LADIII

LADIII, also known as leukocyte adhesion deficiency type 3, is a rare autosomal recessive immunodeficiency characterized by defective activation of integrins on leukocytes and platelets. The condition arises from mutations in the FERMT3 gene, which encodes the protein kindlin-3. This defect disrupts inside-out signaling necessary for integrin activation, leading to impaired leukocyte adhesion and platelet function despite normal surface expression of some adhesion molecules.

The loss of integrin activation prevents firm adhesion and transmigration of neutrophils to sites of infection, resulting in recurrent infections and poor inflammatory responses. Platelet dysfunction adds a bleeding tendency, contributing to mucosal bleeding and bruising. Patients typically present in infancy with severe infections, impaired wound healing, absence of pus at infection sites, and significant bleeding episodes. Leukocyte counts are often elevated due to impaired migration rather than reduced production.

Diagnosis involves a combination of clinical assessment and laboratory testing. Flow cytometry can show normal expression of leukocyte integrins but impaired activation in response to stimuli. Genetic testing identifies biallelic FERMT3 mutations. Functional assays may corroborate defective integrin activation. The rarity of LADIII and overlap with other immunodeficiencies necessitate specialist evaluation.

Treatment focuses on eliminating the underlying defect and managing symptoms. Hematopoietic stem cell transplantation can be curative, restoring functional hematopoietic cells with proper integrin activation. Supportive care includes antimicrobial prophylaxis, aggressive treatment of infections, and management of bleeding episodes, sometimes requiring platelet transfusions. The prognosis improves with transplantation, but without definitive therapy, LADIII is associated with significant morbidity and mortality.