An introduction to the Diagnostic Criteria for PID

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Mary Ellen Conley, Luigi D. Notarangelo and Amos Etzioni representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)*

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 fulfill 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.

Patients with a probable diagnosis are those with all of the clinical and laboratorycharacteristics of a particular disorder but they do not have a documented abnormality in the gene, the mRNA or the protein that is known to be abnormal in the disorder. They are assumed to have a greater than 85% probability that in 20 years they will be given the same diagnosis. Patients with a possible diagnosis are those that have some but not all of the characteristic clinical or laboratory findings of a particular disorder.

Not all of the patients with mutations in a specific gene will fulfill the criteria for a probable or even a possible diagnosis of the disorder associated with that gene. To indicate the range of findings in patients with mutations in a specific gene or who are diagnosed as having a particular syndrome, a short description of the spectrum of disease has been included for each disorder. However, the description is not meant to be all-inclusive.

Information about the family history can be useful in making a diagnosis of immunodeficiency; however, caution should be used. Approximately 50% of patients with an X-linked immunodeficiency, documented by mutation detection, do not have a family history of immunodeficiency because they are the first manifestation of a new mutation. The presence of consanguinity increases the possibility that a patient has a rare autosomal recessive immunodeficiency, but many patients with rare disorders are compound heterozygotes (have different mutations on the maternal and paternal alleles). In a patient with atypical clinical or laboratory findings, the presence of a sibling with more typical disease can suggest a diagnosis, but does not permit a definitive diagnosis in the absence of mutation detection.

A differential diagnosis is provided for many disorders. For some disorders, exclusion criteria are included. Phenotypic criteria are used to describe patients who have all of the typical findings of a particular disorder but they do not have a mutation in the gene associated with the disorder and they have normal protein for the gene associated with the disorder.

*The following individuals participate in the development of the diagnostic criteria:

Francisco A. Bonilla, Children's Hospital Medical Center, Boston, MA; Ewa Bernatowska, The Children's Memorial Health Institute, Warsaw, Poland; Rebecca H. Buckley, Duke University Medical Center, Durham, NC; A. Wesley Burks, Jr., Arkansas Children's Hospital, Little Rock, AR; Jean-Laurent Casanova, INSERM, Hospital Necker, Paris, France; Helen M. Chapel, Oxford Radcliffe Hospital, Oxford, United Kingdom; Mary Ellen Conley, University of Tennessee College of Medicine and St. Jude Children's Research Hospital, Memphis, TN; Max D. Cooper, University of Alabama, Birmingham, AL; Coleen K. Cunningham, SUNY Health Science Center, Syracuse, NY; Charlotte Cunningham-Rundles, Mount Sinai Medical Center, New York, NY; Martha M. Eibl, University of Vienna, Vienna, Austria; Teresa Espanol, Hospital Vall D'Hesooh, Barcelona, Spain; Amos Etzioni, Rambam Medical Center, Haifa, Israel; Alain Fischer, INSERM, Hospital Necker, Paris, France; Ramsay Fuleihan, Yale University, New Haven, CT; Diana Garcia de Olarte, University of Antioquia, Medellin, Columbia; Richard A. Gatti, UCLA Medical Center, Los Angeles, CA; Raif S. Geha, Children's Hospital Medical Center, Boston, MA; Rolf Gustafson, Huddinge University Hospital, Sweden; Lennart Hammarstrom, Center for Biotechnology, Novum, Sweden; A. K. Junker, University of British Columbia, Vancouver, British Columbia, Canada; Barbara Lisowska-Grospierre, INSERM, Hospital Necker, Paris, France; Stephen J. McGeady, Thomas Jefferson School of Medicine, Philadelphia, PA; Luigi D. Notarangelo, University of Brescia, Brescia, Italy; Hans D. Ochs, University of Washington, Seattle, WA; Savita Pahwa, North Shore University Hospital, Manhasset, NY; Robert Roberts, UCLA Medical Center, Los Angeles, CA; Dirk Roos, University of Amsterdam, Amsterdam, Netherlands; Richard Schiff, Miami Children's Hospital, Miami, Florida; Paul R. Scholl, Children's Memorial Hospital, Chicago, IL; Harry W. Schroeder, Jr., University of Alabama, Birmingham, AL; Klaus Schwarz, University of Ulm, Ulm, Germany; Reinhard Seger, University Children's Hospital, Zurich, Switzerland; William T. Shearer, Texas Children's Hospital, Houston, TX; C. I. Edvard Smith, Karolinska Institute, Huddinge, Sweden; Ricardo U. Sorensen, Louisiana State University, New Orleans, LA; John L. Sullivan, University of Massachusetts, Worcester, MA; Kathleen E. Sullivan, Children's Hospital of Philadelphia, Philadelphia, PA; Diane W. Wara, UCSF Medical Center, San Francisco, CA; David Webster, Royal Free Hospital, London, United Kingdom; Kenneth Weinberg, Children's Hospital of Los Angeles, Los Angeles CA; Jerry A. Winkelstein, Johns Hopkins University, Baltimore, MD.