The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.

which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.
Keywords Primary immunodeficiencies . Classification . Phenotypic . IUIS . Inborn errors of immunity Human primary immunodeficiency diseases (PID) comprise 330 distinct disorders with 320 different gene defects listed [1]. Long considered as rare diseases, recent studies tend to show that they are more common than generally thought, if only by their rapidly increasing number [2,3].The International Union of Immunological Societies (IUIS) PID expert committee proposed a PID classification since 1999 [1], which facilitates clinical research and comparative studies worldwide; it is updated every other year to include new disorders or disease-causing genes. This classification is organized in tables, each of which groups PIDs that share a given pathogenesis. As this catalog is not adapted for use by the clinician at the bedside, the now called Inborn Errors of Immunity Committee proposed since 2013 a phenotypic complement to its classification [4]. Moreover, a smartphone application has been published, based on the 2015 phenotypic classification [5]. As the number of inborn errors of immunity is quickly increasing, and at an even faster pace since the advent of next-generation sequencing, this phenotypic classification requires revision at the same pace as the classical IUIS classification.
Here, we present an update of these figures (Figs. 1, 2, 3, 4, 5, 6, 7, 8, and 9), based on the accompanying 2017 report in inborn errors of immunity. We included all diseases included in the 2017 update of the IUIS classification [1] and split some categories in two parts to ease the lecture. An algorithm was assigned to each of the nine main groups of the classification and the same color was used for each group of similar conditions. Disease names are presented in red and genes in bold and italics. Mode of inheritance is expressed when adequate; if not expressed, the default mode of transmission is autosomal recessive. Clinical features that point to several diseases are presented in italics before the disease names. (a) Severe combined immunodeficiencies SCID, defined by CD3 T cell lymphopenia*.

MSH6. MSH6 .
Family or personal history of cancer. Variable IgG, defects, increased IgM in some, Nl Bc, low switched memory Bc.

Isotype, Light Chain, or FuncƟonal Deficiencies with Generally Nl Numbers of Bc
Ig heavy chain mutaƟons and deleƟons. MutaƟon or chromosomal deleƟon at 14q32. May be asymptomaƟc. One or more IgG and/or IgA subclasses as well as IgE may be absent.

Isolated IgG subclass deficiency. Unknown.
Usually asymptomaƟc, a minority may have poor anƟbody response to specific anƟgens and recurrent viral/bacterial infecƟons. ReducƟon in one or more IgG subclass.
IgG subclass deficiency with IgA deficiency. Unknown. Recurrent bacterial infecƟons. Reduced IgA with decrease in one or more IgG subclass.

SelecƟve IgA deficiency. Unknown.
Bacterial infecƟons, autoimmunity mildly increased. Very low to absent IgA with other isotypes normal, normal subclasses and specific anƟbodies.

Specific anƟbody deficiency with normal Ig levels and normal B cells. Unknown.
Reduced ability to produce anƟbodies to specific anƟgens. Ig: Nl.

Transient hypogammaglobuliemia of infancy. Unknown.
Usually not associated with significant infecƟons, normal ability to produce anƟbodies to vaccine anƟgens. IgG and IgA decreased.

High Bc numbers due to consƟtuƟve NF-κB acƟvaƟon
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