Mary Ellen Conley, Luigi D. Notarangelo and Amos Etzioni
Representing PAGID (Pan- American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)1
Clin. Immunol. 1999 93(3):190-197 
The identification of many genes responsible for primary immunodeficiencies has provided us with a new perspective to evaluate these disorders. It has 1) clarified the clinical and laboratory findings that are most consistently associated with a specific gene; 2) demonstrated the spectrum of clinical severity seen in a particular disorder; and, 3) shown that not all of the patients with identical clinical and laboratory findings have mutations in the same gene. This new information allows us to re-evaluate the criteria that we use to make diagnoses.
The diagnostic criteria are meant to establish simple, objective and clear guidelines that ensure that different physicians and scientists are using the same definitions when they include patients in research studies. They may also help physicians formulate a diagnosis in patients with abnormalities of the immune system. The diagnostic criteria are divided into three categories: definitive, probable and possible. To guard against the inclusion of patients who have polymorphic variants in the genes associated with immunodeficiency, and to specify the clinical or laboratory finding that is most consistently abnormal in a particular disorder, the patient must fulfil an inclusion criterion which is characteristic of the disorder.
The patients with a definitive diagnosis are assumed to have a greater than 98% probability that in 20 years they would still be given the same diagnosis. Mutation detection is the most reliable method of making a diagnosis. In some disorders the absence of the specific mRNA or protein is diagnostic. In others, the mRNA and/or protein may be only transiently expressed, may be produced at very low levels, or clinically useful assays may not yet have been developed. The clinical and laboratory findings in several of the X-linked immunodeficiencies are sufficiently distinctive that these findings, when coupled with a family history of disease that is specific to X-linked inheritance, can be used to make a definitive diagnosis. In families with a known mutation in a particular gene, mutation detection can be used to provide a definitive diagnosis in a newborn or fetus.
