Clinical, immunological and pathological features of severe combined immunodeficiency (SCID) at PGIMER, Chandigarh Amit Rawat¹, Sagar Bhattad¹, Deepti Suri¹, Anju Gupta¹, Biman Saikia², Ranjana W Minz², Shobha Sehgal², Kohsuke Imai3, O Ohara4, YL Lau5, KW Chan5, S Singh¹ Department of Pediatrics¹ & Immunopathology², Postgraduate Institute of Medical Education & Research, Chandigarh Department of Pediatrics³, National Defense Medical College, Saitama, Japan, Kazusa DNA Research Institute4, Chiba, Japan Dept of Pediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong Introduction Severe combined immunodeficiency (SCID) is a group of heterogenous genetic defects with impaired cellular and humoral immunity Close to 50 causative genes implicated and the list keeps expanding each passing year Overlapping and similar clinical phenotype with different genetic etiologies Different mutations in same gene with diverse phenoptyes, amply exemplified by mutations in the RAG genes SCID is a medical emergency and universally fatal without a haematopoietic stem cell transplantation Newborn screening for SCID by T receptor excision circles (TRECs) initiated in several states of the US Gene therapy has also been tried in X-linked SCID and SCID due to adenosine deaminase deficiency Figure 3. Etiologic spectrum of infections Figure 4. IL2RG sequencing in 2 cases with X-linked SCID IL2RG: c.515T>G, p.Leu172Arg IL2RG: c. 737G>A, p.Trp246X Figure 5. Thymic atrophy with lymphoid depletion Figure 6. Invasive aspergillosis Materials and methods Thymus – < 2 gms N- 12 gms CD 3+ T cells CD 20+ B cells Analysis of clinical, immunological and pathological features of children diagnosed with SCID from 1995 to 2016 Data retrieved from files and records of Pediatric Immunodeficiency Clinic, Advanced Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India Gene sequencing results were also analyzed, in cases where these were available and correlated with the immunological phenotype Figure 6. Disseminated BCG infection Figure 6. Disseminated CMV infection Results Total number of cases 32 Male / Female ratio 3.57:1 Mean age at diagnosis (Range) 5.5±2.4 months (2-11 months) Mean interval between diagnosis and death 2 months No. of cases with confirmed genetic mutation 8 Absolute lymphocyte count at diagnosis 1.5 ± 0.84 x 109 /L (0.65-3.6 x 109 /L) Phenotype T-B+NK- SCID 8 T-B-NK+ SCID 12 T-B+NK+ SCID 3 T+B-NK+ SCID (Omenn syndrome) 4 T+B- NK+/- (Probable maternal engraftment) 5 Spleen Thymus Liver Adrenal Lungs Liver IHC Lung Lipoid Pneumonia Figure 6. Flow cytometry results in different forms of SCID Gene Exon Nucleotide change Codon change Type of mutation Pt1 IL2RG 4 C.515T>G L172R Point mutation Missense mutation Pt2 5 C.737G>A W246X Nonsense mutation Pt3 2 C.185G>A C62T Pt 4 C.216 G>A E68X Pt 5 RAG2 1 C.1247G>T W416L Pt6 DCLRE1C 1-3 Homozygous deletion of Exon 1-3 Deletion Pt7 IL7RA c616C>T R206X Pt8 RAG1 T-B-NK+ SCID T-B+NK+ SCID T+B-NK+ SCID (Omenn phenotype) T-B-NK- SCID (Omenn phenotype) Conclusion Patient Severe combined immunodeficiency is the most severe form of immunodeficiency It is universally fatal in resource limited settings without haematopoietic stem cell transplantation Disseminated BCG infection is common in SCID pts from developing countries with universal immunization for tuberculosis at birth A low lymphocyte count could serve as screening tool for SCID in developing countries where TREC based newborn screening is not available Decreased naïve T cells (CD45RA) in pt with SCID Decreased CD127 in case of T+B-NK+ SCID Increased HLA DR on T cells in Omenn syndrome Decreased CD 132 expression in X-linked SCID Contact: Dr Amit Rawat, Additional Professor, Advanced Pediatrics Centre, PGIMER, Chandigarh Email: rawatamit@yahoo.com