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RAC2-related immunodeficiency is a rare inborn error of immunity with a broad clinical spectrum ranging from neonatal severe combined immunodeficiency to atypical combined immunodeficiency diagnosed later in life. We describe two unrelated French-Canadian patients carrying a rare, homozygous RAC2 variant (c.202C>T; p.R68W), both presenting with combined immunodeficiency. The first patient developed recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy. She subsequently experienced severe, treatment-refractory cutaneous viral infections. In adulthood, she developed gynecologic and anal neoplasms associated with chronic viral disease, requiring long-term multidisciplinary management. The second patient presented in early childhood with recurrent respiratory infections, marked lymphoproliferation, and generalized lymphadenopathy. He then developed kidney dysfunction due to light-chain deposition disease. Management included immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement. Genetic testing identified the same homozygous p.R68W substitution in both patients. Despite significantly reduced RAC2 protein expression, patient-derived cells exhibited increased effector signaling in the homozygous state, producing a phenotype that phenocopies dominant gain-of-function RAC2 variants. Functional hyperactivation was not observed in heterozygous cells, supporting a dosage-dependent mechanism. These cases expand the clinical and functional spectrum of RAC2 deficiency and have immediate implications for clinical care. Persistent viral disease with oncogenic complications, bronchiectasis, lymphoproliferation, or progressive organ involvement should prompt consideration of RAC2 testing even beyond infancy. From a diagnostic standpoint, reliance on expression alone may be misleading; incorporating targeted signaling assays is essential for accurate variant interpretation. Therapeutically, HCT can be effective in progressive disease with organ damage, while others may require long-term medical management of chronic viral complications. Recognizing this rare, homozygous p.R68W variant and its functional consequences supports a precision-diagnosis approach to RAC2-related immunodeficiency and refines surveillance and treatment strategies for affected patients.

Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.

CD8A encodes the CD8α chain of the dimeric CD8 protein, a critical coreceptor of cytotoxic T cells. We report here the comprehensive immunological evaluation of a child with a CD8A missense mutation, providing evidence that CD8 deficiency increases susceptibility to recurrent respiratory infections without interfering with the TCR-mediated proliferation of T cells. These observations expand the known phenotypes associated with CD8 deficiency.

We report the first prospective study describing the prevalence and clinical consequences of norovirus infection in hospitalized children with primary immunodeficiencies. Fecal samples from 62 children were systematically screened for virus. Norovirus was the most frequent pathogen (11 of 24 positive samples) found in both combined and humoral immunocompromised children. Norovirus shedding was associated with gastrointestinal symptoms and concomitant viremia in 54.5% and 25% of cases, respectively. Norovirus excretion was prolonged: 57.1% of fecal samples were still positive after a median of 9.5-months follow-up. Further large longitudinal studies are needed to evaluate the clinical consequences of norovirus shedding in patients with primary immunodeficiencies.

CD8A encodes the CD8[alpha] chain of the dimeric CD8 protein, a critical coreceptor of cytotoxic T cells. We report here the comprehensive immunological evaluation of a child with a CD8A missense mutation, providing evidence that CD8 deficiency increases susceptibility to recurrent respiratory infections without interfering with the TCR-mediated proliferation of T cells. These observations expand the known phenotypes associated with CD8 deficiency.