomal recessive or autossomal dominant conditions. These defects also have been grouped as Mendelian Susceptibility to Mycobacterial Disease (MSMD). IL-12Rβ1 deficiency is the most common genetic etiology for MSMD. The present clinical case highlights the importance of considering the diagnosis of Defects on IFNγ/IL-12 Axis in subjects with unusual micobacterial diseases.

Severe congenital neutropenia

022

Pinto, P.C.G.; Pinto, J.A.; Atalla, A.; Portugal, C.A.A.; Gontijo, F.P. Hospital Universitário, Universidade Federal de Juiz de Fora

023

Prolonged fever, aseptic meningitis and hepatosplenomegaly responsive to corticosteroid in a 4 year old girl without evidence of infections Guimaraes, T.N.; Cunha L.A.O.; Pinto J.A. Faculdade Medicina da UFMG

IL-12Rβ1 deficiency

024

Guimaraes, T.N.; Nunes J.B.S.; Miranda L.B.; Cunha L.A.O.; Pinto J.A. Faculdade Medicina da UFMG

025

New intronic mutation in X-linked agamaglobulinemia Cunha, L.A.O.; Silva, M.L.; Oliveira, J.B.; Pinto, J.A. Clinical Immunology Division, Hospital das Clínicas Universidade Federal de Minas Gerais

026

Neonatal Onset of IL-1 Mediated Autoinflammatory Syndrome a differential diagnosis for Infantile Systemic Hyalinosis: a case Report Coutinho J.D.C.; Cunha L.A.O.; Pinto, J.A. Clinical Immunology Division, Hospital das Clínicas, Universidade Federal de Minas Gerais

027

BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients Teocchi, M.A.*; Ramalho, V.D.*; Abramczuk, B.M.; Vilela, M.M.S. UNICAMP

The diagnosis of Infantile Systemic Hyalinosis might be challenging specially in a very young patients. Here we report a case of a female infant who developed severe joint restriction along with hypogammaglobulinemia that worsen three days after receiving diphtheria, tetanus toxoids and pertussis vaccine. Her initial clinical presentation was pustular rash located on the occipital and dorsal region, painful, restricted and deformed joints. The laboratory workout revealed normal lymphocyte imunophenotyping and normal inflammatory tests, hypogammaglobulinemia, anemia, high leukocytes counts and high platelets counts. The clinical presentation suggested Neonatal Onset IL-1 Mediated Autoinflammatory Syndrome. She was treated with steroids and immunoglobulin high doses without any clinical improvement. Genetic testing was done to DIRA and no mutations were found. The rash got worst and she developed gingival hypertrophy. A skin biopsy was done and showed accumulation of hyaline substance in the skin, and the diagnosis of Infantile Systemic Hyalinosis was concluded. In conclusion, Neonatal Onset IL-1 Mediated Autoinflammatory Syndrome may mimic Infantile Systemic Hyalinosis in very young aged patients and should be considered as a differential diagnosis.

* The first two authors made equal contributions to this work Introduction: X-linked agammaglobulinemia (XLA) is characterized by a B lymphocyte differentiation block in the bone marrow, leading to hypogammaglobulinemia with few, or the absence of, peripheral B lymphocytes. Mutations in the BTK gene are responsible for XLA and in most cases lead to low protein expression. Misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER). Material and methods: We evaluated eight male Brazilian patients whose diagnosis was based on recurrent infections, markedly reduced levels of IgM, IgG and IgA, and circulating B cell numbers <2%. BTK mutations were identified by sequencing and the mRNA expression of BTK and ER stress markers was assessed with real-time quantitative PCR (RT-qPCR) technology. Results: L We detected four missense mutations, one nonsense mutation, two frameshifts and one splice site defect. Quantitative real-time detection PCR measurements showed a reduced expression of BTK mRNA in patients with mutations that result in a stop codon. However, we found that missense mutations do not affect BTK mRNA expression. XLA patients showed an increased level of XBP1 mRNA, which could be a mechanism to revert cellular ER stress. Conclusions: This is the first study relating XBP1 with BTK mutations and XLA. Our data suggest that defective BTK might affect XBP1 expression in monocytes. As a multifunctional transcriptional factor, our finding on XBP1 upregulation in XLA patients opens several possible avenues of research that will help us to understand the complex pathophysiology in XLA.

Introdution: The autoimmune lymphoproliferative syndrome (ALPS) is a disorder in lymphocyte apoptosis, characterized by a chronic accumulation of non-malignant lymphoid cells, increased circulating TCRα/β+CD4-CD8- cells and autoimmune manifestations. The majority of cases result from a mutation in the FAS gene (ALPS-FAS). Material and methods: We studied an ALPS-FAS patient, his mother, a maternal uncle and a maternal aunt, all of them with a heterozygous substitution in the splice donor site of intron 4, but with different clinical manifestations. The patient´s clinical history includes organomegaly, hemolytic anemia, hypergammaglobulinemia and glomerulonephritis. His mother had congenital herpes infection and leukopenia. His aunt and uncle had glomerulonephritis that declined without specific treatments. The uncle also had hemolytic anemia. The quantification of soluble FAS ligand (sFASL) and interleukin (IL)-10 was performed on frozen serum samples by ELISA. FAS and FASL mRNA relative expression in peripheral blood mononuclear cells were evaluated with real-time quantitative PCR. Results: We observed high sFASL and IL-10 concentrations in the serum of the ALPS-FAS patient and his mother, but normal levels in the serum of the uncle and the aunt. The family showed a depressed FASLG mRNA relative expression in comparison with the controls (p= 0.0381, reference gene: HPRT1 or GAPDH+HPRT1). The FAS mRNA relative expression was similar in both groups. Conclusions: In spite of the well-known apoptotic defect in ALPS patients, mutational consequences are poorly understood. The fact that the same mutation in distinct, but related, subjects causes severe, moderate, mild or absent clinical manifestations is still unexplained. Our study reinforces the role of biomarkers as an important tool to predict ALPS clinical manifestations and to clarify the molecular signalling pathways affected by the FAS mutation.

Introduction: Patients with CVID are often affected by infections and little is known about the pathophysiological mechanisms of innate immunity involved in this protection. The chemotaxis and neutrophil on TLR signaling pathway is crucial part of the innate immunity to protect against infections by gram-positive and gram-negative bacteria, especially regarding the action of TLR2 and TLR4 and the p38 MAPK signaling pathway. Objectives: The aim of this study was to assessment chemotaxis and p38 MAPK signaling pathway activated by TLR2 and TLR4 in neutrophils of patients with CVID patients. Material and methods: We studied 38 patients and 19 healthy controls of both sexes and aged between 13-63 years. The chemotaxis was performed in chamber 48 wells, Neuroprobe. We randomly selected 15 patients with CVI and 9 healthy controls for studying the p38 MAPK signaling pathway, has been performed stimulation with LPS (TLR4) and P3C (TLR2) at times 15 and 60 minutes. Results: All patients and controls had neutrophil migration across the stimulation with f-MLP (p <0.05). However, patients present a reduced CVID chemotactic index when compared to controls, although the absolute migration across the f-MLP not presented difference between the two groups. Furthermore, was observed a higher random migration without stimulation in neutrophils of patients with ICV compared to healthy controls (p <0.001). The stimulation with LPS and P3C induced the expression of p38 MAPK phosphorylation in CVID patients and healthy controls, indicating that activation of TLR2 and TLR4 led to the phosphorylation of p38 MAPK in both groups. When we compare the stimuli in the two times in patients and controls, we observed no statistically significant differences in the expression of MAPK p38 in patients with CVID and controls. Conclusions: We conclude that neutrophil chemotaxis is preserved in patients with CVID and that the random migration of these patients did not change the absolute forward migration by f-MLP, when compared to healthy controls. However, there are reasons to seek for a possible baseline stimulation increases the random migration of neutrophils. The TLR activation induced expression of p38 MAPK phosphorylation in both groups, as the stimulation with LPS (TLR4) and P3C (TLR2) led to the phosphorylation of p38 MAPK, however, the intensity of phosphorylation may have been lower in patients CVID and can express a clinical significance.

Introduction: Common variable immunodeficiency (CVID) is the most prevalent form of severe antibody deficiency affecting both children and adults and is characterized by heterogeneous clinical manifestations which include recurrent infections, chronic lung disease, autoimmune disorders, enteropathy and enhanced risk of malignancy. Considering these distincts symptoms, a phenotypic approach of CVID has been proposed, based upon the type of complications the patient develops. Objectives: The aim of this study is to classify the UFMG CVID cohort in the five phenotypic categories proposed by the European Common Variable Immunodeficiency Disorders registry: patients with no complications, autoimmune diseases, lymphocytic organ infiltration, enteropathy and lymphoid malignancies. Material and methods: Standardized CVID diagnostic criteria were used, consistent with the ESID/PAGID criteria. Clinical, immunologic and follow up data were collected based on medical registries. Results: Data from 85 patients fulfilling the diagnostic criteria for CVID was analysed. The age range was 5 to 75 years, 42 (49,4%) were females, mean followup time was 6,8 years. There were two (3.7%) deaths due to sepsis and lymphoid malignancy. The population was classified into five not mutually exclusive clinical phenotypes (Table). Clinical Phenotype

Chronic lung disease Autoimmune diseases Lymphocytic organ infiltration Enteropathy Malignancy No complications

028

Evaluation of FAS, FASLG and IL10 as FAS mutation biomarkers in a family with Autoimmune Lymphoproliferative Syndrome Abramczuk, B.M.; Teocchi, M.A.; Marega, L.F.; Ramalho, V.D.; Mazzola, T.N. & Vilela, M.M.S. UNICAMP

029

Assessment chemotaxis and p38 MAPK signaling pathway activated by TLR2 and TLR4 in neutrophils of patients with common variable immunodeficiency Pinto, P.C.G.; Andrade, M.V.M.; Batista, S.A.; Nunes, J.B.S.; Vargas, F.R.; Pinto, J.A. UFMG

030

Common Variable Immunodeficiency: a phenotypic approach at a singlecenter cohort Nunes, J.B.S; Cunha L.A.O.; Greco D.B; Pinto, J.A. Division of Immunology, Hospital das Clínicas, Federal University

N (%)

48 (56,4%) 28 (32,9%) 22 ( 25,8%) 12 (14,1%) 5 (5,88%) 13 (15,2%)

Conclusions: CVID is associated with a broad spectrum of disorders, allowing a phenotypic approach of patients. This approach has been well described in a number of reports and the current study presents the characteristics of our CVID population, enabling more detailed analysis and correlations between the clinical phenotypes and severity of disease.

031

Common variable immunodeficiency: broad spectrum of complications in the same patient Nunes J.B.S.; Figueiredo B.C.G.; Cunha L.A.O.; Pinto J.A. Division of Immunology, Hospital das Clínicas, Federal University of Minas Gerais

032

Chronic Granulomatous disease (CGD) presenting with severe sepsis Santos J.P.; Silva, C.S.M., Nunes, J.B.S; Cunha, L.A.O.; Condack, C.E. UFMG

033

Primary Immunodeficiencies: a review of cases of the Clinical Immunology Service of Hospital of the Federal University of Minas Gerais Souza, R.G .; Nunes, J.B; Cunha, L.A.O; Dias, T.R.; Coutinho, J.D.; Pinto, J.A. Division of Immunology, Hospital das Clínicas, Federal University of Minas Gerais

Introduction: Common variable immunodeficiency (CVID) is characterized by heterogeneous clinical symptoms including recurrent sinopulmonary infections, splenomegaly, autoimmune disorders, granulomatous diseases and an enhanced risk of malignancy. An overlap of these events can occur in the same patient. Case Report: A 8-year-old boy was admitted to our service because of recurrent otitis media and lower respiratory tract infections. He presented splenomegaly ( 7 cm below the costal margin) and chronic cough. Immunoglobulins levels were checked revealing low concentrations of all three major isotypes: IgG 0,3 g/L IgA < 0,7 g/L IgM 0,22g/L. There was no humoral immune response to rubella and his isohemagglutinins were absent. Computed tomography (CT) showed bronquiectasias. A diagnosis of CVID was made and immunoglobulin replacement therapy was commenced. Two years later, this patient presented weight loss, multiple lymphadenopathy and increase of splenomegaly (13 cm below the costal margin). Lymph node biopsy revealed B cels non-Hodgking’s lymphoma. Chemotherapy (Cyclophosphamide plus Vincristine plus Methotrexate plus Prednisone) was started and there was remission of the lymphoma. Twelve months after chemotherapy, he presented multiple erythematous plaques with adherent scales involving elbows, knees and buttocks. Lymphadenopaty returned. Skin biopsy showed noncaseating granulomatous inflammation and the new lymph node biopsy was suggestive of sarcoidosis. Fundoscopy revealed preretinal yellow-white nodule located inferiorly in the right eye ( snowball opacity). Corticotherapy and treatment with chloroquine was started, but the patient presented neurological changes suggestive of progressive multifocal leukoencephalopathy . Magnetic resonance imaging and PCR on cerebrospinal fluid were performed. Discussion: CVID progresses with different forms of clinical manifestations, but these may occur simultaneously in the same patient. It has been reported a strong association among granulomatous disease, autoimmune phenomena and splenomegaly.

Introduction: CGD is a genetic disease that leads to an inability to produce superoxide anions in the NADPH oxidase enzyme complex. It mostly affects the phagocytes, incapable to eliminate bacterial and fungal organisms from the body. It also leads to a predisposition to autoimmune diseases and systemic granulomatous lesions. Almost 70% of the cases are related to a single mutation in the CYBB gene (X-linked), although other 4 mutations have also been described. The most common pathogens observed are Staphylococci, Pseudomonas spp., Nocardia spp., Aspergillus spp., and Candida albicans. Case report: BAOV was admitted to our immunology ambulatory at the age of 4 months, after an episode of severe sepsis caused by Burkholderia cepacia. At the age of nine months he came to our ER with a history of fever, irritability and fatigue, already in use of amoxicillin for a urinary tract infection (UTI) previously diagnosed. Laboratory data: Dihydrorhodamine Flow Cytometric Test: Absent Neutrophilic oxidation after ‘in vitro’ stimulation; Immunoglobulins (mg/dL) – IgA: 107; IgG: 2070; IgM: 301; IgE: 27.8. Lymph cells immunophenotyping (cells/µL): T CD3+ 6061; T CD3+CD4+: 3913 T CD3+CD8+: 2013, B CD19+: 506, CD16+: 286, CD56+: 286, NK: 286, NKT: 57. Treatment: His last episode of UTI was caused by Klebsiella pneumoniae, 100,000 CFU/mL. He is still being taken cared of by our group and is using prophylactic SMZ+TMP and itraconazole. The final tests for a bone marrow transplant are ongoing. Conclusions: CGD is a genetic disease that predisposes its carriers to severe infections like skin and liver abscesses, pneumonia e osteomyelitis. Its early diagnosis is of paramount importance, since the use of prophylactic drugs can increase significantly the life expectancy. Bone marrow transplant is curative, although not without significant risk.

Introduction: Despite the rapid progress of science in Primary Immunodeficiencies, population characteristics and disease burden are poorly characterized. Global data on Primary Immunodeficiencies through patient records are an essential component of the public health response.This review aims to describe the spectrum of primary immunodeficiencies in a tertiary pediatric center, the Clinical Hospital of the Immunology Department of the Federal University of Minas Gerais - Orestes Diniz CTR. Material and methods: A retrospective study was conducted in 351 patients with Primary Immunodeficiencies 1986 to April 2015, through chart review. Discussion: This report reveals that a total number of 34 syndromes Primary Immunodeficiencies, and the prevalence was similar in both sexes with 52.7% male and 47.3% female. It was observed that antibody deficiency syndrome accounted for 57% of cases, Common Variable Immunodeficiency the most common diagnosis, a total of 93 patients. The complement deficiency was responsible for 23% of cases, with 84 cases of Hereditary Angioedema, representing the second most prevalent disease. Conclusion: The spectrum of Primary Immunodeficiencies was similar international trends. A public health approach is necessary, including strategies to correct the disparities in access to care, improve the molecular diagnosis and reduce preventable complications of diseases.

Introduction: The Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive disorder originally described as a clinical triad of thrombocytopenia with small platelets, eczema and immunodeficiency. Impaired CD43 glycoprotein in lymphocytes is a typical hallmark of this disorder. The WAS gene was isolated from the chromossome Xp.11.22-p.11-23. Case Report: The patient came to our hospital in march 2013 with trombocytopenia. He presented petechias since 2 month-old. CBC at first admission: WBC 20 860 cells/mm³: Neut: 2294 cells/mm³; Lymph: 16896 cells/mm³; Mono: 625 cells/mm³; HGB: 13.7g/dL, platelets:42000/mm³ MPV: 5,9. He presented mild eczema, otitis and gastrointestinal bleeding. The genetic testing showed an hemizigote intronic mutation c.560+5G>A, that has not been reported with a possible effect on splice site. The patient was treated with allogeneic bone marrow transplant and remains well. Conclusions: The Wiskott-Aldrich Syndrome is a severe disease whose the molecular mechanisms are not yet known. The genetic and molecular test are important to confirm the disease and try to elucidate the mechanisms of disease.

Introduction: Hereditary angioedema (HAE) is an unpredictable and potentially fatal disease. Although considerated a rare disorder, it’s estimated thousands of patients in Brazil, where are only few hundred cases identified. This study objective is to describe the severity, clinical findings and management of these patients before the specialized follow-up. Methods: The patients diagnosed with HAE were submitted to a standardized questionnaire. The data was assembled into a database and a descriptive analysis of it was performed. Variables such as frequency and severity of symptoms were evaluated. Results: Sixty and one patients diagnosed with HAE were evaluated. The maximum time between beginning of the symptoms and the diagnosis was 60 years, with median of 12 years. It was observed that 54 of the patients (88.5%) were hospitalized before the diagnosed, in 28 (45.9%) the hospitalization was necessary more than 10 times and 8 of them (13.1%) have been submitted to intubation or tracheostomy. When asked about the treatment of the crisis, 77.0% has received antihistaminic and 60.6%, corticosteroids. Nine of these patients have been submitted to long-term use of antihistaminic and 5 to long-term use of corticosteroids, both showing no response. Conclusions: The HAE is a challenging disease and it becomes even more difficult when we deal with the lack of knowledge about the disease and therefore the lack of adequate treatments. The awareness about the HAE is the only way to diagnose it in advisable time, prevent its repercussions and mortality, which can reach 56% of them when not treated.

Introduction: Attenuated androgens are the most widely available treatment in the prevention of Hereditary Angioedema (HAE) attacks in our midst. The purpose of this study is to describe the effectiveness and side effects of the long-term treatment with attenuated androgens in patients diagnosed with HAE. Methods: An observational cohort study was conducted with patients diagnosed with HAE and monitored at HC-UFMG. They were evaluated clinically and in laboratory and then submitted to a standardized questionnaire. Results: Forty-five patients made continuous use of danazol. After the beginning of the long-term treatment, a median of 0.28 crisis per year was observed and 18 (40%) patients became totally asymptomatic. The side effects associated with the use of the medication were observed in 35 (77.8%) patients submitted to long-term use. The most expressive alterations were weight gain in 29 (64.4%) patients, menstrual irregularities in 18 (56.2%), dislipidemia in 19 (65.5%). The acceptance of medication was considered good or very good by 32 (71.1%) patients and none of them had to discontinue using the medication because of its side effects. Conclusion: Danazol is necessary in the treatment of most patients where are limited treatment options available, and its presents well described benefits. There are relevant side effects associated with the use of this medication, which increases the need to use the minimal effective dose. The acceptance of the medication by the patients is considerably high, possibly due to an improvement in the quality of life gained during the treatment.

034

Wiskott-Aldrich Syndrome: Report of a new intronic mutation Cunha L.A.O.;Nunes J.B.S.; Nunes T.G.; Babeto, L.T.; Dias T.R.; Albert, M.; Glasmacher, J.; Pinto, J.A. Clinical Immunology Division, Hospital das Clínicas Universidade Federal de Minas Gerais; Munchen University

035

Hereditary Angioedema: Severity, Clinical Findings and Management Before Specialized Follow-up Minafra, F.G.; Fusaro, G.V.; Cunha, L.A.O.; Pinto, J.A. Division of Immunology, Department of Pediatrics, Federal University of Minas Gerais

036

Effectiveness of Long-term use of Danazol in Hereditary Angioedema: 10 years follow-up at the Hospital das Clínicas-UFMG Minafra, F.G.; Fusaro, G.V.; Cunha, L.A.O.; Pinto, J.A. Division of Immunology, Department of Pediatrics, Federal University of Minas Gerais

Griscelli syndrome (type 2)

037

038

Dias, T.R.; Cunha, L.A.O.; Pinto, J.A.

Neonatal onset autoinflammatory syndrome presenting with intravascular coagulopathy: a DIRA case report Dias, T.R.; Cunha, L.A.O.; Sette, A.M.O.; Souza, R.G.; Pinto, J.A. Clinical Immunology Division, Hospital das Clínicas Universidade Federal de Minas Gerais

Introduction: Griscelli Syndrome (GS) is a rare autosomal recessive disorder that manifests with silvery gray hair, which may be accompanied by neurologic abnormalities (type1), immunodeficiency (type 2), or no other abnormality (type 3). Unlike ChédiaK-Higashi syndrome the hair microscopy characteristically reveals large clumps of pigment distributed irregularly along the hair shaft. We describe an infant who had GS type 2. Case Report: AThis paper reports a 11-month-old female child with the clinical symptoms compatible with Griscelli syndrome. The patient was referred to the Immunology Division of Clinical Hospital of the Federal University of Minas Gerais at the age 4-month after episodes of fever, pallor and abdominal distension since 2 month of age. At birth she was noticed to have a silvery gray hair with a metallic sheen. She was the first child of a nonconsaguineous marriage. There was no history of silvery gray hair in any of the family members. There was no delay in the achievement of this child’s developmental milestones. Examination revealed abdomen enlarged with hepatomegaly and splenomegaly. Light microscopy of scalp hair showed large aggregates of pigment granules distributed irregularly along the hair shaft. The patient progressed to accelerated phase with pancytopenia, worsen of splenomegaly, recurrent fever, increase of ferritin and triglycerides, consumption fibrinogen and bone marrow showing hemophagocytosis. Treatment: Protocol of the Second International HLH-2004 (Hemophagocytic Lymphohistiocytosis Study Group) was promptly initiated with remission of accelerated phase. The patient waits compatible bone marrow donor, for curative treatment. Conclusions: Griscelli syndrome type 2 is rare primary immunodeficiency with defective mobilization of melanosome leading to specific findings on skin and hair. Certain immunological T and NK cell defects are associated with an uncontrolled T lymphocyte and macrophage activation. The accelerated phase of the disorder which leads to multiple organ damage can be controlled by immunosuppressives. However, the only curative treatment is bone marrow transplantation.

Introduction: Autoinflammatory syndromes are a newly understood group of conditions characterized by recurrent episodes of fever, rash, and serositis. In many of the inflammatory syndromes genetic abnormalities and consequent disordered regulation of the innate immune system lead to overactivity of proinflammatory cytocines and subsequent inflammatory symptoms. In deficiency of interleukin 1 receptor antagonist (DIRA), the action of these potent proinflammatory proteins is unopposed, leading to severe pustular rash and osteitis. Case report: This paper report 6 month-old male child with the clinical symptoms compatible with DIRA. The patient was referred to the Immunology Division of Clinical Hospital of the University of Minas Gerais at the age 1-month with symptoms which were presented in the immediate neonatal period: pustular rash, joint swelling, osteolitic lesions, respiratory distress and widespread coagulopathy. He was born at a 37 weeks of gestation in good condition. The parents are cousins. Laboratory data: Investigations demonstrated persistent leukocytosis and increased of reactive C protein. The patient progressed needing intermittent nonivasive ventilatory support and using corticosteroids to improve the rash. It was performed hole exome of the patient that showed homozygous mutation (nonsense) of IL1RN gene. Treatment: The patient awaits for specific medication (canaquinumabe-inhibitor IL-1β), which is available in our country. Conclusions: Deficiency of the interleukin-1-receptor antagonist (DIRA) is a autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. This condiction allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement.

Ă?ndice de autores

A Abramczuk, B.M.................................................................................................................................. 26, 27 Albert, M..................................................................................................................................................... 29 Andrade, M.V.M.......................................................................................................................................... 27 Atalla, A...................................................................................................................................................... 25 Azevedo, L.P............................................................................................................................................... 23

B Bahia, M...................................................................................................................................................... 19 Babeto, L.T.................................................................................................................................................. 29 Barbuto J.A.Ma........................................................................................................................................... 18 Barros, N.C................................................................................................................................................. 23 Batista, S.A................................................................................................................................................. 27 Bertolini, D.L............................................................................................................................................... 23 Bezerra, T.A................................................................................................................................................ 23 Brasil, R.A................................................................................................................................................... 22 Brito,T.......................................................................................................................................................... 21 Bustamante, J............................................................................................................................................. 18

C Calich V.L.G................................................................................................................................................ 18 Campeas, A.E............................................................................................................................................. 22 Cancela, C.S.P............................................................................................................................................ 20 Carneiro, L.E.P...................................................................................................................................... 21, 23 Casanova, J.L............................................................................................................................................. 18 Cavalcanti, R.S........................................................................................................................................... 18 Condack, C.E........................................................................................................................................ 20, 23 Costa T.Aa...................................................................................................................................................18 Costa, T........................................................................................................................................................18 Coutinho, J.D.C............................................................................................................................................26 32

Cruz, L.P.B..............................................................................................................................................18,19 Cruz, L.P.B..............................................................................................................................................18,19 Cunha, L.A.O................................................................................................18,19, 20, 25, 26, 27, 28, 29, 30

D Dias, A.D............................................................................................................................................... 20, 21 Dias, T.R.....................................................................................................................................19, 28, 29, 30 Di Gesu R.S.We.......................................................................................................................................... 18 Duarte, A.J.S................................................................................................................................... 20, 21, 23 Duarte, M.C.............................................................................................................................................. 24 Duarte, M.I.S.............................................................................................................................................. 22

F Feriotti C......................................................................................................................................................18 Ferr達o, M.S................................................................................................................................................. 22 Figueiredo B.C.G........................................................................................................................................ 28 Fusaro, G.V................................................................................................................................................. 29

G Glasmacher, J............................................................................................................................................. 29 Gontijo, F.P............................................................................................................................................ 24, 25 Greco D.B................................................................................................................................................... 27 Gryschek, R.C.B..........................................................................................................................................21 Guedes, L.M.A............................................................................................................................................ 24 Guimaraes, T.N........................................................................................................................................... 25

H Hallack Neto, A.E........................................................................................................................................ 24 Hauck, F.......................................................................................................................................................19 33

I Iqbal, A.........................................................................................................................................................18 Issac, C....................................................................................................................................................... 21

J Junior, E.B...................................................................................................................................................18 Junior, W.F.F................................................................................................................................................23

K Kossakowski, V.B........................................................................................................................................ 20

L Linhares, N.D.............................................................................................................................................. 19

M Macedo, I.T................................................................................................................................................. 24 Marega, L.F................................................................................................................................................. 27 Marques, C.O..............................................................................................................................................18 Marques, L.F.S............................................................................................................................................ 18 Mazzola, T.N................................................................................................................................................27 Mendes, R.P................................................................................................................................................ 18 Minafra, F.G................................................................................................................................................ 29 Miranda L.B.................................................................................................................................................25 Muniz Jr. R...................................................................................................................................................23

N Neto, C.A.....................................................................................................................................................18 Nunes, J.B.S...................................................................................................................18,19, 25, 27, 28, 29 34

Nunes, T.G.................................................................................................................................................. 29

O Ochs H.D.....................................................................................................................................................18 Oliveira, F.A.................................................................................................................................................23 Oliveira, J.B..................................................................................................................................... 19, 21, 26 Oliveira, T.C................................................................................................................................................ 20 Orii, N.M...................................................................................................................................................... 21 Oshiro, T...................................................................................................................................................... 21

P Paggiaro, A.O..............................................................................................................................................21 Pagliari, C....................................................................................................................................................22 Pelegrine, H.A.F.......................................................................................................................................... 22 Pena, S.D.J..................................................................................................................................................19 Pinto, J.A............................................................................................................18, 19, 25, 26, 27, 28, 29, 30 Pinto, P.C.G.............................................................................................................................. 23, 24, 25, 27 Portugal, C.A.A............................................................................................................................................25

R Ramalho, V.D........................................................................................................................................ 26, 27 Ribeiro, R.L................................................................................................................................................. 21 Rigato, P.O............................................................................................................................................ 20, 21

S Santos, F.G.M.S.......................................................................................................................................... 18 Santos, J.P............................................................................................................................................ 20, 28 Schimke L.F.................................................................................................................................................18 Schober, T....................................................................................................................................................19 35

Sette, A.M.O................................................................................................................................................30 Silva, C.S.M................................................................................................................................................ 20 Silva, G.R.P................................................................................................................................................. 22 Silva, M.L.....................................................................................................................................................19 Sotto, M.N....................................................................................................................................................22 Souza, R.G..................................................................................................................................................30 Souza, T.M............................................................................................................................................ 23, 24

T Teocchi, M.A......................................................................................................................................... 26, 27 Torgerson, T.................................................................................................................................................18

V Vargas, F.R..................................................................................................................................................27 Vasconcelos, D.M.................................................................................................................... 20, 21, 22 , 23 Vaz, G.H.M.................................................................................................................................................. 23 Vervloet, L.A................................................................................................................................................22 Vieira, A.K...............................................................................................................................................18,19 Vilela, M.M.S......................................................................................................................................... 26, 27

W Weber C.W.................................................................................................................................................. 18

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