Late-Onset X-Linked Lymphoproliferative Disease Type 1 (XLP-1): A Mild Phenotype Possibly Explained by Somatic Reversion in SH2D1A

Introduction X-linked lymphoproliferative disease type 1 (XLP-1) is caused by pathogenic variants in the SH2D1A gene, which encodes the SLAM-associated protein (SAP). Patients develop hypo-gammaglobulinemia and are highly susceptibility to EBV infection. Somatic reversion of inherited variants may lead to mosaicism and milder clinical phenotypes. Presentation of the Case We report a 46-year-old male with a diagnosis of common variable immunodeficiency (CVID) at age 34, who presented with two episodes of meningococcal meningitis within 8 months, both requiring hospitalization. Since childhood, he had chronic sinusitis and recurrent pneumonia, several of which also required hospitalization. Notably, there was no clinical or serological evidence of previous Epstein–Barr virus (EBV) infection. At diagnosis, laboratory studies revealed hypogammaglobulinemia affecting all isotypes and a reduced memory B cell compartment genetic testing through whole exome sequencing identified a hemizygous pathogenic variant in SH2D1A (c.251T>C). Natural killer T cells were present (0.08%) but TCRVb11 and TCRVa24 expressed with a lower intensity compared to normal. SAP expression in CD3+T cells by flow cytometry revealed a bimodal pattern with 97% of cells negative and 3% showing a normal SAP expression. Cell sorting followed by Sanger sequencing demonstrated absence of the pathogenic variant in the SAP-positive population and presence of the variant in SAP-deficient cells, consistent with somatic reversion. Conclusion This case highlights an atypical, late-onset and relatively mild presentation of XLP-1, likely influenced by the presence of a small reverted T cell population. Although detected late in life, these reverting cells may have contributed to a less severe disease course.