X-linked severe combined immunodeficiency due to IL2RG p.V223F variant: clinical evidence that support its...

Severe combined immunodeficiency (SCID) comprises a group of life-threatening inborn errors of immunity (IEI) characterized by profound T-cell deficiency, frequently accompanied by impaired B cell and natural killer (NK) cell function. X-linked SCID (X-SCID), caused by pathogenic variants in IL2RG, accounts for approximately 30% of all SCID cases.

We describe two male siblings born to consanguineous parents with a family history of early sibling deaths due to severe infections. Patient 1 was a 9-month-old boy who developed persistent cough, chronic diarrhea, and subcutaneous nodules following Bacillus Calmette-Guérin (BCG) vaccination. He was subsequently diagnosed with disseminated BCG infection with concomitant Salmonella co-infection. Immunological evaluation revealed a T-B+NK- phenotype. Despite intensive antimicrobial treatment, he died of septic shock at 12 months of age. Patient 2, a one-month-old boy, was evaluated early in life because of family history. Immunophenotyping demonstrated absent T cells, normal B cells, and reduced NK cells, along with the absence of a thymic shadow on chest radiography. Next-generation sequencing identified a hemizygous IL2RG c.667G>T (p.V223F). He received antimicrobial prophylaxis and immunoglobulin replacement therapy; however, he developed disseminated adenovirus infection and died at 8 months of age. Molecular Findings: In silico analyses (UniProt, HOPE, dbNSFP) consistently supported the pathogenic effect of the variant IL2RG p.V223F. Based on this evidence, we propose that its current classification as "likely pathogenic" should be updated to "pathogenic".

These cases underscore the challenges faced by patients with SCID when timely access to curative therapy is not available. They also highlight the importance of readily accessible but highly informative diagnostic clues, such as the absence of a thymic shadow on chest radiography and the occurrence of severe complications following BCG vaccination. Conclusions: This report expands the known genotypic and phenotypic spectrum of SCID and reinforces the critical need for early diagnosis, appropriate genetic counseling in consanguineous families, and equitable access to newborn screening programs and curative treatments, including hematopoietic stem cell transplantation and gene therapy, in order to improve survival outcomes.