Allogeneic stem cell transplantation from an HLA-mismatched unrelated donor was performed for a patient with leukocyte adhesion deficiency type III with a myeloablative regimen including full-dose busulfan. Mixed chimerism with donor-derived T cells at less than 10% was observed within 4 weeks after transplantation. Repeated cycles of discontinuation and resumption of tacrolimus early after transplantation were performed with the aim of reversing the recipient-dominant T-cell chimerism. Specifically, tacrolimus was quickly tapered on day 15 and discontinued on day 20 when the recipient's chimerism increased, and resumed upon the observation of early signs of acute graft-versus-host disease, such as fever and skin rash, on day 24. This process was repeated from day 30 to day 44. All subsets, including granulocytes, T cells, and natural killer cells, attained donor chimerism of more than 90% on day 42 after transplantation and 100% at day 82 and beyond. Immunosuppressant dosage adjustments may be a treatment option for mixed chimerism after stem cell transplantation.

Leukocyte adhesion deficiency III (LAD III) is a very rare autosomal recessive primary immunodeficiency characterized by recurrent infections without pus formation and bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the FERMT3 gene, which encodes kindlin-3, an integrin-binding protein. We present a toddler with unique symptom of intestinal perforation followed by prolonged bleeding due to Glanzmann-like thrombasthenia who was diagnosed as LAD-III. This report presents a toddler with leukocyte adhesion deficiency type III (LAD III), who was diagnosed because of protracted surgical wound and gastrointestinal bleeding following surgery for small bowel perforation at the age of 16 months. The patient's history was positive for febrile episodes after vaccinations, recurrent pulmonary infections, frequent severe epistaxis and ecchymotic purpuric lesions since early infancy. The presence of severe bleeding symptoms encouraged us to consider LAD III. Accordingly, sanger sequencing was performed which identified that the patient was homozygote for mutation in exon 14 of FERMT3 gene, the gene encoding for kindlin-3. Our patient also showed low percentages of CD16 and CD56 on peripheral blood flow cytometry, an unheard finding in LAD type III. LAD III should be considered in differential diagnosis of any child with recurrent infections, persistent leukocytosis, and bleeding disorders. This is the first case of LAD III presenting with intestinal perforation. The present case also showed low percentage of natural killer cells which should be followed in further studies.

Leukocyte adhesion deficiency type III (LAD-III) is caused by amino acid mutations in Kindlin-3, which result in integrin activation defects. The QW motif in the Kindlin family is particularly important for integrin activation, and the Q595P mutation in the QW motif of Kindlin-3 leads to LAD-III. However, the molecular mechanisms underlying this disruption remain unclear. In this study, we employed molecular dynamics (MD) and steered MD simulations to investigate how the pathogenic Q595P mutation in Kindlin-3 alters its interaction with β1-integrin under physiological conditions. Our results show that the Q595P mutation induces conformational changes in neighboring residues, leading to a reduction in binding affinity, specificity, and mechanical strength, primarily driven by hydrophobic changes. Specifically, the Q595P mutation disrupts the torsional dynamics of residues at the Kindlin-3 binding interface by disturbing the hydrophobic environment, weakening the hydrogen bonds that are essential for stabilizing the Kindlin-3/β1-integrin interaction under both forceful and nonforceful conditions. Additionally, it enhances nonspecific hydrophobic interactions on nonbinding surfaces, further destabilizing the overall binding. These findings provide important insights into the molecular mechanisms by which pathogenic mutations in conserved regions of Kindlin-3 lead to integrin activation defects and contribute to the pathogenesis of LAD-III.

Leukocyte adhesion deficiency type III (LAD-III) is a rare autosomal recessive disorder characterized by immune dysfunction and bleeding tendencies. The condition arises from mutations in the FERMT3 gene, which disrupts integrin activation on leukocytes and platelets. This case study focuses on a family with consanguineous parents and multiple affected individuals spanning two generations, all diagnosed with LAD-III due to a novel homozygous mutation in the FERMT3 gene (c.1683-22_1683-19del). Clinical manifestations ranged from mild ecchymosis to severe bleeding necessitating transfusions. The proband, a two-year-old male child, presented with recurrent ecchymosis, neonatal sepsis, and thrombocytopenia. His laboratory results included leukocytosis and microcytic hypochromic anemia with normal coagulation profiles. The diagnosis of LAD-III was confirmed through whole exome sequencing that identified the homozygous FERMT3 mutation. Additionally, the proband's 15-year-old sister, who had been earlier diagnosed with Glanzmann thrombasthenia, was found to carry the same mutation, as were the proband's cousin and the cousin of his father.