title: Natural history and early diagnosis of LAD-1/variant syndrome.
abstract: The syndrome of leukocyte adhesion deficiency (LAD) combined with a severe Glanzmann-type bleeding disorder has been recognized as a separate disease entity. The variability in clinical and cell biological terms has remained largely unclear. We present data on 9 cases from 7 unrelated families, with 3 patients being actively followed for more than 12 years. The disease entity, designated LAD-1/variant syndrome, presents early in life and consists of nonpussing infections from bacterial and fungal origin, as well as a severe bleeding tendency. This is compatible with 2 major blood cell types contributing to the clinical symptoms (ie, granulocytes and platelets). In granulocytes of the patients, we found adhesion and chemotaxis defects, as well as a defect in NADPH oxidase activity triggered by unopsonized zymosan. This last test can be used as a screening test for the syndrome. Many proteins and genes involved in adhesion and signaling, including small GTPases such as Rap1 and Rap2 as well as the major Rap activity-regulating molecules, were normally present. Moreover, Rap1 activation was intact in patients' blood cells. Defining the primary defect awaits genetic linkage analysis, which may be greatly helped by a more precise understanding and awareness of the disease combined with the early identification of affected patients.
authors.affiliation: Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. t.w.kuijpers@amc.uva.nl
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Robin
authors.initials: R
authors.lastname: van Bruggen
authors.forename: Nanne
authors.initials: N
authors.lastname: Kamerbeek
authors.forename: Anton T J
authors.initials: AT
authors.lastname: Tool
authors.forename: Gonul
authors.initials: G
authors.lastname: Hicsonmez
authors.forename: Aytemiz
authors.initials: A
authors.lastname: Gurgey
authors.forename: Axel
authors.initials: A
authors.lastname: Karow
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Verhoeven
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
mesh_terms: D001324:Autoantigens; D001424:Bacterial Infections / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002633:Chemotaxis / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006470:Hemorrhage / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009181:Mycoses / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D024041:Non-Fibrillar Collagens / Q000172:deficiency*; D010375:Pedigree; D015398:Signal Transduction / Q000235:genetics*; D013577:Syndrome; D020668:rap GTP-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D009097:Multienzyme Complexes; D009247:NADH, NADPH Oxidoreductases; D024041:Non-Fibrillar Collagens; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D000097805:Collagen Type XVII; C023107:NADH oxidase; C116756:RAP2A protein, human