scholarly journals Clinical characteristics and genetic analysis of A20 haploinsufficiency

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dan Zhang ◽  
Gaixiu Su ◽  
Zhixuan Zhou ◽  
Jianming Lai
Keyword(s):  
Genetic Testing ◽  
Rheumatoid Factor ◽  
Immunosuppressive Agents ◽  
Disease Patient ◽  
Coombs Test ◽  
Gradual Improvement ◽  
Genetic Characteristics ◽  
Tnfaip3 Gene ◽  
Oral Ulcers ◽  
Tnf Α

Abstract Purpose To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). Methods:The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed. Result Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNFα antagonist, patient 2 was treated with TNF α antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses. Conclusion HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene. It may present as Behçet-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Behçet-like syndrome to achieve early diagnosis and accurate treatment.

Clinical characteristics and genetic analysis of 3 A20 Haploinsufficiency patients

2021 ◽  
Author(s):  
Dan Zhang ◽  
Zhixuan Zhou ◽  
Jianming Lai ◽  
Gaixiu Su
Keyword(s):  
Genetic Testing ◽  
Age Of Onset ◽  
Immunosuppressive Agents ◽  
Disease Patient ◽  
Gastrointestinal Symptoms ◽  
Coombs Test ◽  
Gradual Improvement ◽  
Genetic Characteristics ◽  
Tnfaip3 Gene ◽  
Oral Ulcers

Abstract Backguound To evaluate the clinical and genetic characteristics of 3 children with HA20. Methods The clinical and genetic testing data of 3 children with HA20 treated at CIP between August 2016 and October 2019 were retrospectively analysed. Results Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. For laboratory examination, In patient 1, the WBC,CRP and AESR showed high. In patient 2, the WBC was normal, but CRP and AESR showed high. In patient 3, the WBC, CRP, and AESR showed high. Patient 2 was positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that the 3 patients were heterozygous for mutations in the TNFAIP3 gene. For treatment, patient 1 used TNFα antagonist and thalidomide, patient 2 used TNFαantagonist and sulfasalazine, and patient 3 used hormones and thalidomide. Patients 1 and 2 were followed up for 4 and 3 months, respectively. There was improvement in joint and gastrointestinal symptoms, inflammatory indices and RF were normal, dsDNA and Coombs test became negative. Patient 3 was treated at an outside hospital and showed gradual improvement in oral ulcers and perianal abscesses. Conclusion HA20 is a single-gene auto-inflammatory disease caused by mutation in the TNFAIP3 gene. It presents clinically as a Behçet-like syndrome and can present as various other autoimmune diseases as well. Hormones and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with an early age of onset or Behçet-like presentation to achieve early diagnosis and accurate treatment.

scholarly journals Analysis of the Clinical and Genetic Characteristics of 3 Cases of A20 Haploinsufficiency

2020 ◽  
Author(s):  
Dan Zhang ◽  
Zhixuan Zhou ◽  
Jianming Lai ◽  
Gaixiu Su
Keyword(s):  
Genetic Testing ◽  
Age Of Onset ◽  
Immunosuppressive Agents ◽  
Disease Patient ◽  
Gastrointestinal Symptoms ◽  
Coombs Test ◽  
Gradual Improvement ◽  
Genetic Characteristics ◽  
Tnfaip3 Gene ◽  
Oral Ulcers

Abstract Background To evaluate the clinical and genetic characteristics of 3 children with HA20. Methods The clinical and genetic testing data of 3 children with HA20 treated at CIP between August 2016 and October 2019 were retrospectively analysed. Results Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. For laboratory examination, In patient 1, the WBC,CRP and AESR showed high. In patient 2, the WBC was normal, but CRP and AESR showed high. In patient 3, the WBC, CRP, and AESR showed high. Patient 2 was positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that the 3 patients were heterozygous for mutations in the TNFAIP3 gene. For treatment, patient 1 used TNFα antagonist and thalidomide, patient 2 used TNFαantagonist and sulfasalazine, and patient 3 used hormones and thalidomide. Patients 1 and 2 were followed up for 4 and 3 months, respectively. There was improvement in joint and gastrointestinal symptoms, inflammatory indices and RF were normal, dsDNA and Coombs test became negative. Patient 3 was treated at an outside hospital and showed gradual improvement in oral ulcers and perianal abscesses. Conclusion HA20 is a single-gene auto-inflammatory disease caused by mutation in the TNFAIP3 gene. It presents clinically as a Behçet-like syndrome and can present as various other autoimmune diseases as well. Hormones and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with an early age of onset or Behçet-like presentation to achieve early diagnosis and accurate treatment.

scholarly journals Clinical and genetic characteristics of PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dan Zhang ◽  
Gaixiu Su ◽  
Yan Liu ◽  
Jianming Lai
Keyword(s):  
Genetic Testing ◽  
Pyoderma Gangrenosum ◽  
White Blood Cells ◽  
Skin Lesions ◽  
Coombs Test ◽  
Genetic Characteristics ◽  
Normal Patient ◽  
Angina Patient ◽  
Reactive Protein ◽  
Pyogenic Arthritis

Abstract Objective To summarise the clinical and genetic characteristics of three children with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. Methods This study retrospectively analysed the clinical and genetic data of three children with PAMI syndrome in our hospital between April 2018 and January 2020. Results One male and two female children were 6 years and 5 months, 8 years and 7 months, and 13 years and 3 months of age. All three patients had a recurrent blood trilineage hypoplasia and splenomegaly. Patient 1 had pyoderma gangrenosum, and Ludwig’s angina. Patient 2 had pyogenic arthritis, and pyoderma gangrenosum. Patient 3 had hepatomegaly, pyogenic arthritis, and pulmonary hypertension. Laboratory tests revealed that all three children had elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Patient 1: C-antineutrophilic cytoplasmic antibodies(c-ANCA), positive; antiglobulin test (Coombs), positive. Patient 2: blood zinc, 4.38 mg/L (elevated). Patient 3: Antinuclear antibodies (ANA), 1:100, β2 glycoprotein I, positive; Coombs test, positive; RF, 28.3 U/ml (elevated); C3, 0.77 g/L (decreased). Genetic testing showed that all 3 patients had PSTPIP1 c.748G > A (p.E250K) spontaneous heterozygous mutations, suggesting the diagnosis of PAMI syndrome. Patient 1 was treated with a combination of methylprednisolone and cyclosporine for 8 months. The patient did not develop new skin lesions. The blood count showed mild neutropenia. The spleen was considerably retracted and the CRP became normal. Patient 2 was treated with etanercept and methylprednisolone. The patient had no further arthralgias and pyoderma gangrenosum showed improvement. The spleen was smaller than before. White blood cells were shown to be approximately 2–3 × 109/L. The haematocrit, platelets, CRP, and AESR were normal. Patient 3 was treated with methylprednisolone, methotrexate, and infliximab 4 times. The patient’s joint symptoms disappeared gradually and the liver retracted markedly. The pulmonary artery pressure returned to normal. Moreover, Coombs test result was negative. CRP and AESR were lower than before. Conclusion PAMI syndrome can manifest as pyogenic arthritis, pyoderma gangrenosum, acne, and trilineage hypoplasia, as well as autoimmune diseases. Glucocorticoid and immunosuppressive therapy are partially effective and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing is helpful to confirm diagnosis.

scholarly journals Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 997
Author(s):  
Sophie E. van Peer ◽  
Corine J. H. Pleijte ◽  
Ronald R. de Krijger ◽  
Marjolijn C. J. Jongmans ◽  
Roland P. Kuiper ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Renal Tumor ◽  
Molecular Characteristics ◽  
Extensive Literature ◽  
Cystic Nephroma ◽  
Limited Information ◽  
Review Of The Literature ◽  
Genetic Characteristics ◽  
Excellent Outcome

In children presenting with a predominantly cystic renal tumor, the most likely diagnoses include cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN). Both entities are rare and limited information on the clinical and molecular characteristics, treatment, and outcome is available since large cohort studies are lacking. We performed an extensive literature review, in which we identified 113 CPDN and 167 CN. The median age at presentation for CPDN and CN was 12 months (range: 3 weeks–4 years) and 16 months (prenatal diagnosis–16 years), respectively. No patients presented with metastatic disease. Bilateral disease occurred in both entities. Surgery was the main treatment for both. Two/113 CPDN patients and 26/167 CN patients had previous, concomitant, or subsequent other tumors. Unlike CPDN, CN was strongly associated with somatic (n = 27/29) and germline (n = 12/12) DICER1-mutations. Four CPDN patients and one CN patient relapsed. Death was reported in six/103 patients with CPDN and six/118 CN patients, none directly due to disease. In conclusion, children with CPDN and CN are young, do not present with metastases, and have an excellent outcome. Awareness of concomitant or subsequent tumors and genetic testing is important. International registration of cystic renal tumor cohorts is required to enable a better understanding of clinical and genetic characteristics.

scholarly journals Preimplantation genetic testing for aneuploidy in uterus transplant patients

2021 ◽  
Vol 15 ◽  
pp. 263349412110098
Author(s):  
Rhea Chattopadhyay ◽  
Elliott Richards ◽  
Valerie Libby ◽  
Rebecca Flyckt
Keyword(s):  
Genetic Testing ◽  
In Vitro Fertilization ◽  
Immunosuppressive Agents ◽  
Live Birth Rate ◽  
Preimplantation Genetic Testing ◽  
Vitro Fertilization ◽  
Uterus Transplantation ◽  
Advantages And Disadvantages ◽  
Dilation And Curettage

Uterus transplantation is an emerging treatment for uterine factor infertility. In vitro fertilization with cryopreservation of embryos prior is required before a patient can be listed for transplant. Whether or not to perform universal preimplantation genetic testing for aneuploidy should be addressed by centers considering a uterus transplant program. The advantages and disadvantages of preimplantation genetic testing for aneuploidy in this unique population are presented. The available literature is reviewed to determine the utility of preimplantation genetic testing for aneuploidy in uterus transplantation protocols. Theoretical benefits of preimplantation genetic testing for aneuploidy include decreased time to pregnancy in a population that benefits from minimization of exposure to immunosuppressive agents and decreased chance of spontaneous abortion requiring a dilation and curettage. Drawbacks include increased cost per in vitro fertilization cycle, increased number of required in vitro fertilization cycles to achieve a suitable number of embryos prior to listing for transplant, and a questionable benefit to live birth rate in younger patients. Thoughtful consideration of whether or not to use preimplantation genetic testing for aneuploidy is necessary in uterus transplant trials. Age is likely a primary factor that can be useful in determining which uterus transplant recipients benefit from preimplantation genetic testing for aneuploidy.

AB0527 PHARMACOGENETICS AND PHARMACODYNAMICS OF RESPONSE TO APREMILAST IN A PHASE 3 CLINICAL STUDY IN SUBJECTS WITH ACTIVE BEHÇET’S DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1560.1-1561
Author(s):  
J. Maranville ◽  
I. Medvedeva ◽  
R. Yang ◽  
M. Chen ◽  
L. R. Fang ◽  
...  
Keyword(s):  
Regression Model ◽  
Clinical Response ◽  
Negative Correlation ◽  
Th17 Cells ◽  
Treg Cells ◽  
Interferon Γ ◽  
Positive Correlation ◽  
Percent Change ◽  
Oral Ulcers ◽  
Tnf Α

Background:Apremilast (APR), an oral phosphodiesterase 4 (PDE4) inhibitor, modulates inflammatory mediators1and has demonstrated efficacy in treating oral ulcers in a phase III Behçet’s syndrome study (BCT-002 [RELIEF]).2Objectives:To conduct an exploratory analysis of genetic polymorphisms, plasma biomarkers, and blood leukocytes with clinical response in RELIEF.Methods:Subjects with active Behçet’s disease (BD) were randomized (1:1) to APR 30 mg twice daily or placebo (PBO). The primary clinical efficacy endpoint was the area under the curve for the number of oral ulcers through Week 12 (AUCWk0-12). Among the 207 subjects enrolled, 140 provided consent for DNA genotyping, 116 for plasma biomarker testing, and 96 for leukocyte subset testing. Genotyping was performed on the Illumina Omni2.5 BeadChip (Covance Genomics Laboratory). TNF-α, IL-6, interferon-γ, and IL-17A levels were measured using Simoa Single Molecule Array; IL-8 and IL-23 were measured using the Human DiscoveryMAP multiplex panel (Myriad RBM). Th17, Treg, and CD3 T cells were counted using bisulfite-specific RT-PCR (Epiontis Gmbh). A rank ANCOVA model was used to estimate between-treatment differences (APR vs. PBO) in percent change from baseline for each biomarker/leukocyte subtype over the 12 weeks of treatment. Within each treatment group, the correlation of percent change from baseline at Week 12 in biomarker/leukocyte subtype with the primary efficacy endpoint AUCWk0-12was examined using a univariate regression model. A separate regression model was used to assess the interaction between treatment and the biomarker/leukocyte subtype clinical response.Results:Pharmacogenetic analysis of BD risk variants in HLA-B, IL-10, TLR2, ACE, TNF, GIMAP, PDGFRL, and UBAC2 + 55 genes associated with PDE4 biology yielded no candidate variants that were significantly associated with response to APR or PBO at a Bonferroni-correctedPvalue of 2 x 10−6. Clinical response to APR with respect to HLA-B51 yielded an odds ratio (OR) of 1.21 (95% CI, 0.53-2.75), indicating no significant relationship (Figure 1). Pharmacodynamic changes for IL-6, IL-3, IL-17A, IL-23, and TNF-α were not statistically significant. APR treatment was associated with a significant change in interferon-γ (mean: +107.4%; median: −19.2%) vs. PBO (mean: +78.8%; median: +7.9%) (P=0.0077). Using a univariate regression model, TNF-α showed strong positive correlation with AUCWk0-12in the APR group (r=0.90;P=0.0140); IL-8 had weak positive correlation with AUCWk0-12in the APR group (r=0.04;P=0.0333). A significant negative correlation was observed between the percent change from baseline in the number of Th17 cells and AUCWk0-12in the APR group (r=−0.79;P=0.0392) and a significant positive correlation was observed with the percent change from baseline in the number of Treg cells and AUCWk0-12in the PBO group (r=0.94;P=0.0182). Of all the biomarkers and leukocyte subtypes examined in a regression model using treatment as a factor, only Treg had a statistically significant treatment interaction (P=0.0069).Conclusion:Although there were no genetic predictors of clinical response to APR treatment, strong correlation was observed between the percent change from baseline in plasma TNF-α with AUCWk0-12in the APR group. A negative correlation was observed between percent change from baseline in Th17 cells and AUCWk0-12in the APR group and a positive association was observed between Treg cells and AUCW0-12in the PBO group.References:[1]Schafer P.Biochem Pharmacol. 2012; 83:1583-1590. 2. Hatemi G, et al. Presented at: ACR/ARHP Annual Meeting; November 8–13, 2019; Atlanta, GA. Presentation 0946.Disclosure of Interests: :Joseph Maranville Employee of: Celgene Corporation – employment at the time of study conduct, Irina Medvedeva Employee of: Celgene Corporation – employment at the time of study conduct, Robert Yang Employee of: Celgene Corporation – employment at the time of study conduct, Mindy Chen Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of the conduct, Lorraine (Ruoying) Fang Employee of: Celgene Corporation – employment at the time of study conduct, Sandra Collazo Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of the conduct, Shannon McCue Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of the conduct, Peter Schafer Employee of: Bristol-Myers Squibb – employment; Celgene Corporation – employment at the time of study conduct

scholarly journals Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers

2020 ◽  
Vol 21 (21) ◽  
pp. 7873
Author(s):  
Agostino Bucalo ◽  
Federica Rega ◽  
Arianna Zangrilli ◽  
Valentina Silvestri ◽  
Virginia Valentini ◽  
...  
Keyword(s):  
Rare Allele ◽  
Paradoxical Effect ◽  
Nucleotide Polymorphisms ◽  
Necrosis Factor Alpha ◽  
Genetic Characteristics ◽  
Immune Mediated ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Factor Alpha ◽  
Disease Specific

Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to identify disease-specific markers of the paradoxical effect. A total of 161 IBD and psoriatic patients treated with anti-TNF-α drugs were included in the study. Of these patients, 39 developed PP. All patients were characterized for the main clinical–pathologic characteristics and genotyped for six candidate single nucleotide polymorphisms (SNPs) selected for their possible role in PP susceptibility. In IBD patients, the onset of PP was associated with female sex, presence of comorbidities, and use of adalimumab. IBD patients with PP had a higher frequency of the TNF-α rs1799964 rare allele (p = 0.006) compared with cases without the paradoxical effect, and a lower frequency of the human leucocyte antigen (HLA)-Cw06 rs10484554 rare allele (p = 0.03) compared with psoriatic patients with PP. Overall, these findings point to specific clinical and genetic characteristics of IBD patients with PP and provide data showing that genetic variability may be related to the paradoxical effect of anti-TNF-α drugs with possible implications into clinical practice.

scholarly journals A case of intestinal Behcet’s disease under Adalimumab

2017 ◽  
Vol 4 (3) ◽  
pp. 62
Author(s):  
David T. Dulaney ◽  
Wassem Juakiem ◽  
Katherine Cebe ◽  
Angelo H. Paredes
Keyword(s):  
Behçet’S Disease ◽  
Behcet’S Disease ◽  
Behçet's Disease ◽  
Immunosuppressive Agents ◽  
African American Female ◽  
Behcet's Disease ◽  
Oral Ulcers ◽  
Adalimumab Therapy ◽  
Tnfα Inhibitors ◽  
Tnfα Inhibitor

Behcet’s disease (BD) is a multisystem mucocutaneous inflammatory condition characterized by recurrent genital and oral ulcers, ocular inflammation, and can involve the gastrointestinal tract. Treatment involves the usage of immunosuppressive agents to control the disease with glucocorticoids utilized for treatment of flares. Tumor necrosis factor inhibitors are frequently used to control the disease as well. We present the case of a 40 years old African American female presenting with intestinal BD that was refractory to adalimumab therapy. In conjunction with glucocorticoids, the patient’s intestinal disease was controlled with infliximab therapy. Currently, there have been no studies comparing the efficacy of TNFα inhibitors on the treatment of BD. Future studies are needed to compare the efficacy of TNFα inhibitor agents in the treatment of intestinal manifestations of BD.

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