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 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 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 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 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

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