Clinical Features And Immunological Analysis Of Patients With Alps-related Disorder And Periodic Fever Syndrome

PART Ⅰ CLINICAL AND IMMUNOLOGICAL FEATURES OF PATIENTS WITH ALPS-RELATED DISORDERCHAPTER Ⅰ CLINICAL AND IMMUNOLOGICAL EATURES AND REPERTOIRE OF TWO PATIENTS WITH RASGRP1 MUTATIONObjective: To explore the characteristics of clinical,immunophenotype,TCR and BCR repertoire in two patients of ALPS-like patients with RasGRP1 mutations.Methods: Clinical and immunological analysis were performed and reported.Repertoire of TCR,CD21 high BCR,CD21 low BCR was analyzed by high-throughput sequencing.Results: The patients were suffering from recurrent infection,lymphadenopathy/hepatosplenomegaly and autoimmune.The percentage of follicular helper T cell,CD21 lowB cells were increased.The marker of B cell activation and pERK in BCR pathway downstream were decreased.Repertoire of TCR,CD21 high BCR,CD21 low BCR showed a dominant combination of VD and VJ combinations in patients.The cluster analysis showed that the V genes of the patients were clustered based on the frequency of usage and distance analysis.The length of CDR3 in patients was shorter compared with normal control.Restriction of repertoire diversity was shown in the index of diversity.Conclusion: This study confirmed patients with ALPS-like diseases of RasGRP1 mutation were characterized by recurrent infection,lymphadenopathy/hepatosplenomegaly and autoimmune.Laboratory tests showed impaired B cell activation and ERK phosphorylation in BCR pathway downstream.We speculated that the restriction of repertoire diversity may be related to the process of pathogenic immune response defects and autoimmune processes.CHPTER Ⅱ RAS-ASSOCIATED LYMPHOPROLIFERATIVE DISEASE WITH SOMATIC KRAS MUTATIONObjective: To explore the clinical phenotype of patients with Ras-associated lymphoproliferative disease(RALD)with somatic KRAS mutation.Methods: One RALD patient with KRAS mutation was reported in this study and the clinical features were analyzed.Such kind of patients described before were also searched from the literature and summarized.Results: We described the patient presenting with lymphadenopathy,hepatosplenomegaly,thrombocytopenia and recurrent infections.The patient had normal percentage of TCRαβ+CD4-CD8-T cells and impaired IL-2 withdrawal-induced apoptosis.Genetic test revealed KRAS mutations(c.37G>A,p.G13C)in the patient.A total of 16 RALD cases with KRAS somatic mutation were retrieved from the literature.Based on the available information,chronic lymphoproliferation and autoimmune abnormalities were shown in all patients.A total of five missense mutations(G13C,G13 D,G12D,G12 A,G12S)of KRAS have been identified so far.Conclusion: RALD with somatic KRAS mutation often manifests as hepatosplenomegaly,lymphoproliferation,autoimmune hematocytopenia.RALD should be considered in the patients with autoimmune proliferation,recurrent infections,plus normal TCRαβ+DNT cells and impaired IL-2 withdrawal-induced apoptosis.PART Ⅱ CLINICAL FEATURES OF 17 CASES WITH PERIODIC FEVER SYNDROMEObjective: To analysis the clinical features of periodic fever syndrome(PFS)and improve the understanding of this syndrome.Methods: The 17 cases with PFS were recruited from February,2014 to June,2018 in The University of Hong Kong-Shenzhen Hospital.The clinical features,laboratory data and genetic results were retrospectively analysed.Results: A total of 11 cases were diagnosed as periodic fever,aphthous stomatitis,pharyngitis and adenitis syndrome(PFAPA).The median duration of individual fever episodes 4.5 days,the highest temperature of each episode 40 ℃ and the median interval between episodes 4 weeks.A total of 6 cases were diagnosed as familial Mediterranean fever(FMF).The median duration of individual fever episodes 3.25 days,the highest temperature of each episode 40℃ and the median interval between episodes was 4 weeks.Of the 11 PFAPA patients,11(100%)had pharyngitis,7(63.6%)cervical adenitis,7(63.6%)aphthous stomatitis,3(27.3%)abdominal pain and 1(9.1%)skin rashes.Of the 6 FMF patients,2(33.3%)had abdominal pain,2(33.3%)pharyngitis,2(33.3%)cervical adenitis and 2(33.3%)aphthous stomatitis.Laboratory tests revealed elevated white blood cell(WBC)counts,C-reactive protein(CRP)and erythrocyte sedimentation rate(ESR)but normal procalcitonin(PCT)level in all PFS patients during fever.The microbiological workups and autoantibodies tests were negative.Of the 11 PFAPA patients,4 had a variant allele of MEFV.The 6 FMF patients had 2-3 mutant allele of MEFV.Conclusion: PFS syndrome should be considered in patients suffering from periodic fevers of unknown origin,along with pharyngitis and/or cervical adenopathy.CRP and ESR values were substantially elevated,whereas PCT values were within normal levels.We propose that normal PCT is helpful in making diagnosis and distinguishing febrile attacks from infections.PART Ⅲ CLINICAL AND IMMUNOLOGICAL FEATURES OF X-LINKED AGAMMAGLOBULINAEMIA PATIENTS COMPLICATED WITH HEATOLOGICAL MALIGNANCYObjective: To improve clinicians’ understanding of X-linked agammaglobulinaemia(XLA)complicated with hematological malignancy.Methods: We described the clinical characteristics and immunological features of the first XLA patient complicated with anaplastic large cell lymphoma in China.The relevant literatures at home and abroad were searched and analyzed.Results: The patient presented recurrent respiratory tract infections,otitis media,sinusitis and complicated with anaplastic large cell lymphoma at the age of 5 years.The percentage of peripheral B cells and serum immunoglobulin levels were markedly reduced.Genetic sequencing showed c.1909-2A>G mutation of BTK.Hematological malignancy has been reported in 9 patients with XLA abroad.Conclusion: This study suggests that XLA has a risk of hematological malignancy,so we should raise awareness of the complication.