Natural history and early diagnosis of LAD-1/variant syndrome

Blood. 2007 Apr 15;109(8):3529-37. doi: 10.1182/blood-2006-05-021402. Epub 2006 Dec 21.

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.

Publication types

  • Case Reports
  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens
  • Bacterial Infections / etiology
  • Bacterial Infections / genetics
  • Bacterial Infections / metabolism
  • Bacterial Infections / pathology
  • Blood Platelets / metabolism
  • Blood Platelets / pathology
  • Cell Adhesion / genetics
  • Chemotaxis / genetics*
  • Collagen Type XVII
  • Female
  • Follow-Up Studies
  • Granulocytes / metabolism
  • Granulocytes / pathology
  • Hemorrhage / complications
  • Hemorrhage / genetics*
  • Hemorrhage / metabolism
  • Hemorrhage / pathology
  • Humans
  • Male
  • Multienzyme Complexes / metabolism
  • Mycoses / etiology
  • Mycoses / genetics
  • Mycoses / metabolism
  • Mycoses / pathology
  • NADH, NADPH Oxidoreductases / metabolism
  • Non-Fibrillar Collagens / deficiency*
  • Pedigree
  • Signal Transduction / genetics*
  • Syndrome
  • rap GTP-Binding Proteins / metabolism
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • Autoantigens
  • Multienzyme Complexes
  • Non-Fibrillar Collagens
  • NADH oxidase
  • NADH, NADPH Oxidoreductases
  • RAP2A protein, human
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins