A novel ITGB2 variant with long survival in patients with leukocyte adhesion defect type-I.

Leukocyte adhesion deficiency is an autosomal recessive primary immunodeficiency that has been divided into three types: LAD1 (beta-2 integrin (CD18) family deficiency/defect), LAD2 (absence of fucosylated carbonhydrate ligands for selectins) and LAD3 (defective activation of all beta integrins). However, recently LAD4 has been described in cystic fibrosis patients, with a defect in integrin activation reported in monocytes. LAD-I is the most common type and prevalence of 1 in 1,000,000 live births. Clinical features of LAD patients are recurrent bacterial and fungal infections, omphalitis with delayed umbilical stump separation, significant leukocytosis especially neutrophilia during infection periods, impaired pus formation, and delayed traumatic or surgical wound healing. Flow cytometry is considered a useful tool for rapid diagnosis of the disease. The study of CD18 and CD11 (a, b, c) expression patterns in peripheral blood leukocytes helps to distinguish different phenotypes of LAD-I. In general, patients with ≥ 2% CD18 expression tend to have a less severe infection and often survive until adulthood, whereas < 2% CD18 expression often results in death in infancy. In this case report, three siblings, 10, 15, and 17 years old, diagnosed with leukocyte adhesion defect type 1 in adolescence age group, are presented.

Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency.

OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed wound healing. Allogeneic hematopoietic stem-cell transplantation offers the possibility of curative therapy, and with patient numbers at any individual center being limited, we surveyed the transplant experience at 14 centers worldwide. METHODS: The course of 36 children with a confirmed diagnosis of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research. RESULTS: At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates after matched family donor and unrelated donor transplants were similar, with 11 of 14 matched family donor and 12 of 14 unrelated donor recipients alive; mortality was greatest after haploidentical transplants, after which 4 of 8 children did not survive. Twenty-seven transplant recipients were alive, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients.

Nonmyeloablative conditioning with busulfan before matched littermate bone marrow transplantation results in reversal of the disease phenotype in canine leukocyte adhesion deficiency.

Leukocyte adhesion deficiency (LAD)-1, a primary immunodeficiency disease caused by molecular defects in the leukocyte integrin CD18 molecule, is characterized by recurrent, life-threatening bacterial infections. Myeloablative hematopoietic stem cell transplantation is the only curative treatment for LAD-1. Recently, canine LAD (CLAD) has been shown to be a valuable animal model for the preclinical testing of nonmyeloablative transplantation regimens for the treatment of children with LAD-1. To develop new allogeneic transplantation approaches for LAD-1, we assessed a nonmyeloablative conditioning regimen consisting of busulfan as a single agent before matched littermate allogeneic bone marrow transplantation in CLAD. Three CLAD dogs received busulfan 10 mg/kg intravenously before infusion of matched littermate bone marrow, and all dogs received posttransplantation immunosuppression with cyclosporin A and mycophenolate mofetil. Initially, all 3 dogs became mixed chimeras, and levels of donor chimerism sufficient to reverse the CLAD phenotype persisted in 2 animals. The third dog maintained donor microchimerism with an attenuated CLAD phenotype. These 3 dogs have all been followed up for at least 1 year after transplantation. These results indicate that a nonmyeloablative conditioning regimen with chemotherapy alone is capable of generating stable mixed chimerism and reversal of the disease phenotype in CLAD.

Síndrome de adhesión leucocitaria deficiente: informe de un caso / Leukocyte adhesion deficiency syndrome. A case report

Introducción. El síndrome de adhesión leucocitaria deficiente (ALD) es una alteración de la fagocitosis caracterizada por la deficiencia de una o varias intregrinas a la superfamilia de receptores de la superficie celular y de moléculas de adhesión. Objetivo. Describir las características clínicas de una inmunodeficiencia primaria de prevalencia rara. Caso clínico. Recién nacido masculino de 19 días de vida extrauterina referido al servicio de infectología pediátrica por un cuadro clínico de 15 días de evolución caracterizado por caída tardía del cordón umbilical, fiebre y lesiones dérmicas pápuloeritematosas en el área periumbilical, hipogástrica, inguinal, glútea y en el muslo derecho, misma que progresaron a celulitis y necrosis tisular. Ingresó al hospital con diagnóstico de septicemia secundaria a onfalitis. Hubo respuesta parcial al menejo inicial con antimicrobianos. Posteriormente tuvo infecciones bacteriana y micóticas recurrentes de las vías respiratorias y el tracto gastrointestinal. Tuvo retardo psicomotriz y deterioro severo de su estado nutricional. Falleció por septicemia a los cinco meses de edad. De los exámenes de laboratorio, la biometría hemática mostró leucocitosis persistente entre 42,000 y 133,00 células/mm3, con predominio de neutrófilos, con variaciones entre 64 y 68 por ciento. Se encontró deficiencia de la quimiotaxis de neutrófilos. Por citometría de flujo se observó deficiencia de las adhesinas CD11/18. El resto de los estudios inmunológicos, biopsia de médula ósea y viral fueron normales. Conclusión. Si bien su prevalencia es rara, los defectos de adhesión leucocitaria deben considerarse en los pacientes con caída tardía de cordón umbilical, infecciones severas recurrentes y neutrofilia muy elevada y persistente en quienes se hayan descartado otras inmunodeficiencias primarias y secundarias