The Diagnostic Dilemma of NEMO Syndrome

Abstract

Introduction NEMO syndrome is an X-linked primary immunodeficiency disorder characterized by phenotypic heterogeneity, which complicates its diagnosis and management. Methods This case report describes an 11-year-old patient diagnosed with NEMO syndrome, presenting with early-onset autoinflammatory manifestations and recurrent infections. Case Report The index patient was born to consanguineous parents and developed atopic dermatitis at 2 months of age. At 5 months, he presented with a Kawasaki-like syndrome, followed by recurrent broncho-pneumopathies from ages 3 to 6. A quantitative immunoglobulin assay showed normal levels. At age 7, he was diagnosed with ectodermal anhidrosis, suspected due to the absence of sweating during febrile episodes and the presence of pointed teeth, which was confirmed by skin biopsy. Subsequently, he developed a severe Crohn-like digestive condition with abdominal pain, weight loss, erythema nodosum, and wrist arthritis, accompanied by a persistent inflammatory syndrome. Colonoscopy and MRI revealed inflammatory lesions. Partial remission was achieved with corticosteroids and azathioprine, but infliximab was eventually required. A later immunoglobulin assay revealed hypogammaglobulinemia. These findings, along with recurrent infections and digestive relapses, raised suspicion of an underlying immunodeficiency. An immunological workup and IV immunoglobulin therapy were initially unremarkable. High-throughput sequencing identified a hemizygous IKBKG c.524G>C (p. Arg175Pro) variant—a de novo mutation that does not exist in the mother—which impairs NEMO function and explains the combined phenotype of recurrent infections and immune dysregulation. The child remains stable on regular immunoglobulin therapy, corticosteroids, and immunosuppressive treatment, with no current indication for bone marrow transplantation. Conclusion This case highlights the importance of considering NEMO syndrome in patients with early-onset infections and autoinflammatory manifestations, even in the absence of overt immunological abnormalities. It underscores the critical diagnostic role of genetic testing, particularly targeted sequencing, in atypical and complex presentations.