The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies

Abstract

There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.

Introduction

Human Primary Immunodeficiency Diseases (PID) comprise at least 300 genetically-defined single-gene inborn errors of immunity [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]. They may be even more common, if we consider the emerging monogenic determinants leading to common infectious diseases, such as severe influenza [3]; autoimmune diseases, such as systemic lupus erythematosus [4], and auto-inflammatory diseases, such as Crohn’s disease [5]. The International Union of Immunological Societies (IUIS) PID expert committee has proposed a PID classification [1], which facilitates clinical research and comparative studies world-wide; 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 classification may be cumbersome for use by the clinician at the bedside, the IUIS PID expert committee recently proposed a phenotypic complement to its classification [6]. As the number of PIDs is quickly increasing, and at an even faster pace since the advent of next-generation sequencing, the phenotypic classification from 2013 became outdated and requires revision at the same pace as the classical IUIS classification. Our original phenotypic classification proved successful, which placed it in the 96th percentile for citation rank in Springer journals [7]. Given the success of our user-friendly classification of PIDs, providing a tree-based decision-making process based on the observation of clinical and biological phenotypes, we present here an update of these figures, based on the accompanying 2015 PID classification.

Methodology

We included all diseases included in the 2015 update of the IUIS PID classification [1], keeping the nine major categories unchanged. In addition, we considered other articles proposing a PID classification published recently [8, 9]. 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. In addition, we classed diseases or genes from most common to less common, at the best of our knowledge [10, 11]. These algorithms were first established by a small committee; then validated by one or two experts for each figure.

Results

An update of our classification, validated by the IUIS PID expert committee, is presented in Figs. 1, 2, 3, 4, 5, 6, 7, 8 and 9.

Fig. 1.

Immunodeficiencies affecting cellular and humoral immunity. ADA Adenosine Deaminase, Adp adenopathy, AR Autosomal Recessive inheritance, CBC Complete Blood Count, CD Cluster of Differentiation, CID Combined Immunodeficiency, EBV Epstein-Barr Virus, EO Eosinophils, HHV8 Human Herpes virus type 8, HIGM Hyper IgM syndrome, HLA Human Leukocyte Antigen, HSM Hepatosplenomegaly, HPV Human papilloma virus, IBD Inflammatory bowel disease, Ig Immunoglobulin, MC Molluscum contagiosum, N Normal, not low, NK Natural Killer, NN Neonatal, NP Neutropenia, SCID Severe Combined ImmunoDeficiency, Staph Staphylococcus sp., TCR T-Cell Receptor, XL X-Linked

Fig. 2.

CID with associated or syndromic features. These syndromes are generally associated with T-cell immunodeficiency. αFP alpha- fetoprotein, AD Autosomal Dominant inheritance, AR Autosomal Recessive inheritance, CMF Flow cytometry available, EDA Anhidrotic ectodermal dysplasia, EDA-ID Anhidrotic Ectodermal Dysplasia with Immunodeficiency, FILS Facial dysmorphism, immunodeficiency, livedo, and short stature, FISH Fluorescence in situ Hybridization, HSM Hepatosplenomegaly, HSV Herpes simplex virus, Ig Immunoglobulin, VZV Varicella Zoster virus, WAS Wiskott-Aldrich syndrome, XL X-Linked inheritance

Fig. 3.

Predominantly Antibody deficiencies. Ab Antibody, Adp adenopathy, Anti PPS Anti- pneumococcus Antibody, AR Autosomal Recessive inheritance, CD Cluster of Differentiation, CDG-IIb Congenital disorder of glycosylation, type IIb, CMV Cytomegalovirus, CT Computed Tomography, EBV Epstein-Barr Virus, Dip Diphtheria, GI Gastrointestinal, Hib Haemophilus influenzae serotype b, Hx medical history, Ig Immunoglobulin, SPM Splenomegaly, subcl subclass, Tet Tetanus, XL X-Linked inheritance

Fig. 4.

Diseases of Immune Dysregulation. AD Autosomal Dominant inheritance, ALPS Autoimmune lymphoproliferative syndrome, AR Autosomal Recessive inheritance, CD Cluster of Differentiation, CMF Flow cytometry available, CSF Cerebrospinal fluid, CTL Cytotoxic T-Lymphocyte, EBV Epstein-Barr Virus, GOF Gain-of-function, HLH Hemophagocytic lymphohistiocytosis, HSM Hepatosplenomegaly, IBD Inflammatory bowel disease, IFNγ Interferon gamma, Ig Immunoglobulin, IL interleukin, Inflam Inflammation, NK Natural Killer, NKT Natural Killer T cell, T T lymphocyte, XL X-Linked inheritance

Fig. 5.

Congenital defects of phagocyte number, function, or both. For DHR assay, the results can distinct XL-CGD from AR-CGD, and gp40phox defect from others AR forms. AD Autosomal Dominant inheritance, AML Acute Myeloid Leukemia, AR Autosomal Recessive inheritance, BCG Bacilli Calmette-Guérin, CBC Complete Blood Count, CD Cluster of Differentiation, CGD Chronic Granulomatous Disease, CMML Chronic MyeloMonocytic Leukemia, DHR DiHydroRhodamine, IUGR Intrauterine growth retard, LAD Leukocyte Adhesion Deficiency, NP Neutropenia, PNN Neutrophils, SCN Severe congenital neutropenia, WBC White Blood Cells, XL X-Linked inheritance

Fig. 6.

Defects in Intrinsec and Innate Immunity. AD Autosomal Dominant inheritance, AR Autosomal Recessive inheritance, BCG Bacilli Calmette-Guérin, BL B lymphocyte, CMC Chronic mucocutaneous candidiasis, HSV Herpes simplex virus, IFNγ Interferon gamma, Ig Immunoglobulin, IL interleukin, LOF Loss-of-function, MSMD Mendelian Susceptibility to Mycobacterial Disease, PMN Neutrophils, XL X-Linked inheritance

Fig. 7.

Autoinflammatory Disorders. AD Autosomal Dominant inheritance, AR Autosomal Recessive inheritance, CAMPS CARD14 mediated psoriasis, CANDLE Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, CAPS Cryopyrin-Associated Periodic syndromes, CINCA Chronic Infantile Neurologic Cutaneous and Articular syndrome, DA Duration of Attacks, DITRA deficiency of interleukin 36 Receptor antagonist, FA Frequency of Attacks, HIDS Hyper IgD syndrome, Ig Immunoglobulin, IL interleukin, MKD Mevalonate Kinase deficiency, MWS Muckle-Wells syndrome, NOMID Neonatal Onset Multisystem Inflammatory Disease, PAPA Pyogenic sterile Arthritis, Pyoderma gangrenosum, Acne syndrome, SPM Splenomegaly, TNF Tumor Necrosis Factor, TRAPS TNF Receptor-Associated Periodic Syndrome

Fig. 8.

Complement deficiencies. AD Autosomal Dominant inheritance, GOF Gain-of-function, LOF Loss-of-function, LAD Leukocyte Adhesion Deficiency, SLE Systemic Lupus Erythematosus

Fig. 9.

Phenocopies of primary immunodeficiencies. Ab Antibody, ALPS Autoimmune lymphoproliferative syndrome, CMC Chronic mucocutaneous candidiasis, CID Combined Immunodeficiency, HUS Hemolytic uremic syndrome, IFNγ Interferon gamma, IL Interleukin, MSMD Mendelian Susceptibility to Mycobacteria Disease, VZV Varicella Zoster virus

Discussion

Since our 2013 study, 70 new diseases have been included in the 2015 classification. Four disorders have been removed, as the reports concerning associated immunodeficiency or genetic base were not confirmed. We also eliminated duplication of a disease in more than one figure and profoundly revised some figures, following the 2015 IUIS classification.

Conclusion

The IUIS PID expert committee developed this phenotypic classification in order to help clinicians at the bedside to diagnose PIDs but also to promote collaboration with national and international research centers. Needless to say, the expert committee encourages the development of other types of PID classification. Indeed, given the success encountered by the two current IUIS classifications, others classifications are likely to be useful and complementary.

Abbreviations

αFP

Alpha- fetoprotein

Ab

Antibody

AD

Autosomal dominant inheritance

ADA

Adenosine deaminase

Adp

Adenopathy

ALPS

Autoimmune lymphoproliferative syndrome

AML

Acute myeloid leukemia

Anti PPS

Anti- pneumococcus antibody

AR

Autosomal recessive inheritance

BCG

Bacilli Calmette-Guerin

BL

B lymphocyte

CAMPS

CARD14 mediated psoriasis

CANDLE

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome

CAPS

Cryopyrin-associated periodic syndromes

CBC

Complete blood count

CD

Cluster of differentiation

CDG-IIb

Congenital disorder of glycosylation, type IIb

CGD

Chronic granulomatous disease

CID

Combined immunodeficiency

CINCA

Chronic infantile neurologic cutaneous and articular syndrome

CMC

Chronic mucocutaneous candidiasis

CMF

Flow cytometry available

CMV

Cytomegalovirus

CMML

Chronic myelomonocytic leukemia

CNS

Central nervous system

CSF

Cerebrospinal fluid

CT

Computed tomography

CTL

Cytotoxic T-lymphocyte

DA

Duration of attacks

Def

Deficiency

DHR

DiHydroRhodamine

Dip

Diphtheria

DITRA

Deficiency of interleukin 36 receptor antagonist

EBV

Epstein-Barr virus

EDA

Anhidrotic ectodermal dysplasia

EDA-ID

Anhidrotic ectodermal dysplasia with immunodeficiency

EO

Eosinophils

FA

Frequency of attacks

FCAS

Familial cold autoinflammatory syndrome

FILS

Facial dysmorphism, immunodeficiency, livedo, and short stature

FISH

Fluorescence in situ hybridization

GI

Gastrointestinal

GOF

Gain-of-function

HHV8

Human herpes virus type 8

Hib

Haemophilus influenzae serotype b

HIDS

Hyper IgD syndrome

HIES

Hyper IgE syndrome

HIGM

Hyper Ig M syndrome

HLA

Human leukocyte antigen

HLH

Hemophagocytic lymphohistiocytosis

HPV

Human papilloma virus

HSM

Hepatosplenomegaly

HSV

Herpes simplex virus

HUS

Hemolytic uremic syndrome

Hx

Medical history

IBD

Inflammatory bowel disease

IFNγ

Interferon gamma

Ig

Immunoglobulin

IL

Interleukin

IUGR

Intrauterine growth retard

LAD

Leukocyte adhesion deficiency

LOF

Loss-of-function

MC

Molluscum contagiosum

MKD

Mevalonate kinase deficiency

MSMD

Mendelian susceptibility to mycobacterial disease

MWS

Muckle-wells syndrome

N

Normal, not low

NK

Natural killer

NKT

Natural killer T cell

NN

Neonatal

NOMID

Neonatal onset multisystem inflammatory disease

NP

Neutropenia

PAPA

Pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome

PMN

Neutrophils

SCID

Severe combined immuno deficiency

Sd

Syndrome

SLE

Systemic lupus erythematosus

SPM

Splenomegaly

Staph

Staphylococcus sp.

subcl

Subclass

TCR

T-cell receptor

Tet

Tetanus

T

T lymphocyte

TNF

Tumor necrosis factor

TRAPS

TNF receptor-associated periodic syndrome

VZV

Varicella zoster virus

WBC

White blood cells

XL

X-linked