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T(+) NK(+) IL-2 Receptor gamma Chain Mutation: a Challenging Diagnosis of Atypical Severe Combined Immunodeficiency


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 gamma chain (gammac) 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 naive 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.

Type Journal
ISBN 1573-2592 (Electronic) 0271-9142 (Linking)
Authors Stepensky, P.; Keller, B.; Shamriz, O.; von Spee-Mayer, C.; Friedmann, D.; Shadur, B.; Unger, S.; Fuchs, S.; NaserEddin, A.; Rumman, N.; Amro, S.; Molho Pessach, V.; Abuzaitoun, O.; Somech, R.; Elpeleg, O.; Ehl, S.; Warnatz, K.
Responsible Garvan Author Dr Bella Shadur
Published Date 2018-05-01
Published Volume 38
Published Issue 4
Published Pages 527-536
Status Published in-print
DOI 10.1007/s10875-018-0514-y
URL link to publisher's version