UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

T-B-NK+ SCID: Clinical manifestations, diagnosis, and treatment

Author
Morton J Cowan, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

An extreme form of severe combined immunodeficiency disease (SCID) is the T cell negative (T-), B cell negative (B-), natural killer cell positive (NK+) SCID phenotype, which accounts for about one-quarter of all cases of SCID. Children with T-B-NK+ SCID present early in life with serious infections, failure to thrive, low to absent T and B cell numbers and function, and normal numbers and function of natural killer (NK) cells.

Autosomal recessive defects in several genes, all involved in V(D)J recombination that randomly combines variable, diverse, and joining gene segments in lymphocytes, result in this form of SCID. Some of the proteins encoded by these genes are also involved in DNA repair. Defects in these genes are associated with growth and developmental abnormalities and radiation/chemotherapy sensitivity.

The clinical manifestations, diagnosis, and treatment of T-B-NK+ SCID are reviewed here. The pathogenesis, genetic defects, and radiation sensitivity are discussed in detail separately. An overview of SCID and the different forms of SCID are also presented separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "T-B-NK+ SCID: Pathogenesis and genetics".)

EPIDEMIOLOGY

T-B-NK+ SCID accounts for 20 to 30 percent of all cases of SCID [1-4]. The overall estimated incidence of SCID in the United States is 1:58,000, based upon data from universal newborn screening (NBS) in 10 states plus the Navajo Nation over a four-year period [4]. The X-linked form of SCID accounted for only 19 percent of the identified cases, with the remainder comprised of autosomal recessive forms of SCID. Data from retrospective studies of relatively limited numbers of patients prior to the advent of NBS for SCID suggested there was an incidence of 1:500,000 for autosomal recessive SCID among outbred populations and 1:10,000 for first cousin marriages [5]. Based on the NBS data, it appears that the true incidence for autosomal recessive SCID is closer to 1:72,500, with significantly higher rates in certain founder populations. As an example, the estimated incidence of Athabascan SCID (SCIDA) in the Navajo population is approximately 1:2000 livebirths [4]. (See "Severe combined immunodeficiency (SCID): An overview" and "Newborn screening for primary immunodeficiencies".)

CLINICAL MANIFESTATIONS

In general, children with classic T-B-NK+ SCID present early in life with features typical of all children with SCID, including serious infections and failure to thrive. In addition, many of the specific defects are accompanied by unique clinical features. There is also a theoretical increased risk of malignancy for those with defects that also involve DNA repair. Increased incidence of malignancy has not been observed in children with the classic phenotype of Artemis-deficient SCID (ART-SCID) [6], although Epstein-Barr virus (EBV)-associated lymphoma was reported in two children with ART-SCID and mutations of the distal exon of DLCRE1C (DNA cross-link repair protein 1C) that left a partially functioning protein and the presence of B cells [7]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)

                 

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Nov 17 00:00:00 GMT 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Haddad E, Landais P, Friedrich W, et al. Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood 1998; 91:3646.
  2. Stephan JL, Vlekova V, Le Deist F, et al. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr 1993; 123:564.
  3. Kwan A, Church JA, Cowan MJ, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol 2013; 132:140.
  4. Puck JM, University of California, 2014, personal communication.
  5. Gatti RA, O'Reilly RJ. Severe combined immunodeficiency. In: Birth defects compendium, Bergsma D (Ed), Sinayer Associates, Sunderland, MA 1979. p.575.
  6. O'Marcaigh AS, DeSantes K, Hu D, et al. Bone marrow transplantation for T-B- severe combined immunodeficiency disease in Athabascan-speaking native Americans. Bone Marrow Transplant 2001; 27:703.
  7. Moshous D, Pannetier C, Chasseval Rd Rd, et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest 2003; 111:381.
  8. OMENN GS. FAMILIAL RETICULOENDOTHELIOSIS WITH EOSINOPHILIA. N Engl J Med 1965; 273:427.
  9. Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol 2008; 122:1054.
  10. Sheehan WJ, Delmonte OM, Miller DT, et al. Novel presentation of Omenn syndrome in association with aniridia. J Allergy Clin Immunol 2009; 123:966.
  11. Henderson LA, Frugoni F, Hopkins G, et al. First reported case of Omenn syndrome in a patient with reticular dysgenesis. J Allergy Clin Immunol 2013; 131:1227.
  12. Murphy S, Hayward A, Troup G, et al. Gene enrichment in an American Indian population: an excess of severe combined immunodeficiency disease. Lancet 1980; 2:502.
  13. Rotbart HA, Levin MJ, Jones JF, et al. Noma in children with severe combined immunodeficiency. J Pediatr 1986; 109:596.
  14. Kwong PC, O'Marcaigh AS, Howard R, et al. Oral and genital ulceration: a unique presentation of immunodeficiency in Athabascan-speaking American Indian children with severe combined immunodeficiency. Arch Dermatol 1999; 135:927.
  15. Woodbine L, Neal JA, Sasi NK, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J Clin Invest 2013; 123:2969.
  16. Woodbine L, Gennery AR, Jeggo PA. The clinical impact of deficiency in DNA non-homologous end-joining. DNA Repair (Amst) 2014; 16:84.
  17. Buck D, Malivert L, de Chasseval R, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 2006; 124:287.
  18. van der Burg M, van Veelen LR, Verkaik NS, et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest 2006; 116:137.
  19. Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 2006; 124:301.
  20. Corneo B, Moshous D, Güngör T, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood 2001; 97:2772.
  21. Shearer WT, Dunn E, Notarangelo LD, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol 2014; 133:1092.
  22. Dvorak CC, Cowan MJ, Logan BR, 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. J Clin Immunol 2013; 33:1156.
  23. Kou ZC, Puhr JS, Rojas M, et al. T-Cell receptor Vbeta repertoire CDR3 length diversity differs within CD45RA and CD45RO T-cell subsets in healthy and human immunodeficiency virus-infected children. Clin Diagn Lab Immunol 2000; 7:953.
  24. Santagata S, Villa A, Sobacchi C, et al. The genetic and biochemical basis of Omenn syndrome. Immunol Rev 2000; 178:64.
  25. de Saint-Basile G, Le Deist F, de Villartay JP, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J Clin Invest 1991; 87:1352.
  26. Cassani B, Poliani PL, Moratto D, et al. Defect of regulatory T cells in patients with Omenn syndrome. J Allergy Clin Immunol 2010; 125:209.
  27. Somech R, Simon AJ, Lev A, et al. Reduced central tolerance in Omenn syndrome leads to immature self-reactive oligoclonal T cells. J Allergy Clin Immunol 2009; 124:793.
  28. Walter JE, Rucci F, Patrizi L, et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med 2010; 207:1541.
  29. Pasic S, Djuricic S, Ristic G, Slavkovic B. Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings. Acta Paediatr 2009; 98:1062.
  30. van der Burg M, Ijspeert H, Verkaik NS, et al. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest 2009; 119:91.
  31. Li L, Zhou Y, Wang J, et al. Prenatal diagnosis and carrier detection for Athabascan severe combined immunodeficiency disease. Prenat Diagn 2002; 22:763.
  32. Bertrand Y, Landais P, Friedrich W, et al. Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency. J Pediatr 1999; 134:740.
  33. Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA 2006; 295:508.
  34. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol 2008; 122:1082.
  35. Cowan MJ, Puck JM, University of California, 2014, personal communication.
  36. Griffith LM, Cowan MJ, Kohn DB, et al. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J Allergy Clin Immunol 2008; 122:1087.
  37. Loechelt BJ, Shapiro RS, Jyonouchi H, Filipovich AH. Mismatched bone marrow transplantation for Omenn syndrome: a variant of severe combined immunodeficiency. Bone Marrow Transplant 1995; 16:381.
  38. Di Martino D, Terranova MP, Valetto A, et al. An unusual pattern of B-cell immunological reconstitution after allogeneic stem cell transplantation: a possible correlation with CMV reactivation? Pediatr Transplant 2009; 13:1050.
  39. Çağdaş D, Özgür TT, Asal GT, et al. Two SCID cases with Cernunnos-XLF deficiency successfully treated by hematopoietic stem cell transplantation. Pediatr Transplant 2012; 16:E167.
  40. Schuetz C, Neven B, Dvorak CC, et al. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood 2014; 123:281.
  41. Neven B, Leroy S, Decaluwe H, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood 2009; 113:4114.
  42. Cole BO, Welbury RR, Bond E, Abinun M. Dental manifestations in severe combined immunodeficiency following bone marrow transplantation. Bone Marrow Transplant 2000; 25:1007.
  43. Gomez L, Le Deist F, Blanche S, et al. Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr 1995; 127:76.
  44. Junker AK, Chan KW, Massing BG. Clinical and immune recovery from Omenn syndrome after bone marrow transplantation. J Pediatr 1989; 114:596.
  45. Lanfranchi A, Verardi R, Tettoni K, et al. Haploidentical peripheral blood and marrow stem cell transplantation in nine cases of primary immunodeficiency. Haematologica 2000; 85:41.
  46. Friedrich W, Müller SM. Allogeneic stem cell transplantation for treatment of immunodeficiency. Springer Semin Immunopathol 2004; 26:109.
  47. Friedrich W, Hönig M. HLA-haploidentical donor transplantation in severe combined immunodeficiency. Immunol Allergy Clin North Am 2010; 30:31.
  48. Müller SM, Kohn T, Schulz AS, et al. Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)-identical and HLA-nonidentical stem cell transplantation. Blood 2000; 96:4344.
  49. Griffith LM, Cowan MJ, Notarangelo LD, et al. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol 2014; 133:335.
  50. Dvorak CC, Hung GY, Horn B, et al. Megadose CD34(+) cell grafts improve recovery of T cell engraftment but not B cell immunity in patients with severe combined immunodeficiency disease undergoing haplocompatible nonmyeloablative transplantation. Biol Blood Marrow Transplant 2008; 14:1125.
  51. Schönberger S, Ott H, Gudowius S, et al. Saving the red baby: successful allogeneic cord blood transplantation in Omenn syndrome. Clin Immunol 2009; 130:259.
  52. Benito A, Diaz MA, Alonso F, et al. Successful unrelated umbilical cord blood transplantation in a child with Omenn's syndrome. Pediatr Hematol Oncol 1999; 16:361.
  53. Tomizawa D, Aoki Y, Nagasawa M, et al. Novel adopted immunotherapy for mixed chimerism after unrelated cord blood transplantation in Omenn syndrome. Eur J Haematol 2005; 75:441.
  54. Pulsipher MA, Levine JE, Hayashi RJ, et al. Safety and efficacy of allogeneic PBSC collection in normal pediatric donors: the pediatric blood and marrow transplant consortium experience (PBMTC) 1996-2003. Bone Marrow Transplant 2005; 35:361.
  55. Díaz de Heredia C, Ortega JJ, Díaz MA, et al. Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies. Bone Marrow Transplant 2008; 41:627.
  56. Gennery A, Newcastle University, 2014, personal communication.
  57. Condiotti R, Nagler A. Campath-1G impairs human natural killer (NK) cell-mediated cytotoxicity. Bone Marrow Transplant 1996; 18:713.
  58. Stauch D, Dernier A, Sarmiento Marchese E, et al. Targeting of natural killer cells by rabbit antithymocyte globulin and campath-1H: similar effects independent of specificity. PLoS One 2009; 4:e4709.
  59. Veys P. Reduced intensity transplantation for primary immunodeficiency disorders. Pediatr Rep 2011; 3 Suppl 2:e11.
  60. Law J, Cowan MJ, Dvorak CC, et al. Busulfan, fludarabine, and alemtuzumab as a reduced toxicity regimen for children with malignant and nonmalignant diseases improves engraftment and graft-versus-host disease without delaying immune reconstitution. Biol Blood Marrow Transplant 2012; 18:1656.
  61. Savic RM, Cowan MJ, Dvorak CC, et al. Effect of weight and maturation on busulfan clearance in infants and small children undergoing hematopoietic cell transplantation. Biol Blood Marrow Transplant 2013; 19:1608.
  62. Cowan MJ, Gennery AR. Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do? J Allergy Clin Immunol 2015; 136:1178.
  63. Dvorak CC, Cowan MJ, University of California, 2014, personal communication.
  64. Mostoslavsky G, Fabian AJ, Rooney S, et al. Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proc Natl Acad Sci U S A 2006; 103:16406.
  65. Lagresle-Peyrou C, Yates F, Malassis-Séris M, et al. Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity. Blood 2006; 107:63.