Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome

Abstract X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (γc) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.

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A novel splice-site mutation in the common gamma chain (?c) geneIL2RG results in X-linked severe combined immunodeficiency with an atypical NK+ phenotype

Human Mutation ◽

10.1002/humu.9235 ◽

2004 ◽

Vol 23 (5) ◽

pp. 522-523 ◽

Cited By ~ 19

Author(s):

Samantha L. Ginn ◽

Christine Smyth ◽

Melanie Wong ◽

Bruce Bennetts ◽

Peter B. Rowe ◽

...

Keyword(s):

Splice Site ◽

Severe Combined Immunodeficiency ◽

Splice Site Mutation ◽

Combined Immunodeficiency ◽

Site Mutation ◽

Gamma Chain ◽

Common Gamma Chain ◽

The Common

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Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency

Blood ◽

10.1182/blood-2005-03-0936 ◽

2005 ◽

Vol 106 (6) ◽

pp. 2099-2101 ◽

Cited By ~ 69

Author(s):

Taizo Wada ◽

Tomoko Toma ◽

Hiroyuki Okamoto ◽

Yoshihito Kasahara ◽

Shoichi Koizumi ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Protein Function ◽

Severe Combined Immunodeficiency ◽

Somatic Mosaicism ◽

Omenn Syndrome ◽

Missense Mutations ◽

Combined Immunodeficiency ◽

Reading Frame ◽

Recombination Activating Genes

Abstract Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID. (Blood. 2005; 106:2099-2101)

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A Novel Splice Site Variant in FOXN1 in A Patient with Abnormal Newborn Screening for Severe Combined Immunodeficiency and Congenital Lymphopenia

LymphoSign Journal ◽

10.14785/lymphosign-2021-0013 ◽

2021 ◽

Author(s):

Ori Scott ◽

Jenny Garkaby ◽

Jessica Willett-Pachul ◽

Yehonatan Pasternak

Keyword(s):

Splice Site ◽

Severe Combined Immunodeficiency ◽

Splice Site Mutation ◽

Missense Mutations ◽

Combined Immunodeficiency ◽

Site Mutation ◽

Cd8 Cells ◽

Cell Counts ◽

Epithelial Development ◽

Whole Exome

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.

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Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency

Blood ◽

10.1182/blood-2008-04-153361 ◽

2008 ◽

Vol 112 (10) ◽

pp. 4090-4097 ◽

Cited By ~ 45

Author(s):

Carsten Speckmann ◽

Ulrich Pannicke ◽

Elisabeth Wiech ◽

Klaus Schwarz ◽

Paul Fisch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Severe Combined Immunodeficiency ◽

Interleukin 2 ◽

Intrinsic Defect ◽

Combined Immunodeficiency ◽

Gamma Chain ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Susceptibility To Infection

Abstract 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 α/β and γ/δ 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).

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Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.20.9466 ◽

1994 ◽

Vol 91 (20) ◽

pp. 9466-9470 ◽

Cited By ~ 70

Author(s):

J. P. DiSanto ◽

F. Rieux-Laucat ◽

A. Dautry-Varsat ◽

A. Fischer ◽

G. de Saint Basile

Keyword(s):

T Cells ◽

X Chromosome ◽

Severe Combined Immunodeficiency ◽

Interleukin 2 ◽

Combined Immunodeficiency ◽

Gamma Chain ◽

Interleukin 2 Receptor ◽

Peripheral T Cells

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Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽

10.1182/blood.v91.3.949 ◽

1998 ◽

Vol 91 (3) ◽

pp. 949-955 ◽

Cited By ~ 32

Author(s):

Duilio Brugnoni ◽

Luigi D. Notarangelo ◽

Alessandra Sottini ◽

Paolo Airò ◽

Marta Pennacchio ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Tyrosine Kinase ◽

Cd4 T Cells ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

T Helper ◽

T Helper 1 ◽

In Vitro Susceptibility ◽

And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

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