Leukocyte Adhesion Deficiency Clinical Presentation
- Author: Stephen J Nervi, MD; Chief Editor: Harumi Jyonouchi, MD more...
See the list below:
- Leukocyte adhesion deficiency type I (LAD I) may be diagnosed prior to the onset of infections when delayed umbilical cord separation (normal separation is 3-45 d, with a mean of 10 d) is observed with a persistently high WBC count (>20 X 109/L) in the absence of infection. Patients with leukocyte adhesion deficiency I typically experience from omphalitis, perirectal and labial cellulitis, infections classically seen in patients with neutropenia, otitis media with minimal inflammation, and other indolent necrotic skin infections. Pus is not present, but serosanguineous fluids may be present.
- The most common infectious agents that affect patients with leukocyte adhesion deficiency I include Staphylococcus species, enteric gram-negative bacteria, and fungal organisms, usually Candida albicans. With tooth eruption, gingivitis and periodontitis develop. Wound healing is delayed with poorly formed, thin, and bluish scars. Less frequent, but well-described, complications include aseptic meningitis and croup syndromes of poorly defined etiology. Bacterial typhlitis (inflammation of the cecum commonly found in patients with neutropenia) and intestinal perforation are difficult to diagnose in a timely fashion in patients with leukocyte adhesion deficiency I. Infection is the major cause of death in patients with leukocyte adhesion deficiency I.
- Delayed umbilical cord separation is the classic presentation of leukocyte adhesion deficiency I. However, it is not a reliable finding. In patients with leukocyte adhesion deficiency I, delayed umbilical cord separation is associated with neutrophilia, whereas healthy infants with delayed cord separation lack an elevated WBC count. Omphalitis and perirectal or labial cellulitis associated with extreme neutrophilia (WBC count approximately 45 X 109/L) is highly suggestive of leukocyte adhesion deficiency I.
- Microbicidal activity and oxidative responses against bacteria and Candida species have been shown to be impaired in leukocyte adhesion deficiency I.
- To date, patients described with leukocyte adhesion deficiency II have been of Middle Eastern and Brazilian descent with poor intrauterine or postnatal growth and severe mental retardation recognized shortly after birth. Consanguinity should be sought. Infections in leukocyte adhesion deficiency II are rarely life threatening, but the typical skin and mucosal infections of leukocyte adhesion deficiency I with equally dramatic leukocytosis and absent pus may be observed. Older patients usually manifest fewer infections.
See the list below:
- For patients with leukocyte adhesion deficiency I, fever is the initial manifestation of infection. Skin and mucosal sites of infection must be rigorously inspected because the inflammatory response is so indolent. Cellulitis, necrosis, and serosanguineous fluid characterize local infection in leukocyte adhesion deficiency I.
- Patients with leukocyte adhesion deficiency II have a characteristic facial appearance, short stature, limb malformations, and severe developmental delay.
See the list below:
- Leukocyte adhesion deficiency I is an autosomal recessive disorder caused by mutations in the gene that codes for CD18, the ß chain of ß2 integrins, mapped to chromosome arm 21q22.3. In 50% of patients with leukocyte adhesion deficiency I, the gene defects are point mutations of CD18; missense, nonsense, and splice mutations comprise the remainder. Usually, the alleles have 2 distinct mutations. LAD I variants with CD18 that is nonfunctional because of abnormal conformational changes have also been described.
- Leukocyte adhesion deficiency II is caused by mutations in a gene that codes for guanosine 5'-diphosphate (GDP) fucose transporter, which transports GDP fucose to the Golgi complex where glycan, including sialyl Lewis X (the ligand for E and P selectins), are fucosylated. These mutations cause a defect in fucose transport that also results in the nonimmunologic features of severe growth and mental retardation. Thus far, most patients have presented in consanguineous families, consistent with double homozygosity of the alleles.
- Helmus et al identified a genetic defect of leukocyte adhesion deficiency II in a patient whose Golgi GDP-fucose transporter (GFTP) bore a single amino acid exchange that rendered this protein nonfunctional but correctly localized to the Golgi. They also reported a novel dual defect in which a truncated GFTP is unable to localize to the Golgi complex, causing leukocyte adhesion deficiency II in one patient. Furthermore, the missing part of the GFTP can be dissected into 2 regions: one that is needed for Golgi localization, and one that is required for the function of the GFTP. All patients with leukocyte adhesion deficiency II who are genetically analyzed may be subdivided into 2 groups: one in which single amino acid exchanges in the GFTP impair its function but not its subcellular localization, and another group with a dual defect in function and Golgi expression of the GFTP due to the absence of 2 important molecular regions.
- A leukocyte adhesion deficiency II variant with an absence of cell-associated E selectin but with the presence of the soluble E selectin has also been reported.
- Other variants have been reported, creating the potential for confusion and highlighting the need for a common classification. Alon et al have reported a new form of leukocyte adhesion deficiency associated with defective expression of the Rap-1 activator CalDAG-GEF (guanine exchange factor), resulting in impaired signaling via G-protein–coupled receptor (GPCR) at endothelial contacts. Kinashi et al report an inherited activation defect in Rap1, a small guanosine triphosphate (GTP)ase that works as a key regulator of inside-out integrin activation, associated with a pathologic disorder in leukocyte integrin function. Both groups have labeled their finding, leukocyte adhesion deficiency III. These defects also impair platelet aggregation, leading to bleeding disorders. McDowall et al studied the effect of two mutations in the kindlin3 gene on leukocyte function in vitro.
- Impaired leukocyte adhesion can be caused by 2 common drugs (ie, epinephrine and corticosteroids). Both of these drugs demarginate neutrophils from the peripheral vasculature. The mechanism for steroid demargination is not well understood. Epinephrine acts by causing endothelial cells to release cyclic adenosine monophosphate, which, in turn, interrupts adherence.
- A dominant-negative mutation in Rac2 is reported to cause a clinical syndrome indistinguishable from leukocyte adhesion deficiency I. Integrin expression is intact, but actin-associated functions, such as shape change and chemotaxis, and generation of superoxide dependent on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are defective. Rac2 is a cytosolic GTP–binding protein that acts in a signaling pathway of chemokine receptor-mediated activation of cellular events essential to microbicidal activity.
[Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May. 94(5 Suppl 1):S1-63. [Medline].
Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci. 2012 Feb. 1250(1):50-5. [Medline].
Cagdas D, Yilmaz M, Kandemir N, Tezcan I, Etzioni A, Sanal O. A Novel Mutation in Leukocyte Adhesion Deficiency Type II/CDGIIc. J Clin Immunol. 2014 Nov. 34(8):1009-14. [Medline].
Anderson DC, Schmalsteig FC, Finegold MJ, 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 Oct. 152(4):668-89. [Medline].
Helmus Y, Denecke J, Yakubenia S, et al. Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood. 2006 Feb 2. [Medline].
Alon R, Etzioni A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol. 2003 Oct. 24(10):561-6. [Medline].
Kinashi T, Aker M, Sokolovsky-Eisenberg M, et al. LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood. 2004 Feb 1. 103(3):1033-6. [Medline]. [Full Text].
McDowall A, Svensson L, Stanley P, Patzak I, Chakravarty P, Howarth K, et al. Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro. Blood. 2010 Jun 10. 115(23):4834-42. [Medline].
Lorusso F, Kong D, Jalil AK, et al. Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil Steril. 2006 Feb. 85(2):494.e15-8. [Medline].
Elhasid R, Rowe JM. Hematopoetic Stem Cell Transplantation in Neutrophil Disorders: Severe Congenital Neutropenia, Leukocyte Adhesion Deficiency and Chronic Granulomatous Disease. Clin Rev Allergy Immunol. 2009 May 19. [Medline].
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. 2014 Jul 28. [Medline].
Moutsopoulos NM, Konkel J, Sarmadi M, Eskan MA, Wild T, Dutzan N, et al. Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med. 2014 Mar 26. 6(229):229ra40. [Medline]. [Full Text].
Alon R, Aker M, Feigelson S, et al. A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. Blood. 2003 Jun 1. 101(11):4437-45. [Medline]. [Full Text].
Bauer TR Jr, Hickstein DD. Gene therapy for leukocyte adhesion deficiency. Curr Opin Mol Ther. 2000 Aug. 2(4):383-8. [Medline].
Bauer TR, Gu YC, Tuschong LM, et al. Nonmyeloablative hematopoietic stem cell transplantation corrects the disease phenotype in the canine model of leukocyte adhesion deficiency. Exp Hematol. 2005 Jun. 33(6):706-12. [Medline].
Bunting M, Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol. 2002 Jan. 9(1):30-5. [Medline].
DeLisser HM, Christofidou-Solomidou M, Sun J, et al. Loss of endothelial surface expression of E-selectin in a patient with recurrent infections. Blood. 1999 Aug 1. 94(3):884-94. [Medline].
Eklund EA, Freeze HH. The congenital disorders of glycosylation: a multifaceted group of syndromes. NeuroRx. 2006 Apr. 3(2):254-63. [Medline].
Etzioni A. Leukocyte adhesion deficiencies: molecular basis, clinical findings, and therapeutic options. Adv Exp Med Biol. 2007. 601:51-60. [Medline].
Etzioni A, Frydman M, Pollack S, et al. Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med. 1992 Dec 17. 327(25):1789-92. [Medline].
Etzioni A, Harlan JM. Cell adhesion and leukocyte adhesion defects. Ochs HD, Puck JM, Smith CI, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press Inc; 1998. 375-88.
Etzioni A, Sturla L, Antonellis A, et al. Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet. 2002 Jun 15. 110(2):131-5. [Medline].
Farinha NJ, Duval M, Wagner E, et al. Unrelated bone marrow transplantation for leukocyte adhesion deficiency. Bone Marrow Transplant. 2002 Dec. 30(12):979-81. [Medline].
Fiorini M, Vermi W, Facchetti F, et al. Defective migration of monocyte-derived dendritic cells in LAD-1 immunodeficiency. J Leukoc Biol. 2002 Oct. 72(4):650-6. [Medline].
Gu YC, Bauer TR Jr, Ackermann MR, et al. The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice. Comp Med. 2004 Aug. 54(4):363-72. [Medline].
Harris ES, Shigeoka AO, Li W, et al. A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. Blood. 2001 Feb 1. 97(3):767-76. [Medline]. [Full Text].
Hidalgo A, Ma S, Peired AJ, Weiss LA, et al. Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. Blood. 2003 Mar 1. 101(5):1705-12. [Medline]. [Full Text].
Hixson P, Smith CW, Shurin SB, Tosi MF. Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1. Blood. 2004 Feb 1. 103(3):1105-13. [Medline]. [Full Text].
Hogg N, Stewart MP, Scarth SL, et al. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest. 1999 Jan. 103(1):97-106. [Medline].
Kurkchubasche AG, Panepinto JA, Tracy TF Jr, et al. Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease. J Pediatr. 2001 Jul. 139(1):141-7. [Medline].
Luhn K, Wild MK, Eckhardt M, Gerardy-Schahn R, Vestweber D. The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet. 2001 May. 28(1):69-72. [Medline].
Malawista SE, de Boisfleury Chevance A, et al. Chemotaxis of non-compressed blood polymorphonuclear leukocytes from an adolescent with severe leukocyte adhesion deficiency. Am J Hematol. 2003 Jun. 73(2):115-20. [Medline].
Mancias C, Infante AJ, Kamani NR. Matched unrelated donor bone marrow transplantation in leukocyte adhesion deficiency. Bone Marrow Transplant. 1999 Dec. 24(11):1261-3. [Medline].
Marquardt T, Brune T, Luhn K, et al. Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism. J Pediatr. 1999 Jun. 134(6):681-8. [Medline].
Marquardt T, Luhn K, Srikrishna G, et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood. 1999 Dec 15. 94(12):3976-85. [Medline].
Pasvolsky R, Feigelson SW, Kilic SS, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007 Jul 9. 204(7):1571-82. [Medline].
Roos D, Meischl C, de Boer M, et al. Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations. Exp Hematol. 2002 Mar. 30(3):252-61. [Medline].
Shaw JM, Al-Shamkhani A, Boxer LA, et al. Characterization of four CD18 mutants in leucocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95. Clin Exp Immunol. 2001 Nov. 126(2):311-8. [Medline].
Sturla L, Fruscione F, Noda K, et al. Core fucosylation of N-linked glycans in leukocyte adhesion deficiency/congenital disorder of glycosylation IIc fibroblasts. Glycobiology. 2005 Oct. 15(10):924-34. [Medline].
Sturla L, Rampal R, Haltiwanger RS, et al. Differential terminal fucosylation of N-linked glycans versus protein O-fucosylation in leukocyte adhesion deficiency type II (CDG IIc). J Biol Chem. 2003 Jul 18. 278(29):26727-33. [Medline]. [Full Text].
Uzel G, Kleiner DE, Kuhns DB, Holland SM. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology. 2001 Oct. 121(4):958-64. [Medline].
Uzel G, Tng E, Rosenzweig SD, Hsu AP, Shaw JM, Horwitz ME. Reversion mutations in patients with leukocyte adhesion deficiency type I (LAD-I). Blood. 2007 Sep 17. [Medline].
Wild MK, Luhn K, Marquardt T, Vestweber D. Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs. 2002. 172(3):161-73. [Medline].