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A CASE of TTC7A DEFICIENCY Presented by Dr Bella Shadur Case

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A CASE of TTC7A DEFICIENCY Presented by Dr Bella Shadur Case APID2016 Case Summary: A CASE OF TTC7A DEFICIENCY Presented by Dr Bella Shadur Case summary 4/12 male Non-consanguineous, Anglo-Saxon heritage Presented with severe failure to thrive and diarrhoea o Initially worked up for cow’s milk protein intolerance o No improvement with various HA formulas Colonoscopy: severe inflammation of the entire colon Referred to immunology: could this be IPEX or IL10/IL10R deficiency? Baseline immune work-up demonstrated: o IgG 0.29 (↓), IgA 0.29 (normal), IgM 0.08 (↓), IgE < 5 o Normal lymphocyte subsets o T cell phenotype: normal proliferation to PHA and anti-CD3, STAT5p, TRECs, naïve T cells o Neutrophils: normal NBT and DHR o IPEX: normal FoxP3, CD25 staining, endocrine autoantibodies NAD o HLH: ferritin 50, SAP, XIAP, perforin, NK cell degranulation normal Enrolled in NEOPICS study (Inter-National Early Onset Paediatric IBD Cohort Study) o WES: compound heterozygous for two novel mutations in the TTC7A gene o Segregated in parents (both of whom asymptomatic) o Both predicted to be pathogenic, although one required confirmation via the creation of a DNA ladder Patient stabilised on subcutaneous immunoglobulin and total parenteral nutrition Ongoing monitoring of immune parameters, particularly T cell function For consideration of bone marrow transplant Learning points TTC7A deficiency = Tetratricopeptide repeat domain 7A Located on chromosome 2p21, autosomal recessive Deficiency leads to severe pathology of the gut and the immune system o Gut disease can range from inflammatory bowel disease to multiple intestinal atresia o Immune system defects can range from combined immune deficiency to SCID o The balance of these defects determines the priorities of management Poor genotype-phenotype correlation, even within families Presents soon after birth and is almost universally fatal within the first 1-2yrs of life Pathogenesis is still being discovered but two pathways appear affected: o PI4KA-TTC7A-EFRB3 pathway o TTC7A-RhoA Kinase (ROCK) inhibition o Both pathways appear important for cytoskeletal development, cell adhesion/polarization/migration; defects lead to increased cell apoptosis o Impaired intestinal epithelial polarity impacts on the secretory role of the gut . Remains unclear if gut disease is solely intrinsic gut pathology or partially immune-mediated as well o Impaired adhesion of T cells and dendritic cells Treatment: TPN, microbial prophylaxis, immunoglobulin replacement, immunosuppression, transplant 7 HSCTs reported in the literature, only one survived but has recurrent multiple intestinal atresia References 1. Avitzur Y, Guo C, Mastrapolo LA, Bahrami E, Chen H et al. Mutations in Tetratricopeptide Repeat Domain 7A Result in a Severe Form of Very Early Onset Inflammatory Bowel Disease. Gastroenterology 2014; 146 (4): 1028-1039. 2. Notarangelo, L.D. Multiple Intestinal Atresia with Combined Immune Deficiency. Curr Opin Pediatr 2014; 26(6): 690-696. 3. Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, et al. Multiple Intestinal Atresia with Combined Immune Deficiency Related to TTC7A Defect is a Multiorgan Pathology. Medicine 2014; 93(29): 1-9. 4. Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne AE, Debre M et al. Immune Deficiency- related Enteropathy-Lymphocytopenia-Alopecia Syndrome Results from Tetratricopeptide Repeat Domain 7A Deficiency. J Allergy Clin Immunol 2014; 134: 1354-64. 5. Chen R, Giliana S, Lanzi G, Mias GI, Lonardi S et al. Whole-exome Sequencing Identifies Tetratricopeptide Repeat Domain 7A (TTC7A) Mutations for Combined Immunodeficiency with Intestinal Atresias. J Allergy Clin Immunol 2013; 132: 656-64. 6. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, et al. TTC7A Mutations Disrupt Intestinal Epithelial Apicobasal Polarity. J Clin Invest 2014; 124(1): 328-337. 7. Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, et al. Exome Sequencing Identifies Mutations in the Gene TTC7A in French-Canadian Cases with Hereditary Multiple Intestinal Atresia. J Med Genet 2013; 50: 324-329. 8. Woustos S, Aytekin C, Salzer E, Conde CD, Apaydin S, et al. Hypomorphic Mutations in TTC7A Causes Combined Immunodeficiency with Mild Structural Intestinal Defects. Blood 2015; 125(10): 1674-1675. .
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