Polina Stepensky1, Baerbel Keller2, Oded Shamriz3, Caroline von Spee-Mayer2, David Friedmann2, Bella Shadur4,5,6, Susanne Unger2, Sebastian Fuchs2, Adeeb NaserEddin4, Nisreen Rumman7, Sara Amro7, Vered Molho Pessach8, Omar Abuzaitoun9, Raz Somech10, Orly Elpeleg11, Stephan Ehl2, Klaus Warnatz2. 1. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Hospital, POB 12000, 91200, Jerusalem, Israel. polina@hadassah.org.il. 2. Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany. 3. Pediatric Division, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 4. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Hospital, POB 12000, 91200, Jerusalem, Israel. 5. Immunology Division, Garvan Institute of Medical Research, Sydney, Australia. 6. Graduate Research School, The University of New South Wales, Sydney, Australia. 7. Pediatric Department, Makassed Hospital, Jerusalem, Israel. 8. Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 9. Nablus Specialty Hospital, Palestinian Authority, Nablus, Palestine. 10. Pediatric Department A and the Immunology Services, "Edmond and Lily Safra" Children's Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer affiliated with Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 11. Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Abstract
PURPOSE: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation. METHODS: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation. RESULTS: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation. CONCLUSIONS: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.
PURPOSE: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation. METHODS: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation. RESULTS: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation. CONCLUSIONS: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.
Entities:
Keywords:
IL2RG; Severe combined immunodeficiency; X-SCID; atypical SCID; common gamma chain; p.R222C mutation
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