Novel gain-of-function mutation in STAT1 protein with ALPS-like presentation

Background: Germline mutations in STAT1 lead to primary immunodeficiency affecting both intrinsic and innate immunity. These immunodeficiencies can manifest as either loss-of-function (LOF) mutations or gain-of-function (GOF) mutations. LOF mutations result in a significant reduction in STAT1 protein functionality and are associated with Mendelian susceptibility to mycobacterial disease. Conversely, GOF mutations occur when a gene undergoes a change that enhances its normal function, resulting in an overactive form of the protein. Heterozygous STAT1 GOF mutations are the predominant cause of Chronic Mucocutaneous Candidiasis (CMC) in individuals with inborn errors of immunity. Aim: The study aims to report the clinical features, immune profile, and unique characteristics of a 9-year-old female patient with GOF mutations in STAT1. Results: We present a case of an 8-year-old female who has been genetically diagnosed with a GOF mutation in the STAT1 gene. The patient’s clinical presentation includes lymphadenopathy, splenomegaly, the presence of non-caseating granulomas, and cytopenia. Notably, there is no evidence of mycobacterial infection typically associated with LOF mutations, nor any indication of fungal, viral, or malignant conditions. Furthermore, there are no signs of endocrine abnormalities such as thyroiditis or diabetes mellitus. The patient’s immunological profile reveals evidence of autoimmunity, including symptoms of arthralgia and oral ulcers. Manual calculations of double negative T cells showed no increase in their numbers. The patient did not exhibit typical signs of CMC but presented with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features, expanding the clinical spectrum of STAT1 GOF mutations. Discussion: The clinical and immunological characteristics of GOF mutations in STAT1 vary considerably among case reports. The current case had no evidence of CMC, thus raising the possibility of ALPS-like syndrome as an extension of the commonly addressed features of GOF mutations. Statement of novelty: The absence of CMC in a patient with GOF mutations in STAT1 is a rare presentation that should be considered when evaluating patients with inborn errors of immunity.