Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Background Severe 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. Objective The aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID. Methods From 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. Results A 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. Conclusion FH 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.

[1]  Evan Bolton,et al.  Database resources of the National Center for Biotechnology Information , 2017, Nucleic Acids Res..

[2]  E. Ota,et al.  Diagnostic test accuracy of antigenaemia assay for PCR-proven cytomegalovirus infection-systematic review and meta-analysis. , 2017, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[3]  Anushya Muruganujan,et al.  PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements , 2016, Nucleic Acids Res..

[4]  Chun-yan Jin,et al.  Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  James Y. Zou Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[6]  Bao-Ping Xu,et al.  A novel deletion mutation in IL2RG gene results in X-linked severe combined immunodeficiency with an atypical phenotype , 2016, Immunogenetics.

[7]  T. Fleisher Transplantation Outcomes for Severe Combined Immunodeficiency 2000–2009 , 2015, Pediatrics.

[8]  T. Fleisher Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States , 2015, Pediatrics.

[9]  A. Fischer,et al.  Severe combined immunodeficiencies and related disorders , 2015, Nature Reviews Disease Primers.

[10]  M. Barbouche,et al.  Report of the Tunisian Registry of Primary Immunodeficiencies: 25-Years of Experience (1988–2012) , 2015, Journal of Clinical Immunology.

[11]  L. Bao,et al.  Commonly administered bacille Calmette-Guerin strains induce comparable immune response. , 2015, International journal of clinical and experimental medicine.

[12]  R. Buckley,et al.  Positive Family History, Infection, Low Absolute Lymphocyte Count (ALC), and Absent Thymic Shadow: Diagnostic Clues for All Molecular Forms of Severe Combined Immunodeficiency (SCID). , 2015, The journal of allergy and clinical immunology. In practice.

[13]  J. Puck,et al.  History and current status of newborn screening for severe combined immunodeficiency. , 2015, Seminars in perinatology.

[14]  María Martín,et al.  UniProt: A hub for protein information , 2015 .

[15]  H. Gaspar,et al.  Severe combined immunodeficiency: recent developments and guidance on clinical management , 2015, Archives of Disease in Childhood.

[16]  The Uniprot Consortium,et al.  UniProt: a hub for protein information , 2014, Nucleic Acids Res..

[17]  A. Zbrozek,et al.  Fiscal implications of newborn screening in the diagnosis of severe combined immunodeficiency. , 2014, The journal of allergy and clinical immunology. In practice.

[18]  J. Casanova,et al.  Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 , 2015, Journal of Clinical Immunology.

[19]  J. Franco,et al.  BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies. , 2014, The Journal of allergy and clinical immunology.

[20]  A. Bousfiha,et al.  First Report on the Moroccan Registry of Primary Immunodeficiencies: 15 Years of Experience (1998–2012) , 2014, Journal of Clinical Immunology.

[21]  C. Ortega,et al.  A novel IL2RG mutation presenting with atypical T−B+NK+ phenotype: Rapid elucidation of NK cell origin , 2014, Pediatric blood & cancer.

[22]  F. Alt,et al.  A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. , 2013, The Journal of allergy and clinical immunology.

[23]  李珮華,et al.  Primary immunodeficiency disorders in Southeast Asia : needs, priorities and opportunities , 2014 .

[24]  E. Goudouris,et al.  Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications. , 2014, Journal of investigational allergology & clinical immunology.

[25]  P. Veys,et al.  How I treat severe combined immunodeficiency. , 2013, Blood.

[26]  R. Long,et al.  Severe Combined Immunodeficiency (SCID) in Canadian Children: A National Surveillance Study , 2013, Journal of Clinical Immunology.

[27]  A. S. Shaikh,et al.  Severe combined immune deficiency syndrome. , 2013, Journal of the College of Physicians and Surgeons--Pakistan : JCPSP.

[28]  L. Notarangelo,et al.  The Natural History of Children with Severe Combined Immunodeficiency: Baseline Features of the First Fifty Patients of the Primary Immune Deficiency Treatment Consortium Prospective Study 6901 , 2013, Journal of Clinical Immunology.

[29]  S. Ryoo,et al.  BCG vaccine in Korea , 2013 .

[30]  J. Church,et al.  Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome. , 2013, The Journal of allergy and clinical immunology.

[31]  R. Altman,et al.  Collective judgment predicts disease-associated single nucleotide variants , 2013, BMC Genomics.

[32]  Robert E Black,et al.  Global burden of childhood pneumonia and diarrhoea , 2013, The Lancet.

[33]  D. El-Ghoneimy,et al.  Clinical Predictors of Primary Immunodeficiency Diseases in Children , 2012, Allergy, asthma & immunology research.

[34]  A. Jenei,et al.  Bare lymphocyte syndrome: an opportunity to discover our immune system. , 2012, Immunology letters.

[35]  A. Fischer,et al.  Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients. , 2011, Blood.

[36]  Y. Lau,et al.  Improving care, education, and research: the Asian primary immunodeficiency network , 2011, Annals of the New York Academy of Sciences.

[37]  L. Jeddane,et al.  Primary immunodeficiencies in highly consanguineous North African populations , 2011, Annals of the New York Academy of Sciences.

[38]  A. Kilian,et al.  Genomic characterization, high-density mapping and anchoring of DArT markers to the reference genome of Eucalyptus , 2011, BMC Proceedings.

[39]  F. Y. Chai,et al.  BCG Adenitis-Need for Increased Awareness. , 2011, The Malaysian journal of medical sciences : MJMS.

[40]  L. Notarangelo,et al.  Severe combined immunodeficiency (SCID): from molecular basis to clinical management. , 2011, Acta bio-medica : Atenei Parmensis.

[41]  A. Gennery,et al.  Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. , 2011, Blood.

[42]  Aman Verma,et al.  The BCG World Atlas: A Database of Global BCG Vaccination Policies and Practices , 2011, PLoS medicine.

[43]  M. Abbadi,et al.  Study of primary immunodeficiencies in Algeria , 2011, BMC Proceedings.

[44]  Steven M. Holland,et al.  Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 , 2009, Front. Immun..

[45]  L. Notarangelo,et al.  Severe combined immunodeficiency (SCID): from molecular basis to clinical management. , 2011, Acta bio-medica : Atenei Parmensis.

[46]  Tong-Xin Chen,et al.  Molecular Diagnosis of Severe Combined Immunodeficiency—Identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 Mutations in a Cohort of Chinese and Southeast Asian Children , 2011, Journal of Clinical Immunology.

[47]  A. Furano,et al.  The mutational spectrum of non-CpG DNA varies with CpG content. , 2010, Genome research.

[48]  L. Jeddane,et al.  The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population , 2010, European Journal of Pediatrics.

[49]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[50]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[51]  S. Reda,et al.  Primary Immunodeficiency Diseases in Egyptian Children: A Single-Center Study , 2009, Journal of Clinical Immunology.

[52]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[53]  N. Rezaei,et al.  Severe combined immunodeficiency: A cohort of 40 patients , 2008, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[54]  Igor Rudan,et al.  Epidemiology and etiology of childhood pneumonia. , 2008, Bulletin of the World Health Organization.

[55]  M. Keels,et al.  Oral conditions. , 2007, Pediatrics in review.

[56]  Emidio Capriotti,et al.  Bioinformatics Original Paper Predicting the Insurgence of Human Genetic Diseases Associated to Single Point Protein Mutations with Support Vector Machines and Evolutionary Information , 2022 .

[57]  A. Fischer,et al.  Human leucocyte antigen‐identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft‐versus‐host disease and pre‐existing viral infections , 2006, British journal of haematology.

[58]  M. Wong,et al.  A novel splice‐site mutation in the common gamma chain (γc) gene IL2RG results in X‐linked severe combined immunodeficiency with an atypical NK+ phenotype , 2004, Human mutation.

[59]  R. Buckley Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. , 2004, Annual review of immunology.

[60]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology Information: update , 2004, Nucleic acids research.

[61]  P. Stenson,et al.  Human Gene Mutation Database (HGMD®): 2003 update , 2003, Human mutation.

[62]  A. Gennery,et al.  Diagnosis of severe combined immunodeficiency , 2001, Journal of clinical pathology.

[63]  K. Izuhara,et al.  A G to A transition at the last nucleotide of exon 6 of the γc gene (868G→A) may result in either a splice or missense mutation in patients with X-linked severe combined immunodeficiency , 1999, Human Genetics.

[64]  M. Vihinen,et al.  Immunodeficiency mutation databases (IDbases). , 1998, Human mutation.

[65]  J. Puck,et al.  Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. , 1997, Blood.

[66]  J. Puck,et al.  Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. , 1997, The Journal of pediatrics.

[67]  R. Elhasid,et al.  Major histocompatibility complex class II deficiency: a clinical review. , 1996, Blood reviews.

[68]  R. Hague,et al.  Early diagnosis of severe combined immunodeficiency syndrome. , 1994, Archives of disease in childhood.

[69]  A. Fischer,et al.  Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. , 1993, The Journal of pediatrics.

[70]  M. Ehrlich,et al.  Spontaneous deamination of cytosine and 5-methylcytosine residues in DNA and replacement of 5-methylcytosine residues with cytosine residues. , 1990, Mutation research.

[71]  M. Ehrlich,et al.  Heat- and alkali-induced deamination of 5-methylcytosine and cytosine residues in DNA. , 1982, Biochimica et biophysica acta.

[72]  H. Stern Cytomegalovirus Infection * , 1975, The British journal of clinical practice.