Immunodeficiency 52 (IMD52) is caused by an autosomal recessive LOF mutation in the LAT gene (602354) with variable manifestations, including severe combined immunodeficiency (SCID), autoimmune hematologic disorders, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly.
Patients develop severe recurrent infections in infancy. Without bone marrow transplantation, most patients die.
The clinical features are due to a defect in T cell receptor signaling caused by the LOF mutation in the LAT gene.
Keller et al (2016) reported on three siblings born to consanguineous Arab parents in whom IMD52 manifested as a variable immune disorder with recurrent infections, lymphoproliferation, and autoimmune disease. The course of the disease varied, but all presented between 5 and 10 months of age. The first patient developed autoimmune hemolytic anemia, immune-mediated thrombocytopenia with lymphadenopathy and massive splenomegaly. He died at the age of 7 years after splenectomy, from disseminated CMV infection with pulmonary involvement.
The second patient with this mutation suffered from cerebral palsy and megalocystic leukoencephalopathy, which was probably due to perinatal toxoplasmosis infection. Since his first year of life, he had recurrent respiratory infections with bronchiectasis, hepatosplenomegaly, lymphadenopathy, and persistent papular exanthema. Later in childhood, he developed varicella and CMV infections. At the age of 8 years, he underwent successful hematopoietic stem cell transplantation. Immunological examination revealed profound dysregulation of the immune system: the patient had normal lymphocyte counts and Ig levels at an early age. Later, a progressive breakdown of the immune system developed with lymphocytopenia of CD4+ T cells and B cells and hypogammaglobulinemia.
Bacchelli et al (2017) reported a consanguineous Pakistani family in which severe combined T, B+, NK+ immunodeficiency manifested in 5 patients IMD52. Clinically, severe recurrent infections and failure to thrive were evident. T-cells were reduced, and a lack of proliferative response of T-cells was demonstrable. B and NK cell counts were normal.