Combined immunodeficiency due to JAK3 mutation in a child presenting with skin granuloma

• Published in: Journal of allergy and clinical immunology Vol. 137; no. 3; pp. 948 - 951.e5
• Main Authors: Scarselli, Alessia, MD, Di Cesare, Silvia, BSc, Di Matteo, Gigliola, BSc, PhD, De Matteis, Arianna, MD, Ariganello, Paola, MD, Romiti, Maria Luisa, BSc, PhD, Cascioli, Simona, BSc, De Vito, Rita, MD, Bertaina, Alice, MD, PhD, Locatelli, Franco, MD, PhD, Gaspar, H. Bobby, MD, PhD, Aiuti, Alessandro, MD, PhD, Rossi, Paolo, MD, PhD, Gilmour, Kimberly, MD, PhD, Cancrini, Caterina, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2016; Elsevier Limited
• Subjects: Age; Allergy and Immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biopsy; Blood; Child, Preschool; Deoxyribonucleic acid; Diagnosis, Differential; Diarrhea; DNA; DNA repair; Female; Gene Expression; Genomes; Granuloma - diagnosis; Humans; Immunoglobulins; Immunology; Immunophenotyping; Infections; Janus Kinase 3 - genetics; Janus Kinase 3 - metabolism; Lymphocytes; Mutation; Patients; Phosphorylation; Protein expression; Proteins; Severe Combined Immunodeficiency - diagnosis; Severe Combined Immunodeficiency - genetics; Skin Diseases - diagnosis; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tetanus
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.09.017

The R403H mutation is present in the Catalogue of Somatic Mutations In Cancer database and was found to be associated with severe combined immunodeficiency (SCID) in a single Chinese patient in whom it was present in a compound heterozygous state (the other mutation being R1085Q).1 The R403H mutation is predicted to affect the protein stability by MuStab and MUpro Web servers and is defined as a disease-related variant by the SNP&GO server. Because of the severe immunological alterations associated with worsening of immunodysregulation and organ infiltration by autoreactive T cells, we decided to perform HLA-partially matched hematopoietic stem cell transplantation (HSCT) depleted of TCR-αβ+/CD19+ lymphocytes using the father as donor. Appendix Parameter Patient (age, 27 mo) Normal values for age White blood cell per mm3* 5,830 5,200-11,000 Lymphocyte phenotype (absolute count per mm3) 30.7% (1.790) 1,400-5,500 CD3+[dagger] 21.5% (384) 52% to 92% (850-4,300) CD4+[dagger] 15% (268) 25% to 66% (500-2,700) CD8+[dagger] 4.5% (80.5) 9% to 49% (200-1,800) CD16+CD56+[dagger] 7.6 % (136) 2% to 25% (61-510) CD19+[dagger] 69% (1.236) 8% to 39% (180-1,300) CD4+CD31+CD45RA+ (RTE)[dagger] 0.3% (0.8) 37% to 100% (190-2,600) CD4+CD27+CD45RA+ (naive)[dagger] 0.5% (1.34) 52% to 92% (300-2,300) CD8+CD27+CD45RA+CCR7+ (naive)[dagger] 0.2% (0.16) 19% to 100% (53-1,100) CD4+HLADR+* 41% 3% to 12% (30-140) CD8+HLADR+* 56.7% 7% to 37% (50-340) Regulatory T (CD4+CD25+CD127low FoxP3high) 6.4% 4.86% to 7.09% CD3+CD4+IFNγ+ 45.7% 6.9% to 18.1% Lymphoproliferation test (103 cpm)[double dagger] Unstimulated 0.8 <2 PHA (2.5 μg/mL) 7.1 >30 PHA + IL-2 (20 U/mL) 9.4 >40 PWM (0.35 μg/mL) 6.9 >18 OKT3 (1.5 μg/mL) 2.8 >20 OKT3 + IL-2 6.3 >30 OKT3 + aCD28 3.1 >25 PMA + IONO 34.1 >20 Unstimulated 0.7 <2 Candida 1 >5 Tetanus 0.8 >5 TCRVβ spectratyping Percentage of polyclonal families (CD3+) 22.8% >70% TREC (copies/100 ng DNA) <25 1,106-15,787 Serum immunoglobulin levels§ IgG (mg/dL)§ 676 462-1,710 IgA (mg/dL)§ 24 27-173 IgM (mg/dL)§ 26 62-257 IgE (kU/L)|| <2 1.1-49.0 Blood group isohemagglutinins (IgM-anti-B) Absent (>1:8) IgG subclasses|| IgG1 576 290-970 IgG2 17.8 36-214 IgG3 10 80-630 IgG4 <0.35  Specific antibodies Tetanus toxoid (IU/mL) 0.5 >0.1 Hepatitis B (mUI/mL) 33.26 >=11 Hemophilus influenzae (mg/L) 0.3 >0.15 Pneumococcus (mg/L)¶ <3.3 >35 B-cell subpopulations# CD19+27+ 1.8% 8% to 15% CD27+IgM+ 1.4% 5% to 11% CD27+IgM- 0.16% 2% to 5% CD20+CD24++CD38++ 27.6% 10% to 30% CpG stimulation Lymphocyte proliferate but differentiate poorly in plasma cells and produce only IgM+  Table E1 Summary of immunological data Patient data have been collected on the first admission in the Immuno-Infectivology Unit.