ABSTRACT
BACKGROUND: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation. METHODS: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre. RESULTS: From August 2013 to April 2023, our centre's densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID. CONCLUSIONS: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID.
Subject(s)
Neonatal Screening , Severe Combined Immunodeficiency , Humans , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/immunology , Infant, Newborn , Neonatal Screening/methods , Ontario/epidemiology , Male , Female , Retrospective Studies , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Lymphopenia/genetics , Lymphopenia/diagnosisABSTRACT
BACKGROUND: Genetic faults in several components of the nuclear factor-κB pathway cause immunodeficiency. Most defects lead to combined immunodeficiency with a range of severity. Heterozygous mutations in NFKB1 were associated with common variable immunodeficiency, however, homozygous mutations have not been described. OBJECTIVE: We studied the molecular basis of combined immunodeficiency in a patient who presented with failure to thrive, persistent EBV viremia and hepatitis, pneumocystis jirovecii pneumonitis, and generalized lymphadenopathy. METHODS: Whole genome and exome sequencing followed by Sanger confirmation were performed to identify the genetic defect. Molecular and cellular techniques were used to assess the variant impact on the nuclear factor-κB pathway and lymphocyte function. RESULTS: Genetic analysis revealed a novel homozygous mutation in NFKB1, c.2878G>A, p.Gly960Arg (G960R). This affected p105 phosphorylation and p50 formation on antigen and cytokine stimulation, as well as attenuating nuclear signal transmission. As a result, both T- and B-cell maturation and function were perturbed. The number of memory CD4+ T cells were reduced, while CD8+ T cells consisted predominately of expanded differentiated populations. The function of T cells were diminished as shown by reduced responses to mitogens as well as diminished cytokine secretion. B-cell maturation was also affected, with decreased IgD+CD27+ memory B cells while transitional B cells were increased, likely contributing to the reduced ability to produce specific antibodies. CONCLUSION: Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of nuclear factor-κB pathway signaling, resulting in aberrations in T- and B-cell maturation and function.
Subject(s)
NF-kappa B p50 Subunit/genetics , Severe Combined Immunodeficiency/genetics , Homozygote , Humans , Infant , Male , Mutation , PedigreeABSTRACT
INTRODUCTION: Adenosine deaminase (ADA) deficiency causes severe immunodeficiency that is lethal in infancy. Enzyme replacement therapy (ERT) can improve the metabolic, immune and non-immune abnormalities in patients prior to transplantation, however, its benefits over extended periods are not well characterized. We describe a 28-year-old female who received ERT for 27 years. She suffered from EBV negative B cell lymphoma of the hip at 14 years of age and Guillian-Barre Syndrome 2 years later. At 22 years of age, she experienced a gastrointestinal infection with Mycobacterium genavense. At 26 years of age, lymphoma reoccurred with multiple liver lesions followed by Mycobacterium genavense infection with dissemination to the brain. Throughout this period, ADA activity in the plasma was within the therapeutic range. Repeated evaluations demonstrated very low lymphocyte counts and impaired T cell function. CONCLUSIONS: ERT might be insufficient to maintain normal immunity over extended periods in some ADA-deficient patients.
Subject(s)
Adenosine Deaminase/deficiency , Agammaglobulinemia/drug therapy , Enzyme Replacement Therapy , Severe Combined Immunodeficiency/drug therapy , Adenosine Deaminase/therapeutic use , Adult , Agammaglobulinemia/epidemiology , Female , Humans , Morbidity , Severe Combined Immunodeficiency/epidemiologyABSTRACT
Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.
Subject(s)
Ataxia Telangiectasia Mutated Proteins , Ataxia Telangiectasia , Mutation , Neonatal Screening , Severe Combined Immunodeficiency , Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia/immunology , Ataxia Telangiectasia/therapy , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Case-Control Studies , Humans , Immunoglobulins, Intravenous/administration & dosage , Infant , Infant, Newborn , Male , Ontario , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/therapy , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Vaccination , Whole Genome SequencingABSTRACT
BACKGROUND: Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. OBJECTIVE: We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity. METHODS: We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. RESULTS: A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2. CONCLUSION: Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.
Subject(s)
CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/immunology , Guanylate Cyclase/genetics , Guanylate Cyclase/immunology , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Adult , CARD Signaling Adaptor Proteins/deficiency , Child, Preschool , Female , Guanylate Cyclase/deficiency , Humans , Interferon-gamma/genetics , Interleukin-2/genetics , Male , Mutation , NF-kappa B/genetics , Prospective Studies , Retrospective Studies , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes/immunology , Exome Sequencing/methodsSubject(s)
Hematopoietic Stem Cell Transplantation , Immune Reconstitution , Immunologic Deficiency Syndromes , Recovery of Function , Adolescent , Allografts , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Immunologic Deficiency Syndromes/therapy , Infant , Infant, Newborn , Male , Middle Aged , Time FactorsABSTRACT
PURPOSE: Inherited defects in the adenosine deaminase (ADA) enzyme can cause severe combined immune deficiency (SCID) and systemic abnormalities. Management options for ADA-deficient patients include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). Here, we describe the long-term benefits of these treatments. METHODS: Survival, infections, systemic sequelae, and laboratory assessments were recorded for all ADA-deficient SCID patients, managed at a single center since 1985, who survived 5 or more years following treatment. RESULTS: Of 20 ADA-deficient patients, the 8 (40%) who survived 5 or more years (range 6-29.5 years, median 14 years) were included in the study. Among the long-term survivors, two patients were treated exclusively with ERT, five underwent HSCT (three from HLA-matched sibling donors, two from HLA-mismatched related donors), and one received GT. The long-term survivors often suffered from recurrent respiratory infections; however, opportunistic infections occurred in only one patient. Systemic sequelae included lung disease such as bronchiectasis and asthma (four patients), neurologic abnormalities (six patients), metabolic disturbances (two patients), allergy and autoimmunity (six patients), and neoplasms (three patients). Normal CD4+ T cell numbers and function, as well as antibody production, were usually observed after HSCT and GT, but not after ERT. Late deaths occurred in two patients at 15 and 25 years after HSCT, respectively, and were attributed to respiratory failure. CONCLUSIONS: ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.
Subject(s)
Adenosine Deaminase/deficiency , Adenosine Deaminase/genetics , Agammaglobulinemia/therapy , Enzyme Replacement Therapy , Genetic Therapy , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency/therapy , Adolescent , Adult , Agammaglobulinemia/genetics , Autoimmunity , Bronchiectasis , Child , Female , Humans , Male , Respiratory Tract Infections , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/mortality , Survival Analysis , Young AdultABSTRACT
Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.
Subject(s)
Cardiomyopathies/genetics , Immunologic Deficiency Syndromes/genetics , Introns , Mental Retardation, X-Linked/genetics , Osteochondrodysplasias/genetics , Point Mutation , RNA Splicing , RNA, Small Nuclear/genetics , Retinal Diseases/genetics , Alleles , Base Sequence , Child, Preschool , Dwarfism/genetics , Female , Fetal Growth Retardation/genetics , Humans , Male , Microcephaly/genetics , Molecular Sequence Data , Nucleic Acid Conformation , Pedigree , Primary Immunodeficiency Diseases , RNA, Small Nuclear/chemistry , Untranslated RegionsSubject(s)
DiGeorge Syndrome/immunology , Measles-Mumps-Rubella Vaccine/adverse effects , Measles-Mumps-Rubella Vaccine/therapeutic use , Adolescent , Ambulatory Care , Antibodies, Viral/blood , CD4 Lymphocyte Count , Child , Child, Preschool , Humans , Interviews as Topic , Measles/prevention & control , Measles virus/immunology , Mumps/prevention & control , Mumps virus/immunology , Rubella/prevention & control , Rubella virus/immunology , Telephone , Vaccination/adverse effects , Young AdultABSTRACT
Little information is currently available on the outcome and the long-term restoration of immune function in infants with Omenn syndrome (OS) treated with bone marrow transplantation (BMT). We prospectively followed patients with OS who received matched unrelated donor (MUD) BMT at our center. Engraftment, immune reconstitution, and transplant-related complications were recorded. Humoral and cellular immunity were evaluated. Six patients with OS were diagnosed at a mean age of 4.6 months and received a matched unrelated donor BMT as the first BMT at the mean age of 9.4 months. All six patients are alive and well at a mean 95 months after transplant. All patients have evidence of full hemopoetic engraftment and robust immune function. We have shown here that matched unrelated donor BMT is highly effective in curing patients with OS regardless of their genotype. This mode of treatment should be preferred for patients with OS when a related identical donor is not available.
Subject(s)
Bone Marrow Transplantation/methods , Severe Combined Immunodeficiency/surgery , Anti-Inflammatory Agents/therapeutic use , Biomarkers/blood , Bone Marrow Cells/immunology , Chimerism , Female , Graft vs Host Disease/immunology , Histocompatibility/immunology , Humans , Immunoglobulins/blood , Infant , Living Donors , Lymphocyte Count , Male , Methylprednisolone/therapeutic use , Prospective Studies , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/mortality , Treatment OutcomeABSTRACT
The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
Subject(s)
Cell Differentiation/immunology , Genetic Diseases, Inborn/immunology , Interleukin-17/immunology , Receptors, Interleukin-12/immunology , STAT3 Transcription Factor/immunology , Signal Transduction/immunology , T-Lymphocytes, Helper-Inducer/immunology , Cell Differentiation/genetics , Cytokines/genetics , Cytokines/immunology , Female , Genetic Diseases, Inborn/genetics , Humans , Interleukin-1 Receptor-Associated Kinases/genetics , Interleukin-1 Receptor-Associated Kinases/immunology , Interleukin-17/genetics , Male , Mutation , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/immunology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/immunology , Quantitative Trait Loci/immunology , Receptor, Transforming Growth Factor-beta Type I , Receptor, Transforming Growth Factor-beta Type II , Receptors, Interleukin-12/genetics , Receptors, Transforming Growth Factor beta/genetics , Receptors, Transforming Growth Factor beta/immunology , STAT3 Transcription Factor/genetics , Signal Transduction/geneticsABSTRACT
A group of Canadian nurses and transfusion safety officers developed 10 recommendations for the infusion of intravenous immunoglobulin (IVIG) in acute care hospitals and clinics. The recommendations address issues related to documentation, patient consent, difference among IVIG brands, selection of a brand on the basis of patients' risk factors, contraindications, needs, action plans for adverse events, rapid infusion protocols, and setup of infusion pumps, tubing, and filter equipment. The Canadian group encouraged institutions to include nurses on committees that examine infusion protocols.
Subject(s)
Clinical Protocols , Immunoglobulins, Intravenous/therapeutic use , Infusions, Intravenous , Canada , Documentation/standards , Humans , Immunoglobulins, Intravenous/adverse effects , Informed Consent/standards , Infusions, Intravenous/nursing , Infusions, Intravenous/standards , Nurse's Role , Nursing Assessment/standards , Nursing Records/standards , Patient Care Planning/standards , Patient Selection , Practice Guidelines as Topic , Risk Assessment/standards , Safety Management/standardsABSTRACT
CONTEXT: Bone marrow transplantation (BMT) using stem cells obtained from a family-related, HLA-identical donor (RID) is the optimal treatment for patients with severe combined immune deficiency (SCID). In the absence of an RID, HLA-mismatched related donors (MMRDs) are often used. However, compared with RIDs, use of MMRDs for BMT is associated with reduced survival and inferior long-term immune reconstitution. Use of HLA-matched unrelated donors (MUDs) represents another potential alternative for BMT. OBJECTIVE: To compare outcomes and immune reconstitution in a large cohort of patients with SCID who received RID, MUD, or MMRD BMT. DESIGN, SETTING, AND PATIENTS: Retrospective study of medical records from 94 infants diagnosed as having SCID who received BMT between 1990 and 2004 at 1 Canadian and 1 Italian pediatric referral center. Thirteen, 41, and 40 patients received RID, MUD, and MMRD BMT, respectively. MAIN OUTCOME MEASURES: Survival and graft failure, along with incidence of graft-vs-host disease, infections, and other complications; immune reconstitution was assessed in children who survived for more than 2 years after BMT. RESULTS: Survival after RID BMT was highest. Twelve (92.3%) of 13 patients who received RID BMT, 33 (80.5%) of 41 who received MUD BMT, and 21 (52.5%) of 40 patients who received MMRD BMT survived. Compared with MMRD BMT, survival was significantly higher with RID (P = .008) or with MUD (P = .03). Graft failures and need for repeat BMT were more common in patients receiving MMRD BMT than in those who underwent MUD BMT. Long-term reconstitution of a full T-cell repertoire was achieved more frequently following MUD BMT (94.7%) than after MMRD BMT (61.1%) (P = .02). Acute graft-vs-host disease was documented in 73.1% of patients following MUD BMT but in only 45% after MMRD BMT (P = .009). Conversely, interstitial pneumonitis was observed more frequently after MMRD BMT (14 [35.0%] of 40) than after MUD BMT (3 [7.3%] of 41; P = .002). CONCLUSION: Our study suggests that in the absence of a relative with identical HLA, MUD BMT may provide better engraftment, immune reconstitution, and survival for patients with SCID than MMRD BMT.