When to Consider an Inborn Error of Immunity: A Guide for Physicians

Introduction The term inborn errors of immunity (IEIs) refers to the rapidly expanding group of genetic disorders causing dysregulation of the immune system. With improved genetic testing in recent years, the number of defined IEIs and their range of phenotypic presentations have grown vastly, with more than 480 IEIs now described. This review outlines common IEIs with a focus on clinical presentations across different specialties, including guidelines regarding when an underlying IEI should be considered. Method We conducted a comprehensive review of peer-reviewed articles, registries, and case series describing systemic manifestations in IEIs, focusing on clinical and biochemical diagnostic features. Results IEIs cause diverse clinical manifestations, including infection, autoimmunity, lymphoproliferation, allergy, and malignancy, with initial manifestations often appearing long before the diagnosis of an IEI is made. Furthermore, IEIs are increasingly diagnosed in adulthood, and a family history of disease is not always apparent. Physicians in all specialties are likely to encounter patients with IEIs, often before a formal diagnosis of an IEI is made or immunology consultation sought. Early diagnosis of an IEI improves patient outcomes through access to specialist immunology services and the potential for more specific, targeted treatment options. Conclusion Early diagnosis of IEIs remains a challenge due to the wide array of clinical manifestations. All physicians need an understanding of IEIs and presenting manifestations to facilitate timely diagnosis, immunologist referral, and potential access to targeted therapies.