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Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey.

ABSTRACT: Infants affected with severe combined immunodeficiency (SCID) are susceptible to severe and recurrent infections and do not survive unless provided with immune reconstituting treatments. In the absence of population-based newborn screening, infants with SCID who do not have an affected older relative are ascertained only after they have developed infections. However, only limited data are available from the perspective of patients and families to indicate what proportion of SCID cases might benefit from earlier detection by pre-symptomatic screening, whether adequate treatment facilities are available, and how screening could improve SCID treatment outcomes. A survey of parents of children with SCID evaluated family history, pre- and post-diagnosis events, outcomes, and impact of SCID on families. Affected infants diagnosed with SCID as neonates had better survival, demonstrating the potential benefit of universal newborn screening.

SUBMITTER: Chan A

PROVIDER: S-EPMC3022101 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey.

Chan Alice A Scalchunes Christopher C Boyle Marcia M Puck Jennifer M JM

Clinical immunology (Orlando, Fla.) 20101028 1

Infants affected with severe combined immunodeficiency (SCID) are susceptible to severe and recurrent infections and do not survive unless provided with immune reconstituting treatments. In the absence of population-based newborn screening, infants with SCID who do not have an affected older relative are ascertained only after they have developed infections. However, only limited data are available from the perspective of patients and families to indicate what proportion of SCID cases might bene ...[more]

PMID: 21035402

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Project description:BackgroundSevere combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis.ObjectiveThe aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID.MethodsFrom 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study.ResultsA total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette-Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 109/L with over 88% patients below 3 × 109/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis.ConclusionFH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 109/L.

Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP

Project description:The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Dataset Information

Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey.

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Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey.

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