Omenn Syndrome Differential Diagnoses

Diagnostic Considerations

The major reason for a missed or delayed diagnosis of Omenn syndrome is the eczematoid appearance of the dermatitis when the infections have not yet appeared. The eczema associated with diarrhea raises the possibility of a food allergy. Nevertheless, Omenn syndrome is usually accompanied by a failure to thrive not expected with common atopic dermatitis and by hypereosinophilia. Furthermore, the dermatitis has the unique appearance of pachydermia, which progresses to desquamation.

The clinical presentation also may suggest the possibility of other forms of severe combined immunodeficiency (SCID) complicated by maternal T-cell engraftment or transfusion-related graft versus host disease (GVHD). Patients with these conditions are typically more lymphopenic than those with other diseases.

Hyperimmunoglobulin E (HIE) syndrome in infants may need to be considered because these infants have eczema and infections with Candida species and S aureus. However, patients with Omenn syndrome are likely to have invasive infections, such as staphylococcal sepsis, whereas patients with HIE syndrome have infections limited to the lung, skin, and mucosal surfaces.

Noninfectious cutaneous granulomas may rarely be evident in patients with the Omenn syndrome.

Differential Diagnoses

• Histiocytosis
• Hyperimmunoglobulinemia E (Job) Syndrome
• Pediatric Atopic Dermatitis
• Pediatric Graft Versus Host Disease
• Severe Combined Immunodeficiency
• T-Cell Disorders

Workup



Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Coauthor(s)

Robert Y Lin, MD Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology, and Director of Utilization Review, Department Medicine, New York Downtown Hospital

Robert Y Lin, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, New York Allergy & Asthma Society

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

David J Valacer, MD

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, New York Academy of Sciences

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology



Terry W Chin, MD, PhD Associate Director, Pediatric Allergy/Immunology/Pulmonology, Miller Children's Hospital, Long Beach Memorial Medical Center; Associate Professor, Department of Pediatrics, University of California, Irvine, School of Medicine

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, Clinical Immunology Society, Western Society for Pediatric Research, California Thoracic Society

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

References

1. Al-Herz W, Nanda A. Skin manifestations in primary immunodeficient children. Pediatr Dermatol. 2011 Sep-Oct. 28(5):494-501. [Medline].
2. 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].
3. 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].
4. 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].
5. 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].
6. 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].
7. 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].
8. 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].
9. 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].
10. 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].
11. 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].
12. 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].
13. 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].
14. 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].
15. 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].
16. Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. 2008 Nov. 28(4):833-49. [Medline]. [Full Text].
17. Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005 Nov. 25(11 Pt 2):78S-84S. [Medline].
18. 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].
19. Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. 2008 Nov. 28(4):765-78, viii. [Medline].
20. 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].
21. 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].
22. Aleman K, Noordzij JG, de Groot R, et al. Reviewing Omenn syndrome. Eur J Pediatr. 2001 Dec. 160(12):718-25. [Medline].
23. 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].
24. 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].
25. Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey. Clin Immunol. 2011 Jan. 138(1):3-8. [Medline]. [Full Text].
26. 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].
27. Lacy CF, Armstrong LL, Goldman MP, Lance LL (Editors). Drug Information Handbook 2008-2009. 16th edition. Cleveland, Ohio: Lexi-Comp, Inc; 2008.
28. Ege M, Ma Y, Manfras B, et al. Omenn syndrome due to ARTEMIS mutations. Blood. 2005 Jun 1. 105(11):4179-86. [Medline]. [Full Text].
29. 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].
30. 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].
31. 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].
32. 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].
33. 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].
34. 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].
35. Omenn GS. Familial reticuloendotheliosis with eosinophilia. N Engl J Med. 1965 Aug 19. 273:427-32. [Medline].
36. 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].
37. Santagata S, Villa A, Sobacchi C, et al. The genetic and biochemical basis of Omenn syndrome. Immunol Rev. 2000 Dec. 178:64-74. [Medline].
38. Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am. 2000 Dec. 47(6):1355-69. [Medline].
39. Signorini S, Imberti L, Pirovano S, et al. Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome. Blood. 1999 Nov 15. 94(10):3468-78. [Medline]. [Full Text].
40. 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].
41. 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].
42. 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].

A unique dermatitis characterizes Omenn syndrome. The dermatitis initially resembles eczema, but with a pachydermia, as observed here. The lesions progress to desquamation. Failure to thrive is evident. This infant weighed 6 pounds at age 6 months; his weight had not changed since birth.

Common viral infections are fatal in severe combined immunodeficiency (SCID). This female infant died before bone marrow stem cell engraftment could occur, when varicella became resistant to acyclovir. The nasal bridge reveals superinfection with Klebsiella pneumoniae. Lymphedema, a characteristic of Omenn syndrome, is also shown.

• Table. Immune Globulin, Intravenous[17, 18, 16, 19]

Table. Immune Globulin, Intravenous

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)
Carimune NF (CSL Behring)	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
Flebogamma (Grifols USA)	Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization	5.1-6	Sucrose free, contains 5% D-sorbitol	Liquid 5%	< 50
Gammagard Liquid 10% (Baxter Bioscience)	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
Gamunex (Talecris Biotherapeutics)	Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation	4-4.5	Contains no sugar, contains glycine	Liquid 10%	46
Gammaplex (Bio Products)	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
Iveegam EN (Baxter Bioscience)	Cohn-Oncley fraction II/III; ultrafiltration; pasteurization	6.4-7.2	5% solution: 5% glucose, 0.3% NaCl	Lyophilized powder 5%	< 10
Polygam S/D Gammagard S/D (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)
Octagam (Octapharma USA) 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
Panglobulin (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% (CSL Behring)	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