Omenn Syndrome Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD more...
Conventional care for any patient with severe combined immunodeficiency (SCID) includes isolation to prevent infection and also meticulous skin and mucosal hygienic care while the patient is awaiting stem cell reconstitution. Signs of sepsis and pulmonary infections may be subtle; thus, fever alone requires a detailed search for infectious agents. Empirical broad-spectrum antibiotics are administered parenterally while cultures and body fluid analyses are in progress. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis. In individual cases, prophylaxis with antiviral agents (eg, acyclovir) or antibiotics may be appropriate. Parenteral nutrition is customarily provided as therapy for diarrhea and failure to thrive.
Bone marrow or other stem cell reconstitution is first-line conventional therapy for most forms of SCID, including Omenn syndrome, although the mortality rate is higher when compared to other types of SCID. Workup includes major histocompatibility complex (MHC) typing to identify a fully matched sibling, or, in the case of consanguinity, possibly a parent. Reconstitution by using a matched unrelated donor or haploidentical parent has also been successful, although more complications and higher mortality have been reported. Preparatory immunosuppression of malfunctioning activated T cells has decreased the incidence of graft failure in Omenn syndrome. Nutritional support and T-cell suppression prior to BMT may reduce the risk of complications. Pretransplantional evaluation routinely includes testing of the recipient and the donor for infectious agents, such as cytomegalovirus (CMV), HIV, and hepatitis viruses.
Specific therapy for dermatitis and eosinophilia in Omenn syndrome is immunosuppression with cyclosporine. Interferon gamma has been administered in an attempt to down-regulate interleukin 4 (IL-4) and interleukin 5 (IL-5) production by the oligoclonal Th2 cells. Interferon gamma may independently modulate the inflammatory reaction by enhancing phagocytic functions.
Ancillary therapy includes intravenous immunoglobulin (IVIG) replacement. Live viral vaccines should not be administered.
In the future, the identification of the recombinase mutations as the cause of Omenn syndrome should enable gene transfer therapy. At this time, successful gene therapy is available only for the X-linked T-B+ form of SCID, in which mutations in the common γ chain are necessary for function of the cell surface receptors of interleukin 2 (IL-2), IL-4, interleukin 7 (IL-7), interleukin 9 (IL-9), and interleukin 15 (IL-15).
Promptly initiate workup for stem cell reconstitution with the bone marrow transplant (BMT) team. In the meantime, consult a gastroenterologist and a nutritionist for important support.
A patient with chronic diarrhea and a failure to thrive requires consultation with a gastroenterologist and nutritionist to adequately provide calories, nutrients, and vitamins. Parenteral or enteral nutrition supplementation is usually necessary.
Infants with any form of SCID should be isolated to decrease the risk of common viral and bacterial infections. Patients should avoid crowds in locations such as stores, doctors' offices, and hospitals, and they and their caregivers should engage in customary hygiene practices such as strict hand washing.
Al-Herz W, Nanda A. Skin manifestations in primary immunodeficient children. Pediatr Dermatol. 2011 Sep-Oct. 28(5):494-501. [Medline].
Couëdel C, Roman C, Jones A, Vezzoni P, Villa A, Cortes P. Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. J Clin Invest. 2010 Apr. 120(4):1337-44. [Medline]. [Full Text].
Wang YQ, Cui YX, Feng J. [Clinical phenotype and gene diagnostic analysis of Omenn syndrome]. Zhonghua Er Ke Za Zhi. 2013 Jan. 51(1):64-8. [Medline].
Marrella V, Maina V, Villa A. Omenn syndrome does not live by V(D)J recombination alone. Curr Opin Allergy Clin Immunol. 2011 Dec. 11(6):525-31. [Medline].
Bai X, Liu J, Zhang Z, Liu C, Zhang Y, Tang W, et al. Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome. Immunol Res. 2015 Oct 17. [Medline].
Jaouad IC, Ouldim K, Ali Ou Alla S, Kriouile Y, Villa A, Sefiani A. Omenn syndrome with mutation in RAG1 gene. Indian J Pediatr. 2008 Sep. 75(9):944-6. [Medline].
Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: Inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008 Dec. 122(6):1082-6. [Medline].
Wong SY, Lu CP, Roth DB. A RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a novel mechanism for antigen receptor repertoire restriction. J Immunol. 2008 Sep 15. 181(6):4124-30. [Medline].
Pannicke U, Hönig M, Schulze I, Rohr J, Heinz GA, Braun S, et al. The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. Hum Mutat. 2010 Feb. 31(2):197-207. [Medline].
Mancebo E, Recio MJ, Martinez-Busto E, et al. Possible role of Artemis c.512C>G polymorphic variant in Omenn syndrome. DNA Repair (Amst). 2011 Jan 2. 10(1):3-4. [Medline].
Marrella V, Poliani PL, Casati A, et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J Clin Invest. 2007 May. 117(5):1260-9. [Medline].
Khiong K, Murakami M, Kitabayashi C, et al. Homeostatically proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model. J Clin Invest. 2007 May. 117(5):1270-81. [Medline].
Henderson LA, Frugoni F, Hopkins G, Al-Herz W, Weinacht K, Comeau AM, et al. First reported case of Omenn syndrome in a patient with reticular dysgenesis. J Allergy Clin Immunol. 2013 Apr. 131(4):1227-30, 1230.e1-3. [Medline].
Nanda A, Al-Herz W, Al-Sabah H, Al-Ajmi H. Noninfectious cutaneous granulomas in primary immunodeficiency disorders: report from a national registry. Am J Dermatopathol. 2014 Oct. 36(10):832-7. [Medline].
Harp J, Coggshall K, Ruben BS, Ramírez-Valle F, He SY, Berger TG. Cutaneous granulomas in the setting of primary immunodeficiency: a report of four cases and review of the literature. Int J Dermatol. 2015 Jun. 54 (6):617-25. [Medline].
Caglayan Sozmen S, Isik S, Arikan Ayyildiz Z, Yildiz K, Cakır Y, Ozer E, et al. Cyclosporin treatment improves skin findings in omenn syndrome. Pediatr Dermatol. 2015 Mar-Apr. 32 (2):e54-7. [Medline].
Gozdzik J, Czogala W, Skoczen S, et al. Rapid full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in Omenn syndrome. Pediatr Transplant. 2008 Oct 25. [Medline].
Schonberger S, Ott H, Gudowius S, et al. Saving the red baby: Successful allogeneic cord blood transplantation in Omenn syndrome. Clin Immunol. 2008 Dec 7. [Medline].
Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005 Nov. 25(11 Pt 2):78S-84S. [Medline].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005 Aug 15. 62(16 Suppl 3):S5-11. [Medline].
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. 2008 Nov. 28(4):765-78, viii. [Medline].
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 Jul 31. 371(5):434-46. [Medline]. [Full Text].
Brown L, Xu-Bayford J, Allwood Z, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. 2011 Mar 17. 117(11):3243-6. [Medline].
Aleman K, Noordzij JG, de Groot R, et al. Reviewing Omenn syndrome. Eur J Pediatr. 2001 Dec. 160(12):718-25. [Medline].
Brooks EG, Filipovich AH, Padgett JW, Mamlock R, Goldblum RM. T-cell receptor analysis in Omenn's syndrome: evidence for defects in gene rearrangement and assembly. Blood. 1999 Jan 1. 93(1):242-50. [Medline].
Brugnoni D, Airo P, Facchetti F, et al. In vitro cell death of activated lymphocytes in Omenn's syndrome. Eur J Immunol. 1997 Nov. 27(11):2765-73. [Medline].
Chilosi M, Facchetti F, Notarangelo LD, et al. CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: evidence for a T helper 2-mediated condition. Eur J Immunol. 1996 Feb. 26(2):329-34. [Medline].
Lacy CF, Armstrong LL, Goldman MP, Lance LL (Editors). Drug Information Handbook 2008-2009. 16th edition. Cleveland, Ohio: Lexi-Comp, Inc; 2008.
Gennery AR, Hodges E, Williams AP, et al. Omenn's syndrome occurring in patients without mutations in recombination activating genes. Clin Immunol. 2005 Sep. 116(3):246-56. [Medline].
Giliani S, Bonfim C, de Saint Basile G, et al. Omenn syndrome in an infant with IL7RA gene mutation. J Pediatr. 2006 Feb. 148(2):272-4. [Medline].
Gomez L, Le Deist F, Blanche S, et al. Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr. 1995 Jul. 127(1):76-81. [Medline].
Gruber TA, Shah AJ, Hernandez M, et al. Clinical and genetic heterogeneity in Omenn syndrome and severe combined immune deficiency. Pediatr Transplant. 2008 Sep 15. [Medline].
Grunebaum E, Bates A, Roifman CM. Omenn syndrome is associated with mutations in DNA ligase IV. J Allergy Clin Immunol. 2008 Dec. 122(6):1219-20. [Medline].
Mazzolari E, Moshous D, Forino C, et al. Hematopoietic stem cell transplantation in Omenn syndrome: a single-center experience. Bone Marrow Transplant. 2005 Jul. 36(2):107-14. [Medline].
Omenn GS. Familial reticuloendotheliosis with eosinophilia. N Engl J Med. 1965 Aug 19. 273:427-32. [Medline].
Rieux-Laucat F, Bahadoran P, Brousse N, et al. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. J Clin Invest. 1998 Jul 15. 102(2):312-21. [Medline]. [Full Text].
Santagata S, Villa A, Sobacchi C, et al. The genetic and biochemical basis of Omenn syndrome. Immunol Rev. 2000 Dec. 178:64-74. [Medline].
Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am. 2000 Dec. 47(6):1355-69. [Medline].
Thampakkul S, Ballow M. Replacement intravenous immune serum globulin therapy in patients with antibody immune deficiency. Immunol Allergy Clin North Am. 2001. 21(1):165. [Full Text].
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 Nov. 75(5):441-4. [Medline].
Villa A, Santagata S, Bozzi F, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998 May 29. 93(5):885-96. [Medline].
|Brand(Manufacturer)||Manufacturing Process||pH||Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)||Parenteral Form and Final Concentrations||IgA Content (mcg/mL)|
|Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration||6.4-6.8||6% solution: 10% sucrose, < 20 mg NaCl/g protein||Lyophilized powder 3%, 6%, 9%, 12%||Trace|
|Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization||5.1-6||Sucrose free, contains 5% D-sorbitol||Liquid 5%||< 50|
|Gammagard Liquid 10%
|Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation||4.6-5.1||0.25M glycine||Ready-for-use Liquid 10%||37|
|Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation||4-4.5||Contains no sugar, contains glycine||Liquid 10%||46|
|Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation||4.8-5.1||Contains sorbitol (40 mg/mL); do not administer if fructose intolerant||Ready-for-use solution 5%||< 10|
|Cohn-Oncley fraction II/III; ultrafiltration; pasteurization||6.4-7.2||5% solution: 5% glucose, 0.3% NaCl||Lyophilized powder 5%||< 10|
(Baxter Bioscience for the American Red Cross)
|Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated||6.4-7.2||5% solution: 0.3% albumin, 2.25% glycine, 2% glucose||Lyophilized powder 5%, 10%||< 1.6 (5% solution)|
9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events
|Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization||5.1-6||10% maltose||Liquid 5%||200|
(Swiss Red Cross for the American Red Cross)
|Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration||6.6||Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl||Lyophilized powder 3%, 6%, 9%, 12%||720|
|Privigen Liquid 10%
|Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration||4.6-5||L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)||Ready-for use liquid 10%||< 25|