Omenn syndrome represents a therapeutic challenge as a state of florid immune dysregulation born out of autoreactive oligoclonal T cells due to hypomorphic variants in genes associated with severe combined immunodeficiency (SCID). In the era of newborn screening, patients with Omenn SCID are often identified earlier in the disease course with a more subtle clinical presentation than is classically taught. With appropriate screening and subsequent management, outcomes of Omenn syndrome may be improved.
We analyzed the patients diagnosed with Omenn syndrome at the Children’s Hospital of Philadelphia from 2007 to 2025 (n = 7). Data collected included initial presenting signs and symptoms, laboratory features at diagnosis and over time, and management strategy.
The patients in this series were diagnosed with Omenn syndrome at a median age of 9 days (interquartile range [IQR] 7-12) and were 57% female, and six had RAG1-associated SCID (86%). Frequent signs at diagnosis included rash (100%), lymphadenopathy (43%), and hepatomegaly and/or splenomegaly (43%). Common laboratory features at diagnosis were greater than 80% of CD4 T cells with memory phenotype (100%), eosinophilia (86%), elevated IgE (71%), abnormal T cell receptor excision circles (TREC; 100%), and oligoclonal T cells (14%, only 1 patient with T cell receptor vβ repertoire analysis pre-transplant). Maternal engraftment was negative in the six patients for whom it was tested; the only patient not tested was born in 2009. All patients were treated with systemic corticosteroids, 86% with tacrolimus, 29% with cyclosporine, and 29% with antithymocyte globulin. Median age at transplant was 90 days (IQR 73-94). The median time from Omenn syndrome presentation to transplant was 70 days (IQR 64-82).
We describe seven patients with Omenn syndrome diagnosed and managed early in life at a single center. Patients demonstrated the characteristic clinical and laboratory findings consistent with Omenn syndrome, with all presenting with a rash and nearly half with lymphadenopathy and hepatomegaly and/or splenomegaly. Most patients had eosinophilia and elevated IgE levels, and all patients had abnormal TREC results and greater than 80% of CD4 T cells with memory phenotype. The majority were successfully managed with systemic corticosteroids and tacrolimus alone, without the need for cyclosporine or antithymocyte globulin. Early diagnosis of Omenn syndrome facilitated timely initiation of targeted therapy and progression to hematopoietic stem cell transplantation within the first three months of life.
