BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Ann and Robert H Lurie Children's Hospital of Chicago Chicago Ill

Baylor Texas Children's Hospital Houston Tex

Boston Children's Hospital Boston Mass

Children's Hospital at Westmead Sydney Australia

Children's Hospital Boston Boston Mass

Children's Hospital Los Angeles Keck School of Medicine Los Angeles Calif

Children's Hospital of Philadelphia Philadelphia Pa

Children's Hospital of Wisconsin Milwaukee Wis

Cincinnati Children's Hospital Medical Center Cincinnati Ohio

Department of Clinical Immunology and Allergology St Anne's University Hospital in Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Immunology Institute of Biomedical Sciences University of São Paulo São Paulo Brazil

Department of Pediatrics and Adolescent Medicine Center for Chronic Immunodeficiency University Medical Center Freiburg Germany

Department of Rheumatology University of Lübeck Lübeck Germany

Division of Allergy Immunology and Rheumatology Department of Pediatrics Federal University of São Paulo São Paulo Brazil

Division Pediatrics Pediatrische Immunologie en Infectieziekten Wilhelmina Children's Hospital UMC Utrecht Utrecht The Netherlands

Duke University Durham NC

Ege University Faculty of Medicine Izmir Turkey

Emory University Atlanta Ga

Geffen SOM at David Geffen School of Medicine at UCLA Los Angeles Calif

Hospital de Niños Dr Ricardo Gutierrez Buenos Aires Argentina

Hospital for Sick Children Toronto Ontario Canada

Hospital Vall d'Hebron Barcelona Spain

Ippokration General Hospital Thessaloniki Greece

Laboratory of Host Defenses NIAID National Institutes of Health Bethesda Md

Lucerne Switzerland

Memorial Sloan Kettering Cancer Center New York NY

Mother and Child Health Institute Belgrade Serbia

Mount Sinai Hospital New York NY

National Jewish Health Denver Colo

Regional Immunology Service Belfast United Kingdom

Research and Clinical Center for Pediatric Hematology Oncology and Immunology Moscow Russia

Research Center for Immunodeficiencies Pediatrics Center of Excellence Children's Medical Center Tehran University of Medical Sciences Tehran Iran

Royal Free Hospital London United Kingdom

Royal Victoria Infirmary Newcastle upon Tyne United Kingdom

Saint Louis University St Louis Mo

Sophia Children's Hospital Athens Athens Greece

Sydney Children's Hospital Randwick Australia

UC San Francisco San Francisco Calif

Unidad de Immunodeficiencias Primarias y la Unidad de Hematología y Oncología Pediátrica Instituto de Investigacíon Hospital 12 de Octubre Madrid Spain

University Hospital Center Zagreb Croatia

University Hospital Motol Prague Czech Republic

University Hospitals Leuven Leuven Belgium

University of Oxford Oxford United Kingdom

University of South Florida All Childrens FL St Petersburg Fla

University of Texas Southwestern Medical Center and Children's Medical Center Children's Health Dallas Tex

University of Utah School of Medicine Salt Lake City Utah

University of Washington and Seattle Children's Research Institute Seattle Wash

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Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003;82:373–84. PubMed

Rosen FS, Kevy SV, Merler E, Janeway CA, Gitlin D. Recurrent bacterial infections and dysgamma-globulinemia: deficiency of 7S gamma-globulins in the presence of elevated 19S gamma-globulins. Report of two cases Pediatrics. 1961;28:182–95. PubMed

Burtin P. An example of atypical agammaglobulinemia (a case of severe hypogammaglobulinemia with increase of the beta-2 macroglobulin. Rev Fr Etud Clin Biol. 1961;6:286–9. PubMed

Cooper MD, Faulk WP, Fudenberg HH, Good RA, Hitzig W, Kunkel HG, et al. Clin Immunol Immunopathol; Meeting report of the Second International Workshop on Primary Immunodeficiency Disease in Man; St. Petersburg, Florida. February, 1973; 1974. pp. 416–45. PubMed

Mayer L, Posnett DN, Kunkel HG. Human malignant T cells capable of inducing an immunoglobulin class switch. J Exp Med. 1985;161:134–44. PubMed PMC

Mayer L, Kwan SP, Thompson C, Ko HS, Chiorazzi N, Waldmann T, et al. Evidence for a defect in “switch” T cells in patients with immunodeficiency and hyperimmunoglobulinemia M. N Engl J Med. 1986;314:409–13. PubMed

Levitt D, Haber P, Rich K, Cooper MD. Hyper IgM immunodeficiency. A primary dysfunction of B lymphocyte isotype switching. J Clin Invest. 1983;72:1650–7. PubMed PMC

Mensink EJ, Thompson A, Sandkuyl LA, Kraakman ME, Schot JD, Espanol T, et al. X-linked immunodeficiency with hyperimmunoglobulinemia M appears to be linked to the DXS42 restriction fragment length polymorphism locus. Hum Genet. 1987;76:96–9. PubMed

Padayachee M, Feighery C, Finn A, McKeown C, Levinsky RJ, Kinnon C, et al. Mapping of the X-linked form of hyper-IgM syndrome (HIGM1) to Xq26 by close linkage to HPRT. Genomics. 1992;14:551–3. PubMed

Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993;259:990–3. PubMed

Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993;72:291–300. PubMed

DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993;361:541–3. PubMed

Fuleihan R, Ramesh N, Loh R, Jabara H, Rosen RS, Chatila T, et al. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993;90:2170–3. PubMed PMC

Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993;361:539–41. PubMed

Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I, et al. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994;180:1263–72. PubMed PMC

Miga A, Masters S, Gonzalez M, Noelle RJ. The role of CD40-CD154 interactions in the regulation of cell mediated immunity. Immunol Invest. 2000;29:111–4. PubMed

Etzioni A, Ochs HD. The hyper IgM syndrome—an evolving story. Pediatr Res. 2004;56:519–25. PubMed

Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol. 2006;117:855–64. PubMed

Noelle RJ. The role of gp39 (CD40L) in immunity. Clin Immunol Immunopathol. 1995;76(suppl):S203–7. PubMed

Jain A, Atkinson TP, Lipsky PE, Slater JE, Nelson DL, Strober W. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest. 1999;103:1151–8. PubMed PMC

Ziegner UH, Kobayashi RH, Cunningham-Rundles C, Espanol T, Fasth A, Huttenlocher A, et al. Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol. 2002;102:19–24. PubMed

Seyama K, Kobayashi R, Hasle H, Apter AJ, Rutledge JC, Rosen D, et al. Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome. J Infect Dis. 1998;178:318–24. PubMed

Banatvala N, Davies J, Kanariou M, Strobel S, Levinsky R, Morgan G. Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome): a case series review. Arch Dis Child. 1994;71:150–2. PubMed PMC

Lee WI, Huang JL, Yeh KW, Yang MJ, Lai MC, Chen LC, et al. Clinical features and genetic analysis of Taiwanese patients with the hyper IgM syndrome phenotype. Pediatr Infect Dis J. 2013;32:1010–6. PubMed

Cabral-Marques O, Klaver S, Schimke LF, Ascendino EH, Khan TA, Pereira PV, et al. First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes. J Clin Immunol. 2014;34:146–56. PubMed

Madkaikar M, Gupta M, Chavan S, Italia K, Desai M, Merchant R, et al. X-linked hyper IgM syndrome: clinical, immunological and molecular features in patients from India. Blood Cell Mol Dis. 2014;53:99–104. PubMed

Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131:47–54. PubMed

Thomas C, de Saint Basile G, Le Deist F, Theophile D, Benkerrou M, Haddad E, et al. Brief report: correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. N Engl J Med. 1995;333:426–9. PubMed

Bordigoni P, Auburtin B, Carret AS, Schuhmacher A, Humbert JC, Le Deist F, et al. Bone marrow transplantation as treatment for X-linked immunodeficiency with hyper-IgM. Bone Marrow Transplant. 1998;22:1111–4. PubMed

Hadzic N, Pagliuca A, Rela M, Portmann B, Jones A, Veys P, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med. 2000;342:320–4. PubMed

Duplantier JE, Seyama K, Day NK, Hitchcock R, Nelson RP, Jr, Ochs HD, et al. Immunologic reconstitution following bone marrow transplantation for X-linked hyper IgM syndrome. Clin Immunol. 2001;98:313–8. PubMed

Khawaja K, Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience. Arch Dis Child. 2001;84:508–11. PubMed PMC

Tomizawa D, Imai K, Ito S, Kajiwara M, Minegishi Y, Nagasawa M, et al. Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience. Am J Hematol. 2004;76:33–9. PubMed

Jacobsohn DA, Emerick KM, Scholl P, Melin-Aldana H, O’Gorman M, Duerst R, et al. Nonmyeloablative hematopoietic stem cell transplant for X-linked hyper-immunoglobulin m syndrome with cholangiopathy. Pediatrics. 2004;113:e122–7. PubMed

Tsuji Y, Imai K, Kajiwara M, Aoki Y, Isoda T, Tomizawa D, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006;37:469–77. PubMed

Kikuta A, Ito M, Mochizuki K, Akaihata M, Nemoto K, Sano H, et al. Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction. Bone Marrow Transplant. 2006;38:665–9. PubMed

Sato T, Kobayashi R, Toita N, Kaneda M, Hatano N, Iguchi A, et al. Stem cell transplantation in primary immunodeficiency disease patients. Pediatr Int. 2007;49:795–800. PubMed

Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126:602–10. e1–11. PubMed

Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, et al. Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: a single-center experience. Pediatr Transplant. 2015;19:634–9. PubMed

Allewelt H, Martin PL, Szabolcs P, Chao N, Buckley R, Parikh S. Hematopoietic stem cell transplantation for CD40 ligand deficiency: single institution experience. Pediatr Blood Cancer. 2015;62:2216–22. PubMed

Gennery AR, Khawaja K, Veys P, Bredius RG, Notarangelo LD, Mazzolari E, et al. Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993–2002. Blood. 2004;103:1152–7. PubMed

Mitsui-Sekinaka K, Imai K, Sato H, Tomizawa D, Kajiwara M, Nagasawa M, et al. Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan. J Allergy Clin Immunol. 2015;136:1018–24. PubMed

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and work-flow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81. PubMed PMC

Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006;85:193–202. PubMed

Cole T, Pearce MS, Cant AJ, Cale CM, Goldblatt D, Gennery AR. Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;132:1150–5. PubMed

Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, et al. Clinical features and genetic analysis of 20 Chinese patients with X-linked hyper-IgM syndrome. J Immunol Res. 2014;2014:683160. PubMed PMC

Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet. 2003;361:553–60. PubMed

Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985–2000. Blood. 2002;100:4344–50. PubMed

Filipovich AH, Stone JV, Tomany SC, Ireland M, Kollman C, Pelz CJ, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97:1598–603. PubMed

Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, et al. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N Engl J Med. 2014;371:434–46. PubMed PMC

Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980–2009: an international collaborative study. Blood. 2011;118:1675–84. PubMed PMC

Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, et al. Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood. 2016;127:2513–22. PubMed