Patients with T<sup>+/low</sup> NK<sup>+</sup> IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency

Fuchs, Sebastian; Rensing‐Ehl, Anne; Erlacher, Miriam; Vraetz, Thomas; Hartjes, Lara; Janda, Aleš; Rizzi, Marta; Lorenz, Myriam Ricarda; Gilmour, Kimberly; Basile, Geneviève de Saint; Roifman, Chaim M.; Cheuk, S. Fai; Gennery, Andrew R.; Thrasher, Adrian J.; Fuchs, Ilka; Schwarz, Klaus; Speckmann, Carsten; Ehl, Stephan

doi:10.1002/eji.201444689

Cited by 30 publications

(49 citation statements)

References 56 publications

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“…One infant, who presented at age 7 months with Pneumocystis pneumonia, had the known, recurrent, hypomorphic X-linked IL2RG mutation, Arg222Cys. 23 His delayed-onset leaky SCID was successfully treated with a conditioned HCT from a matched, unrelated donor. The other was a delayed-onset case of incomplete ADA deficiency, diagnosed at 23 months of age after repeated otitis and hospitalization for pneumonia.…”

Section: Cases Of Scidmentioning

confidence: 99%

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

et al. 2019

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OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified.METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes.RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age.CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

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Section: Cases Of Scidmentioning

confidence: 99%

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

et al. 2019

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“…Two cases of SCID were discovered to have been missed by NBS. One infant, who presented at age 7 months with Pneumocystis pneumonia, had the known, recurrent, hypomorphic X‐linked IL2RG mutation Arg222Cys . His delayed‐onset, leaky SCID was successfully treated with a conditioned HCT from a matched unrelated donor.…”

Section: Findings From Scid Newborn Screening In Californiamentioning

confidence: 99%

“…One infant, who presented at age 7 months with Pneumocystis pneumonia, had the known, recurrent, hypomorphic X-linked IL2RG mutation Arg222Cys. 42 His delayed-onset, leaky SCID was successfully treated with a conditioned HCT from a matched unrelated donor. The other was a delayed-onset case of incomplete ADA-deficiency, diagnosed at 23 months of age after repeated otitis and hospitalization for pneumonia.…”

Section: Missed Cases Of Leaky Scid That Presented After the Newbormentioning

confidence: 99%

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Puck

2018

Immunological Reviews

131

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Summary The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots made possible universal newborn screening (NBS) for severe combined immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to pemit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the USA, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the newborn screening assay for insufficient TRECs in dried blood spots also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

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“…X-LINKED SEVERE COMBINED IMMUNO-deficiency (SCID-X1) is a rare, lifethreatening disorder caused by mutations in the gene that encodes the common γ-chain (IL2RG [GenBank accession number, D11086.1]), which is shared by multiple cytokine receptors necessary for the development and function of lymphocytes. [1][2][3] Unless the condition is detected by newborn screening before the appearance of symptoms or identified on the basis of a positive family history, affected infants present with severe opportunistic infections during the first months of life because of defects in both cellular and humoral immunity. Laboratory studies typically show the lack of T cells, natural killer (NK) cells, and functional B cells.…”

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confidence: 99%

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

et al. 2019

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BACKGROUND Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four in-fants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, .)

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Patients with T^+/low NK⁺ IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency

Abstract: X-linked severe combined immunodeficiency (X-SCID) leads to a TKeywords: Atypical SCID r Common gamma chain r Cytokine signaling r Leaky SCID r Severe combined immunodeficiencyAdditional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 30 publications

References 56 publications

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

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Patients with T+/low NK+ IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency

Abstract: X-linked severe combined immunodeficiency (X-SCID) leads to a TKeywords: Atypical SCID r Common gamma chain r Cytokine signaling r Leaky SCID r Severe combined immunodeficiencyAdditional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 30 publications

References 56 publications

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010–2017

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

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Patients with T^+/low NK⁺ IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency