Lökosit Adezyon Defekti (Tip I ve Tip III) Tanısıyla İzlenen 14 Hastanın Klinik, İmmünolojik Özellikleri ve Tedavi Sonuçlarının Değerlendirilmesi

Year 2020, , 286 - 294, 26.06.2020

Zehra Şule Haskoloğlu , Sevgi Köstel Bal Candan İslamoğlu Avniye Baskın Dilara Beşli Caner Aytekin Figen Doğu , Aydan İkincioğulları

https://doi.org/10.12956/tchd.685332

Abstract

Giriş-Amaç: Lökosit Adezyon Defekti (LAD), lökositlerin adezyon, migrasyon, kemotaksis ve ekstravazasyonunda rol alan moleküllerin eksikliklerine bağlı gelişen, nadir görülen, otozomal resesif katılımlı, üç ayrı tipi olan (LAD-I, LAD-II ve LAD-III) bir primer immün yetmezlik hastalığıdır. Tekrarlayan bakteriyel, fungal enfeksiyonlar ve lökositoz ile karakterizedir. Bu çalışmada, LAD-I ve LAD-III tanısı konulan hastaların klinik, immünolojik özelliklerinin, tedavi ve hematopoietik kök hücre nakli (HKHN) sonuçlarının değerlendirilmesi amaçlanmıştır.
Gereç ve Yöntem: Bu çalışmaya, Mart 2008 ile Haziran 2018 tarihleri arasında bölümümüzde LAD tanısı konulan, takip ve tedavileri yapılan 14 hasta dâhil edildi. Hastaların demografik, klinik, laboratuvar özellikleri, genetik mutasyonları, izlemleri ve HKHN sonuçları geriye dönük olarak değerlendirildi.
Bulgular: Hastaların 12’si LAD-I (%86), 2’si LAD-III (%14) idi. Tüm hastalarda (9 kız/5 erkek) akraba evliliği, 3 hastada benzer şikâyetlerle kaybedilen kardeş öyküsü vardı. Göbek bağının düşmesinde gecikme 13/14(%93), omfalit 12/14(%86), nekrotizan cilt yaraları 9/14(%64), pnömoni 5/14(%36), gingivit 4/14(%29) ve moniliazis 4/14(%29) en sık rastlanan klinik bulgulardı. Tüm hastalarda lökositoz ve nötrofili mevcuttu. CD18 ekspresyonu %2’den düşük olan 10 hasta ağır LAD-I, CD18 ekspresyonları %16 ve %19 olan 2 hasta ise hafif-orta ağırlıkta LAD-I olarak değerlendirildi. 8 hastada mutasyonlar genetik analiz ile gösterildi. Kardeş olan 3 hastada ITGB2 geninde yeni bir mutasyon saptandı. Nakil yapılmayan hastalar, tekrarlayan cilt ve solunum enfeksiyonları nedeniyle çok kez ayaktan veya hastanede yatarak tedavi aldı. En sık rastlanan enfeksiyon ajanları S.aureus ve E.faecium oldu. 6 hastaya tam uyumlu aile içi ve 1 hastaya tam uyumlu akraba dışı donörden HKHN yapıldı. Tüm hastalarda engrafman sağlandı ve ciddi bir komplikasyon izlenmedi. LAD-III tanılı bir olgu nakil yapılamadan kanama nedeniyle kaybedildi. Tüm hastalarda hayatta kalma oranı %93 iken HKHN yapılanlarda %100 oldu.
Sonuç: Göbek bağının düşmesinde gecikme, tekrarlayan cilt ve mukoza enfeksiyonları olan ve lökositozla gelen her olguda LAD tanısı akla gelmelidir. Hematopoetik kök hücre nakli bu hastalar için küratif tedavi yöntemidir.


Abstract
Introduction-Aim
Leukocyte Adhesion Deficiency (LAD) is a rare autosomal recessive primary immunodeficiency that is due to deficiencies of molecules involved in adhesion, migration, chemotaxis and extravasation of leukocytes with three different types (LAD-I, LAD-II, LAD-III). It is characterised by recurrent bacterial, fungal infections and leucocytosis. In this study, it is aimed to evaluate clinical, immunological features, treatment and follow-up of patients diagnosed with LAD-I and III.

Material-Method
In this study there were 14 LAD patients who were diagnosed, treated and followed up in our department between March 2008- June 2018. The demographic, clinical, laboratory features, genetic mutations, follow-up and hematopoietic stem cell transplantation (HSCT) results of patients were evaluated retrospectively.

Results
There were 12 (86%) patients with LAD-I, and 2 (14%) of them were LAD-III. All patients (9 female/5 male) had consanguinity, 3 patients had history of sibling death with similar complaints. The most common clinical findings were 13 (93%) delayed umbilical cord separation, 12 (86%) omphalitis, 9 (64%) necrotising skin wounds, 5 (36%) pneumonia, 4 (29%) gingivitis and 4 (29%) moniliasis. All patients had neutrophilia and leucocytosis. There were 10 severe LAD-I patients with CD18 expression lower than 2% and 2 mild-moderate LAD-I patients with CD18 expression 16% and 19%. Mutations were demonstrated in 8 patients by genetic analysis. A new mutation in the ITGB2 gene was detected in 3 sibling patients. Patients who were not transplanted received multiple outpatient/inpatient treatments due to recurrent skin and respiratory infections. S.aureus and E.faecium were most common infectious agents. HSCT was performed in 6 patients from full matched related donors and in 1 patient from full matched unrelated donor. Engraftment was achieved in all patients without serious complications. One patient with LAD-III died due to bleeding before transplantation. While the survival rate was 93% in all patients, it was 100% in HSCT patients.

Conclusion
LAD diagnosis must be considered in patients with delayed umbilical cord separation, recurrent skin and mucosal infections and leucocytosis. Hematopoietic stem cell transplantation is a curative treatment for these patients.

Keywords

Lökosit adezyon defekti, klinik, izlem

Supporting Institution

Bu çalışma için hiç bir kurumdan destek alınmamıştır.

Project Number

-

Thanks

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References

• van de Vijver E, van den Berg TK, Kuijpers TW. Leukocyte adhesion deficiencies. Hematol Oncol Clin North Am 2013; 27 (1): 101-16.
• Kruger P, Zaffarzadeh M, Weber ANR, Rieber N, Radsak M, von Bernuth H et al. Neutrophils: Between host defense, immune modulation and tissue injury, Plos Pathl 2015;11:1-23.
• Dinauer MC., Neutrophil Defects and Diagnosis Disorders of Neutrophil Function: An Overview.In: Quinn MT., De Leo FR. (eds). Neutrophil.Methods and Protocols. 3rd ed. New York, Springer Science-Business Media. 2020;11-31.
• von Adrian, Berger EM, Ramezani L, Chambers JD, Ochs HD, Harlan JM, et al. In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes. J Clin Invest 1993;91:2893-2897.
• Schymeinsky J, Mocsai A, Walzog B. Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications. Thromb Haemost. 2007;98 (2):262–273
• Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987;48:549–54.
• Aytekin C, İkincioğulları A. Lökosit adezyonu ve lökosit adezyon defekti sendromları. Astım Allerji İmmünoloji 2004; 2(3):157-66.
• Novoa AE, Kasbekar S, Thrasher AJ, Kohn DB, Sevilla J, Nguyen T, et al. Leukocyte adhesion deficiency-I: A comprehensive review of all published cases. J Allergy Clin Immunol Pract 2018;6(4):1418-1420.e10.
• Hayward AR, Harvey BA, Leonard J, Greenwood MC, Wood CB, Soothill JF. Delayed separation of the umbilical cord, widespread infections, and defective neutrophil mobility. Lancet 1979; 1 (8126): 1099-101.
• Parvaneh N, Mamishi S, Rezaei A, Rezaei N, Tamizifar B, Parvaneh L, et al. Characterization of 11 new cases of leukocyte adhesion deficiency type 1 with seven novel mutations in the ITGB2 gene. J Clin Immunol 2010;30 (5): 56-760
• Madkaikar M, Currimbhoy Z, Gupta M, Desai M, Rao M. Clinical profile of leukocyte adhesion deficiency type I. Indian Pediatr 2012;49 (1):43-5.
• Movahedi M, Entezari N, Pourpak Z, Mamishi S, Chavoshzadeh Z, Gharagozlou M, et al. Clinical and laboratory findings in Iranian patients with leukocyte adhesion deficiency (study of 15 cases). J Clin Immunol 2007;27(3):302-7.
• Teimourian S, De Boer M, Roos D, Isaian A, Bemanian MH, Lashkary S, et al. Genetic analysis of 13 Iranian families with leukocyte adhesion deficiency type 1. J Pediatr Hematol Oncol 2019; 41 (1): e3-e6. https://journals.lww.com/jpho-online/Abstract/2019/01000/Genetic_Analysis_of_13_Iranian_Families_With.22.aspx. Accessed January 2019.
• Deshpande P, Kathirvel K, Alex AA, Korula A, George B, Shaji RV, et al. Leukocyte adhesion deficiency-I: clinical and molecular characterization in an Indian population. Indian J Pediatr 2016;83 (8):799-804.
• Qasim W, Cavazzana-Calvo M, Davies EG, Davis J, Duval M, Eames G, et al. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency. Pediatrics 2009;123(3):836-40.
• De Rose Du, Giliani S, Notarangelo LD, Lougaris V, Lanfranchi A, Moratto D, et al. Long term outcome of eight patients with type 1 Leukocyte AdhesionDeficiency (LAD-1): Not only infections, but high risk of autoimmune complications. Clin Immunol. 2018(191):75-80.
• Wolach B, Gavrieli R, Wolach O, Stauber T, Abuzaitoun O, Kuperman A, et al. Leucocyte adhesion deficiency-A multicentre national experience. Eur J Clin Invest. 2019 Feb;49(2):e13047. Https://Onlinelibrary.Wiley.Com/Doi/10.1111/Eci.13047. Accessed 09 November 2018.
• Engel ME, Hickstein DD, Bauer TR Jr, Calder C, Manes B, Frangoul H. Matched unrelated bone marrow transplantation with reduced-intensity conditioning for leukocyte adhesion deficiency. Bone Marrow Transplant.2006;37(7):717-718.
• Hamidieh AA1, Pourpak Z, Hosseinzadeh M, Fazlollahi MR, Alimoghaddam K, et al. Bone Marrow Transplant. 2012 May;47(5):646-650.
• Horikoshi Y, Umeda K, Imai K, Yabe H, Sasahara Y, Watanabe K, et al. J Pediatr Hematol Oncol. Allogeneic Hematopoietic Stem Cell Transplantation for Leukocyte Adhesion Deficiency.2018;40(2):137-140.
• Mellouli F, Ksouri H, Barbouche R, Maamer M, Hamed LB, Hmida S, et al. Successful treatment of Fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions. BMC Dermatol. 2010 Oct 7;10:10. https://bmcdermatol.biomedcentral.com/articles/10.1186/1471-5945-10-10. Accessed 7 October 2010
• Gazit Y, Mory A, Etzioni A, Frydman M, Scheuerman O, Gershoni-Baruch R, et al. Leukocyte adhesion deficiency type II: long-term follow-up and review of the literature. J Clin Immunol 2010;30 (2): 308-313.
• Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 2009; 113 (19): 4740-4746.
• Stepensky PY, Wolach B, Gavrieli R, Rousso S, Ben Ami T, Goldman V, et al. Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation. J Pediatr Hematol Oncol 2015;37 (4):264-8.
• Futosi K1,Fodor S,Mócsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol 2013;17(3):6386-50.
• Koivisto L, Heino J, Hakkinen L, Larjava H. Integrins in Wound Healing. Adv Wound Care (New Rochelle) 2014, 3(12):762-783.