Abstract
Background
Leukocyte adhesion deficiency type 1 (LAD I) is an autosomal recessive disorder caused by mutations in the ITGB2 gene, encoding the β2 integrin family. Severe recurrent infections, impaired wound healing, and periodontal diseases are the main features of disease.
Methods
In order to investigate clinical and molecular manifestations of new LAD I cases, 11 patients diagnosed in one center during 7 years were studied. Patients were screened for the ITGB2 gene mutations, using polymerase chain reaction, followed by single-strand conformation polymorphism and sequencing.
Results
The most common first presenting feature of the patients was omphalitis. The mean age of cord separation was 19.9 ± 1 days. The most common clinical manifestations of the patients during the follow-up period included omphalitis, skin ulcers with poor healing, sepsis, and otitis media. During the follow-up, eight patients died. Eight homozygous changes, including seven novel mutations, were detected: two splicing (IVS4−6C>A, IVS7+1G>A), three missense (Asp128Tyr, Ala239Thr, and Gly716Ala), and three frameshift deletions (Asn282fsX41, Tyr382fsX9, and Lys636fsX22).
Conclusion
Our results indicate that different mutations underlie the development of LAD I. Definitive molecular diagnosis is valuable for genetic counseling and prenatal diagnosis. Regarding clinical presentations, it seems that omphalitis is the most consistent finding seen in LAD I infants.
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References
Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. The leukocyte integrins. J Biol Chem. 2000;275:23409–12.
Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol. 2010;38:54–60.
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;123:836–40.
Anderson DC, Schmalsteig FC, Finegold MJ, Hughes BJ, Rothlein R, Miller LJ, et al. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis. 1985;152:668–89.
Anderson DC, Schmalstieg FC, Shearer W, Becker-Freeman K, Kohl S, Smith CW, et al. Leukocyte LFA-1, OKM1, p150, 95 deficiency syndrome: functional and biosynthetic studies of three kindreds. Fed Proc. 1985;44:2671–7.
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;27:302–7.
Roos D, Law SK. Hematologically important mutations: leukocyte adhesion deficiency. Blood Cells Mol Dis. 2001;27:1000–4.
Roos D, Meischl C, de Boer M, Simsek S, Weening RS, Sanal O, et al. Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations Exp Hematol. 2002;30:252–61.
Etzioni A, Harlan JM. Cell adhesion and leukocyte adhesion defects. In: Ochs HD, Smith CIE, Puck J, editors. Primary immunodeficiency diseases. 2nd ed. New York: Oxford University Press; 2007. p. 550–64.
Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26:519–32.
Novack AH, Mueller B, Ochs H. Umbilical cord separation in the normal newborn. Am J Dis Child. 1988;142:220–3.
Oudesluys-Murphy AM, Eilers GA, de Groot CJ. The time of separation of the umbilical cord. Eur J Pediatr. 1987;146:387–9.
Razvi S, Murphy R, Shlasko E, Cunningham-Rundles C. Delayed separation of the umbilical cord attributable to urachal anomalies. Pediatrics. 2001;108:493–4.
Cox DP, Weathers DR. Leukocyte adhesion deficiency type 1: an important consideration in the clinical differential diagnosis of prepubertal periodontitis. A case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:86–90.
D'Agata ID, Paradis K, Chad Z, Bonny Y, Seidman E. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut. 1996;39:605–8.
Uzel G, Kleiner DE, Kuhns DB, Holland SM. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology. 2001;121:958–64.
Weitzman JB, Wells CE, Wright AH, Clark PA, Law SK. The gene organisation of the human beta 2 integrin subunit (CD18). FEBS Lett. 1991;294:97–103.
Matsuura S, Kishi F, Tsukahara M, Nunoi H, Matsuda I, Kobayashi K, et al. Leukocyte adhesion deficiency: identification of novel mutations in two Japanese patients with a severe form. Biochem Biophys Res Commun. 1992;184:1460–7.
Tsai YC, Lee WI, Huang JL, Hung IJ, Jaing TH, Yao TC, et al. Neutrophil function and molecular analysis in severe leukocyte adhesion deficiency type I without separation delay of the umbilical cord. Pediatr Allergy Immunol. 2008;19:25–32.
Nagahata H. Bovine leukocyte adhesion deficiency (BLAD): a review. J Vet Med Sci. 2004;66:1475–82.
Vihinen M, rredondo-Vega FX, Casanova JL, Etzioni A, Giliani S, Hammarstrom L, et al. Primary immunodeficiency mutation databases. Adv Genet. 2001;43:103–88.
Uzel G, Tng E, Rosenzweig SD, Hsu AP, Shaw JM, Horwitz ME, et al. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood. 2008;111:209–18.
Corbi AL, Vara A, Ursa A, Garcia Rodriguez MC, Fontan G, Sanchez-Madrid F. Molecular basis for a severe case of leukocyte adhesion deficiency. Eur J Immunol. 1992;22:1877–81.
Wright AH, Douglass WA, Taylor GM, Lau YL, Higgins D, Davies KA, et al. Molecular characterization of leukocyte adhesion deficiency in six patients. Eur J Immunol. 1995;25:717–22.
Acknowledgement
This study was supported by grants from the Iran National Science Foundation and Tehran University of Medical Sciences.
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Parvaneh, N., Mamishi, S., Rezaei, A. et al. Characterization of 11 New Cases of Leukocyte Adhesion Deficiency Type 1 with Seven Novel Mutations in the ITGB2 Gene. J Clin Immunol 30, 756–760 (2010). https://doi.org/10.1007/s10875-010-9433-2
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DOI: https://doi.org/10.1007/s10875-010-9433-2