Case Report: Activated phosphoinositide 3-kinase δ syndrome mimicking Hyper-IgM syndrome: early hepatosplenomegaly as a key diagnostic clue.
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BACKGROUND: APDS is a combined immunodeficiency disorder, characterized by impaired antibody production and lymphoproliferation, with a high risk of malignancy and autoimmunity. The disease may be caused by autosomal dominant gain-of-function variants in the PIK3CD or loss-of-function variants in the PIK3R1 gene. CASE SUMMARY: We report an 11-year-old girl with a history of recurrent respiratory infections, lymphoproliferation, and hepatosplenomegaly from early childhood. She was diagnosed with Hyper-IgM syndrome (HIGM) because of decreased IgA and IgG but increased IgM, and was treated with immunoglobulin replacement therapy, but there was no improvement in respiratory symptoms, and hepatosplenomegaly remained marked. Immunologic testing showed that, in addition to a reduced peripheral B-cell count, there was also a reduced CD4+ T-cell count and an inverted CD4/CD8 ratio, suggesting a diagnosis other than classical HIGM. The patient was diagnosed with APDS, confirmed by whole-exome sequencing, identifying the PIK3CD c.3061G>A p.(Glu1021Lys) variant. OUTCOME: The patient maintained on immunoglobulin replacement therapy and corticosteroid therapy, with subsequent addition of sirolimus, and showed a rapid response with improvement in chronic productive cough, enlarged lymph nodes, and hepatosplenomegaly after 2 months. After 6 months of treatment, lymphodenopathy had resolved, and the liver and spleen returned to normal size. CONCLUSION: Early hepatosplenomegaly and lymphadenopathy are important warning signs of APDS in children with a Hyper IgM-like phenotype. This is particularly relevant in patients with CD4+ T-cell lymphopenia, an inverted CD4/CD8 ratio, and marked B-cell lymphopenia. Sirolimus improved lymphoproliferative manifestations and partially controlled chronic respiratory and gastrointestinal disease but did not eliminate the need for immunoglobulin replacement therapy.