Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency.
X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)- and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas alpha/beta and gamma/delta T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).
Speckmann
Carsten
C
Center for Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Pannicke
Ulrich
U
Wiech
Elisabeth
E
Schwarz
Klaus
K
Fisch
Paul
P
Friedrich
Wilhelm
W
Niehues
Tim
T
Gilmour
Kimberly
K
Buiting
Karin
K
Schlesier
Michael
M
Eibel
Hermann
H
Rohr
Jan
J
Superti-Furga
Andrea
A
Gross-Wieltsch
Ute
U
Ehl
Stephan
S
D000917:Antibody Formation / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002675:Child, Preschool; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D054503:Lymphoid Progenitor Cells / Q000276:immunology / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008297:Male; D017354:Point Mutation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy
C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D016692:Receptors, Antigen, T-Cell, gamma-delta