Double-hit RAG2 mutation presenting with hyper-immunoglobulin E and preserved T cells diagnostic challenge: a case...

This case represents a 2-month old female infant with a rare and challenging case of Omenn syndrome that was the result of a compound heterozygous mutation in recombination-activating gene 2, an occurrence infrequently documented in the literature. The presentation was challenging as the patient complained of recurrent infections and generalized rash. Immunological workup demonstrated preserved T cells and extremely high immunoglobulin E levels. This case highlights the significance of considering leaky severe combined immunodeficiency in the differential diagnosis of early life erythroderma and recurrent infections, despite the absence of typical severe combined immunodeficiency findings.

We report the case of a 2-month-old Palestinian Arab female infant, born to nonconsanguineous parents, with a positive family history of immunodeficiency, who presented with persistent high-grade fever, diffuse erythrodermic rash, recurrent lower respiratory tract infections, and failure to thrive. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. Initial laboratory investigations showed eosinophilia and markedly elevated serum immunoglobulin E levels. Immunological workup demonstrated profound B-cell lymphopenia, preserved natural killer cell counts, and a cluster of differentiation 4/cluster of differentiation 8 T-cell imbalance. Chest radiography revealed absence of a thymic shadow. Whole exome sequencing identified compound heterozygous mutations in the recombination-activating gene 2, confirming the diagnosis of Omenn syndrome. The patient received aggressive antimicrobial therapy and supportive immunologic care. Despite optimal medical management, she succumbed to infection-related complications at 7 months of age, prior to undergoing hematopoietic stem cell transplantation.

This case underscores the diagnostic and therapeutic challenges in managing Omenn Syndrome, particularly in settings where routine newborn screening for severe combined immunodeficiency is not available. Early recognition and genetic diagnosis are vital to initiate life-saving interventions such as hematopoietic stem cell transplantation. Increased awareness among clinicians regarding atypical presentations of primary immunodeficiency can lead to earlier referrals, improved outcomes, and reduction in diagnostic delays.