Advertisement

Journal of Clinical Immunology

, Volume 38, Issue 1, pp 96–128 | Cite as

International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

  • Capucine Picard
  • H. Bobby Gaspar
  • Waleed Al-Herz
  • Aziz Bousfiha
  • Jean-Laurent Casanova
  • Talal Chatila
  • Yanick J. Crow
  • Charlotte Cunningham-Rundles
  • Amos Etzioni
  • Jose Luis Franco
  • Steven M. Holland
  • Christoph Klein
  • Tomohiro Morio
  • Hans D. Ochs
  • Eric Oksenhendler
  • Jennifer Puck
  • Mimi L. K. Tang
  • Stuart G. Tangye
  • Troy R. Torgerson
  • Kathleen E. SullivanEmail author
Open Access
Original Article

Abstract

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

Keywords

IUIS primary immune deficiency immune dysregulation autoinflammatory disorders 

Introduction

In 1970, Drs. Fudenberg, Good, Hitzig, Kunkel, Roitt, Rosen, Rowe, Seligmann, and Soothill met under the auspices of the World Health Organization to classify the emerging “primary immune deficiencies.” This august group focused on understanding whether immunodeficiencies could be categorized as B cell disorders or T cell disorders [1, 2]. Their initial report identified 16 distinct immunodeficiencies and included the prophetic comment that “the variable immunodeficiency group probably lumps together a series of syndromes…. Included in this group are cases previously classified as ‘congenital’, non-sex linked or sporadic hypogammaglobulinemia, primary ‘dysgammglobulinemia’ of both childhood and adult life, and ‘acquired’ primary hypogammaglobulinemia. It is hoped that careful analysis of such patients…. will result in delineation of several homogeneous syndromes…”. Indeed, the emergence of monogenic causes of hypogammaglobulinemia (Table 3) and disorders with variable immunoglobulin abnormalities associated with immune dysregulation (Table 4) have been the groups of immunodeficiencies most transformed by the advent of new technologies. Another group dramatically impacted by resetting of the clinical radar and new techniques has been the set of disorders associated with a limited spectrum of infectious susceptibility. The graphs in Fig. 1 define the transformation of the field over the interval during which next-generation sequencing came to prominence. The tremendous progress, energy, and enthusiasm in the field currently have led to a greater need than ever for a current cataloging of the disorders.
Fig. 1

Each publication of the World Health Organization and IUIS Primary Immunodeficiencies Committee was reviewed for the number of conditions listed and displayed graphically [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. The rapid increase in the twenty-first century relates to improved awareness and increasing use of sequencing. Assuming 20,000 coding genes in the human genome, inborn errors of immunity are implicated through mutations in 1.7% of these genes. There are now 330 specific disorders, 320 monogenic defects, 312 distinct genes (nine genes with both LOF and GOF and C4 deficiency requiring defects in both C4A and C4B). a The categorization of the inborn errors of immunity according the schema in the current manuscript. b The categorization of the inborn errors of immunity according to their inheritance

The new disorders (since 2015 [3]) represent an impressive spectrum of phenotypes. There are 354 distinct disorders with 344 different gene defects listed. The emerging dominance of next-generation sequencing has driven the rapid increase in the number of recognized disorders which has led to two major consequences. Often new inborn errors of immunity are initially described in a single kindred or a small number of kindreds. This may lead to incorrect assumptions about prevalence and phenotype. In fact, for most disorders, we have little idea of the prevalence within even the recognized population with the described phenotype. The second consequence of the rapid rise of next-generation sequencing is a striking expansion of the phenotypic spectrum associated with many diseases. Where once the phenotype of a given disorder was clear, the spectrum of manifestations often extends impressively once the ascertainment is not linked to a preconceived idea [20]. As a community, we recognize the importance of publishing cases and small series and to report specific mutations with clinical findings because publications are used to define likelihood of causality during bioinformatic analysis of next-generation sequencing results.

In 1999, the Committee on Primary Immunodeficiencies came under the auspices of the International Union of Immunological Societies (IUIS). The current committee met on February 23–24, 2017, in London to update the classification of human primary immunodeficiencies. Inclusion in this “master list” requires a body of literature supporting causality of a gene defect and a penetrance indicating clinical relevance [21]. Committee members vote on inclusion of each new disorder and this publications lists those included as of the February 2017 meeting. The landscape is changing so rapidly, and the number of primary immunodeficiencies growing so fast, that two major changes have been implemented. The published list will continue to serve as a reference; however, this list will now be available as a csv file on the IUIS website to enable sorting according to gene, disease name, or clinical/laboratory feature. This file will also include the associated ICD10 codes in order to promote harmonization of utilization. The second major change is to the nomenclature. The term primary immunodeficiency has an important legacy—the abbreviations PID or PIDD are often used by patient organizations and are recognized around the world. However, this terminology does limit the conceptualization of disorders to those in which susceptibility to infection is the main manifestation. The improving recognition of immune dysregulation diseases, including the growing field of autoinflammatory disorders and interferonopathies, has mandated that a more encompassing terminology be used. This manuscript, therefore, utilizes “inborn errors of immunity” as the descriptor for the work and the categorization. In addition to embracing technology to remain updated, the companion publication “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” will provide a phenotype-oriented approach to the IUIS categorization of disorders. Moreover, a new free application can be found as “PID phenotypical diagnosis” or “PID classification” from iTunes and Android app stores [22, 23]. Information that is readily accessible is the new standard, and the IUIS Expert Committee on Primary Immunodeficiencies believes that improved access to information will positively impact patient care around the world.

The tables divide disease categories according to common phenotypes for ease of review and searching. Table 1 lists combined immunodeficiencies, Table 2 lists combined immunodeficiencies with syndromic features, Table 3 lists predominantly antibody deficiencies, Table 4 lists diseases of immune dysregulation, Table 5 lists defects of phagocyte number or function, Table 6 lists defects in intrinsic and innate immunity, Table 7 lists autoinflammatory diseases, Table 8 lists complement deficiencies, and Table 9 lists phenocopies of inborn errors of immunity. The division into phenotypes for the purpose of this list does not imply that the presentation is homogeneous. Each disorder is listed only once for the sake of simplicity although distinct modes of inheritance can be listed separately. There are nine genes for which both loss-of-function and gain-of-function variants have been identified: CFB, C3, CARD11, STAT1, STAT3, WAS, JAK1, IFIH1, and ZAP70. For these, the loss-of-function and gain-of-function aspects are listed. Within each table, there are additional sub-tables that segregate into coherent phenotypic sets. At the end of each table, the new disorders, added for this publication, are listed for easy reference. Other features important for navigation of the list include the use of OMIM links [24]. For additional information on a gene, the links can be accessed from within the online publication. For the second time, we also include non-inborn errors of immunity in Table 9, representing phenocopies of inborn errors which might be important to consider diagnostically.
Table 1

Immunodeficiencies affecting cellular and humoral immunity

Disease

Genetic defect

Inheritance

OMIM

T cells

B cells

Ig

Associated features

1. T-B+ severe combined immune deficiency (SCID)

 γc deficiency (common gamma chain SCID, CD132 deficiency)

IL2RG

XL

308380

Very low

Normal to high

Low

Low NK

 JAK3 deficiency

JAK3

AR

600173

Very low

Normal to high

Low

Low NK

 IL7Rα deficiency

IL7R

AR

146661

Very low

Normal to high

Low

Nl NK

 CD45 deficiency

PTPRC

AR

151460

Very low

Normal

Low

Nl γ/δ Τ cells

 CD3δ deficiency

CD3D

AR

186790

Very low

Normal

Low

Nl NK, no γ/δ T cells

 CD3ε deficiency

CD3E

AR

186830

Very low

Normal

Low

Nl NK, no γ/δ T cells

 CD3ζ deficiency

CD247

AR

186780

Very low

Normal

Low

Nl NK, no γ/δ T cells

 Coronin-1A deficiency

CORO1A

AR

605000

Very low

Normal

Low

Detectable thymus, EBV

 LAT deficiency

LAT

AR

602354

Nl to low number

Nl to low

High

Adenopathy, splenomegaly, recurrent infections, autoimmunity

2. T-B- SCID

 RAG1 deficiency

RAG1

AR

179615

Very low

Very low

Decreased

Nl NK

 RAG2 deficiency

RAG2

AR

179616

Very low

Very low

Decreased

Nl NK

 DCLRE1C (Artemis) deficiency

DCLRE1C

AR

605988

Very low

Very low

Decreased

Nl NK, radiation sensitive

 DNA PKcs deficiency

PRKDC

AR

176977

Very low

Very low

Variable

Nl NK, radiation sensitive, microcephaly

 Cernunnos/XLF deficiency

NHEJ1

AR

611290

Very low

Very low

Decreased

Nl NK, radiation sensitive, microcephaly

 DNA ligase IV deficiency

LIG4

AR

601837

Very low

Very low

Decreased

Nl NK, radiation sensitive, microcephaly

 Reticular dysgenesis

AK2

AR

103020

Very low

Nl to low

Decreased

Granulocytopenia and deafness

 Adenosine deaminase (ADA) deficiency

ADA

AR

608958

Very low

Low, decreasing

Low, decreasing

Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects

3. Combined immunodeficiencies generally less profound than severe combined immunodeficiency

 DOCK2 deficiency

DOCK2

AR

603122

Low

Normal

IgG Nl or low, poor antibody responses

Nl NK cells, but defective function. Poor interferon responses in hematopoietic and non-hematopoietic cells

 CD40 ligand deficiency (CD154)

CD40LG (TNFSF5)

XL

300386

Nl to low

sIgM+, IgD+ cells present, absent sIgG+, IgA+, and IgE+ cells

IgM normal or high, other Ig isotypes low

Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, biliary tract and liver disease, Cryptosporidium infections

 CD40 deficiency

CD40 (TNFRSF5)

AR

109535

Normal

sIgM+, IgD+ cells present, absent sIgG+, IgA+ and IgE+ cells

IgM normal or high, other Ig isotypes low

Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections

 ICOS deficiency

ICOS

AR

604558

Normal

Normal

Low

Recurrent infections, autoimmunity, gastroenteritis, granulomas

 CD3γ deficiency

CD3G

AR

186740

Nl number, but low TCR expression

Normal

Normal

 

 CD8 deficiency

CD8A

AR

186910

Absent CD8, nl CD4

Normal

Normal

Recurrent infections, may be asymptomatic

 ZAP-70 deficiency (ZAP70 LOF)

ZAP70

AR

176947

Low CD8, Nl CD4 number but poor function

Normal

Normal

May have immune dysregulation, autoimmunity

 MHC class I deficiency

TAP1

AR

170260

Low CD8, Nl CD4, absent MHC I on lymphocytes

Normal

Normal

Vasculitis, pyoderma gangrenosum

 MHC class I deficiency

TAP2

AR

170261

Low CD8, Nl CD4, absent MHC I on lymphocytes

Normal

Normal

Vasculitis, pyoderma gangrenosum

 MHC class I deficiency

TAPBP

AR

601962

Low CD8, Nl CD4, absent MHC I on lymphocytes

Normal

Normal

Vasculitis, pyoderma gangrenosum

 MHC class I deficiency

B2M

AR

109700

Low CD8, Nl CD4, absent MHC I on lymphocytes

Normal

Normal

Sinopulmonary infections, cutaneous granulomas. Absent β2m associated proteins MHC I, CD1a, CD1b, CD1c

 MHC class II deficiency group A

CIITA

AR

600005

Low CD4 cells

Absent MHC II expression on lymphocytes

Normal

Nl to low

Respiratory and gastrointestinal infections, liver/biliary tract disease

 MHC class II deficiency group B

RFXANK

AR

603200

Low CD4 cells

Absent MHC II expression on lymphocytes

Normal

Nl to low

Respiratory and gastrointestinal infections, liver/biliary tract disease

 MHC class II deficiency group C

RFX5

AR

601863

Low CD4 cells

Absent MHC II expression on lymphocytes

Normal

Nl to low

Respiratory and gastrointestinal infections, liver/biliary tract disease

 MHC class II deficiency group D

RFXAP

AR

601861

Low CD4 cells

Absent MHC II expression on lymphocytes

Normal

Nl to low

Respiratory and gastrointestinal infections, liver/biliary tract disease

 DOCK8 deficiency

DOCK8

AR

243700

Low, poor proliferation, few, poorly functioning Treg

Low, low CD27+ memory B cells Poor peripheral B cell tolerance

Low IgM, Nl to high IgG and IgA, high IgE

Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis

 Rhoh deficiency

RHOH

AR

602037

Nl number, low naïve T cells, restricted repertoire, poor proliferation to CD3

Normal

Normal

HPV infection, lung granulomas, molluscum contagiosum, lymphoma

 MST1 deficiency

STK4

AR

614868

Low, low terminal differentiated effector memory (TEMRA) cells, low naïve T cells, poor proliferation

Low

High

Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease

 TCRα deficiency

TRAC

AR

615387

Absent TCRαβ, all T cells are γδ, poor proliferation

Normal

Normal

Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea

 LCK deficiency

LCK

AR

615758

Low CD4+, low Treg, restricted T cell repertoire, poor TCR signaling

Normal

Nl IgG and IgA, high IgM

Recurrent infections, immune dysregulation, autoimmunity

 MALT1 deficiency

MALT1

AR

615468

Nl number, poor proliferation

Normal

Nl levels, poor specific antibody response

Bacterial, fungal and viral infections

 CARD11 deficiency (LOF)

CARD11

AR

615206

Nl number, predominant naïve T cells, poor proliferation

Normal, transitional B cell predominance

Absent/low

Pneumocystis jirovecii pneumonia, bacterial and viral infections

 BCL10 deficiency

BCL10

AR

616098

Nl number, low memory T and Treg cells, poor antigen and anti-CD3 proliferation

Nl number, decreased memory and switched B cells

Low

Recurrent bacterial and viral infections, candidiasis, gastroenteritis

 BCL11B deficiency

BCL11B

AD

617237

Low, poor proliferation

Normal

Normal

Congenital abnormalities, neonatal teeth, dysmorphic facies, absent corpus callosum, neurocognitive deficits

 IL-21 deficiency

IL21

AR

615767

Nl number, nl/low function

Low

Low IgG

Severe early-onset colitis, recurrent sinopulmonary infections

 IL-21R deficiency

IL21R

AR

615207

Nl number, low cytokine production, poor antigen proliferation

Normal

Nl number, poor specific antibody responses

Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease

 OX40 deficiency

TNFRSF4

AR

615593

Nl numbers, low antigen specific memory CD4+

Nl numbers, low memory B cells

Normal

Impaired immunity to HHV8, Kaposi’s sarcoma

 IKBKB deficiency

IKBKB

AR

615592

Nl number, absent Treg and γ/δ T cells, impaired TCR activation

Nl number, poor function

Low

Recurrent bacterial, viral, fungal infections, opportunistic infections

 NIK deficiency

MAP3K14

AR

604655

Nl number, poor proliferation to antigen

Low, low switched memory B cells

Low Ig’s

Low NK number and function, recurrent bacterial, viral and Cryptosporidium infections

 RelB deficiency

RELB

AR

604758

Nl number, poor diversity, poor function

  

Recurrent infections

 Moesin deficiency

MSN

XL

300988

Nl number, defective migration, proliferation

Low number

Low Ig’s over time

Recurrent infections with bacteria, varicella, neutropenia

 TFRC deficiency

TFRC

AR

616740

Nl number, poor proliferation

Nl number, low memory B cells

Low

Recurrent infections, neutropenia, thrombocytopenia

SCID/CID spectrum: Infants with SCID who have maternal T cell engraftment may have T cells in normal numbers that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID, or still less profound combined immunodeficiency (CID) phenotypes. Both OS and leaky SCID can be associated with > 300 autologous T cells/μL of peripheral blood and reduced, rather than absent, proliferative responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4 T lymphopenia can be found in an allelic series of RAG1 and other SCID-associated genes. Total number of disorders in Table 1: 49 (17 SCID, 32 CID). New disorders: 5, MOESIN, BCL11B, TFRC, RELB, LAT. Removed gene: UNC119 deficiency has been removed. The UNC119 variant reported previously is a benign polymorphism in unaffected individuals

SCID severe combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, Nl normal, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function

Table 2

Combined immunodeficiencies with associated or syndromic features

Disease

Genetic defect

Inheritance

OMIM

T cells

B cells

Ig

Associated features

1. Immunodeficiency with congenital thrombocytopenia

 Wiskott-Aldrich syndrome (WAS LOF)

WAS

XL

300392

Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3

Normal numbers

Low IgM and antibody responses to polysaccharides, often high IgA and IgE

Thrombocytopenia with small platelets, recurrent bacterial and viral infections, bloody diarrhea, eczema, lymphoma, autoimmune disease, IgA nephropathy, vasculitis. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASp

 WIP deficiency

WIPF1

AR

602357

Reduced, defective lymphocyte responses to anti-CD3

Normal or low

Normal, except for high IgE

Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea, WAS protein absent

 ARPC1B deficiency

ARPC1B

AR

604223

Normal

Normal numbers

Normal except for high IgA and IgE

Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching

2. DNA repair defects other than those listed in Table 1

 Ataxia-telangiectasia

ATM

AR

607585

Progressive decrease, abnormal proliferation to mitogens

Normal

Often low IgA, IgE and IgG subclasses, increased IgM monomers, antibodies variably decreased

Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations

 Nijmegen breakage syndrome

NBS1

AR

602667

Progressive decrease

Variably reduced

Often low IgA, IgE, and IgG subclasses, increased IgM, antibodies variably decreased

Microcephaly, dysmorphic facies, lymphomas, solid tumors, increased radiosensitivity, chromosomal instability

 Bloom Syndrome

BLM (RECQL3)

AR

604610

Normal

Normal

Low

Short stature, dysmorphic facies, sun-sensitive erythema, marrow failure, leukemia, lymphoma, chromosomal instability

 Immunodeficiency with centromeric instability and facial anomalies, ICF1

DNMT3B

AR

602900

Decreased or normal, responses to PHA may be decreased

Decreased or normal

Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency

 

 Immunodeficiency with centromeric instability and facial anomalies, ICF2

ZBTB24

AR

614064

Decreased or normal,

Decreased or normal

Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency

 

 Immunodeficiency with centromeric instability and facial anomalies, ICF3

CDCA7

AR

609937

responses to PHA may be decreased

Decreased or normal

Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency

 

 Immunodeficiency with centromeric instability and facial anomalies, ICF4

HELLS

AR

603946

Decreased or normal

Decreased or normal

Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency

 

 PMS2 deficiency

PMS2

AR

600259

Normal

Low B cells, switched and non-switched

Low IgG and IgA, high IgM, abnormal antibody responses

Recurrent infections, café-au-lait spots, lymphoma, colorectal carcinoma, brain tumors

 RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome)

RNF168

AR

612688

Normal

Normal

Low IgG or IgA

Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly, increased radiosensitivity

 MCM4 deficiency

MCM4

AR

602638

Normal

Normal

Normal

NK cells: low number and function. Viral infections (EBV, HSV, VZV), short stature, B cell lymphoma, adrenal failure

 POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome)

POLE

AR

174762

Decreased T cell proliferation

Low memory B cells

Low IgG2 and IgM, lack of antibody to PPS

Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature

 POLE2 (polymerase ε subunit 2) deficiency

POLE2

AR

602670

Lymphopenia, lack of TRECS, absent proliferation in response to antigens

Very low

Hypogammaglobulinemia

Recurrent infections, disseminated BCG infections, autoimmunity (type 1 diabetes, hypothyroidism, facial dysmorphism

 Ligase I deficiency

LIG1

AR

126391

Lymphopenia, decreased mitogen response

Normal

Low IgA and IgG

Reduced antibody responses

Recurrent respiratory infections, growth retardation, sun sensitivity, lymphoma, radiation sensitivity

 NSMCE3 deficiency

NSMCE3

AR

608243

Number decreased, poor response to mitogens and antigens

Normal

Normal

Decreased Ab responses to PPS normal IgG, IgA, elevated IgM

Severe lung disease (possibly viral), thymic hypoplasia, chromosomal breakage, radiation sensitivity

 ERCC6L2 (Hebo deficiency)

ERCC6L2

AR

615667

Lymphopenia

Low

Normal

Facial dysmorphism, microcephaly, bone marrow failure

 GINS1 deficiency

GINS1

AR

610608

Low or normal

Low or normal

High IgA, low IgM and IgG

Neutropenia, IUGR, NK cells very low

3. Thymic defects with additional congenital anomalies

 DiGeorge/velocardiofacial syndrome

Chromosome 22q11.2 deletion syndrome (22q11.2DS)

Large deletion (3 Mb) typically in chromosome 22

AD

602054

Decreased or normal, 5% have < 1500 CD3T cells/μL in neonatal period

Normal

Normal or decreased

Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability

DiGeorge/velocardiofacial syndrome

Unknown

Sporadic

 

Decreased or normal

Normal

Normal or decreased

Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability

 TBX1 deficiency

TBX1

AD

602054

Decreased or normal

Normal

Normal or decreased

Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability

 CHARGE syndrome due to CHD7 deficiency

CHD7

AD

608892

Decreased or normal, response to PHA may be decreased

Normal

Normal or decreased

Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs

 CHARGE syndrome due to SEMA3E deficiency

SEMA3E

AD

608166

Decreased or normal, response to PHA may be decreased

Normal

Normal or decreased

Coloboma, heart anomaly, choanal atresia, intellectual retardation, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs

 CHARGE syndrome

Unknown

  

Decreased or normal, response to PHA may be decreased

Normal

Normal or decreased

Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs

 Winged helix nude FOXN1 deficiency

FOXN1

AR

600838

Very low

Normal

Decreased

Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect

 Chromosome 10p13-p14 deletion Syndrome (10p13-p14DS)

Del10p13-p14

AD

601362

Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens, hypolastic thymus may be present

Normal

Normal

Hypoparathyroidism, renal disease, deafness, growth retardation, facial dysmorphism, cardiac defects may be present, recurrent infections +/−

4. Immuno-osseous dysplasias

 Cartilage hair hypoplasia (CHH)

RMRP

AR

157660

Varies from severely decreased (SCID) to normal, impaired lymphocyte proliferation

Normal

Normal or reduced, antibodies variably decreased

Short-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine

 Schimke immuno-osseous dysplasia

SMARCAL1

AR

606622

Decreased

Normal

Normal

Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure

 MYSM1 deficiency

MYSM1

AR

612176

T cell lymphopenia, reduced naïve T cells

Immature B cells

Hypogammaglobulinemia

Short stature, recurrent infections, congenital bone marrow failure, myelodysplasia, immunodeficiency affecting B cells and granulocytes, skeletal anomalies, cataracts, developmental delay.

 MOPD1 deficiency

RNU4ATAC

AR

601428

Normal

Normal

Normal, specific antibodies variably decreased

Recurrent bacterial infections, lymphadenopathy, spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly

 EXTL3 deficiency

EXTL3

AR

 

Reduced

Normal

Variably decreased

Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay

5. Hyper IgE syndromes (HIES)

 AD-HIES

STAT3 deficiency

(Job syndrome)

STAT3

AD LOF

102582

Normal overall, Th-17 and T-follicular helper cells decreased

Normal, reduced switched and non-switched memory B cells, BAFF expression increased

High IgE, specific antibody production decreased

Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, pulmonary aspergillus, Pneumocystis jirovecii, eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, coronary and cerebral aneurysm formation

 Comel-Netherton syndrome

SPINK5

AR

605010

Normal

Low Switched and non-switched B cells

High IgE and IgA

Antibody variably decreased

Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive

 PGM3 deficiency

PGM3

AR

172100

CD8 and CD4 T cells may be decreased

Low B and memory B cells

Normal or elevated IgG and IgA, most high IgE, eosinophilia

Severe atopy, autoimmunity, bacterial and viral infections, skeletal anomalies dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability cognitive impairment, hypomyelination

6. Dyskeratosis congenita (DKC), myelodysplasia, short telomeres

 XL-DKC due to dyskerin deficiency

DKC1

XL

300126

Progressive decrease

Progressive decrease

Variable hypogammaglobulinemia

Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/− recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson syndrome (HHS) may occur in some DKC patients

 AR-DKC due to nucleolar protein family A member 2 (NHP2) deficiency

NHP2

AR

606470

Decreased

Variable

Variable

 

 AR-DKC due to nucleolar protein family A member 3 (NHP3) or NOP10 deficiency

NOP10

AR

606471

Decreased

Variable

Variable

 

 AD/AR-DKC due to regulator of telomere elongation (RTEL1) deficiency

RTEL1

AD or AR

608833

Decreased

Variable

Variable

 

 AD-DKC due to TERC deficiency

TERC

AD

602322

Variable

Variable

Variable

 

 AD/AR-DKC due to TERT deficiency

TERT

AD or AR

187270

Variable

Variable

Variable

 

 AD-DKC due to TINF2 deficiency

TINF2

AD

604319

Variable

Variable

Variable

 

 AD/AR-DKC due to TPP1 deficiency

TPP1

AD or AR

609377

Variable

Variable

Variable

 

 AR-DKC due to DCLRE1B deficiency

DCLRE1B/SNM1/APOLLO:

AR

609683

Variable

Variable

Variable

 

 AR-DKC due to PARN deficiency

PARN

AR (AD?)

604212

Variable

Variable

Variable

 

 AR-DKC due to WRAP53 deficiency

WRAP53

AR

612661

Not reported

Not reported

Not reported

 

 Coats plus syndrome due to STN1 deficiency

STN1

AR

613128

Variable

Variable

Not known

Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres

 Coats plus syndrome due to CTC1 deficiency

CTC1

AR

613129

Normal

Normal

Normal

Intrauterine growth retardation, sparse graying hair, dystrophic nails, trilinear bone marrow failure, osteopenia, gastrointestinal hemorrhage due to vascular ectasia, retinal telangiectasia, intracranial calcification, abnormal telomeres

 SAMD9

SAMD9

AD (GOF)

617053

Not reported

Not reported

Not reported

IUGR with gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen

 SAMD9L

SAMD9L

AD (GOF)

159550

Normal

Low

Not reported

Cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction

7. Defects of vitamin B12 and folate metabolism

 Transcobalamin 2 deficiency

TCN2

AR

613441

Normal

Variable

Decreased

Megaloblastic anemia, pancytopenia, if untreated for prolonged periods results in intellectual disability

 SLC46A1/PCFT deficiency causing hereditary folate malabsorption

SLC46A1

AR

229050

Variable numbers and activation profile

Variable

Decreased

Megaloblastic anemia, if untreated for prolonged periods results in intellectual disability

 Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency

MTHFD1

AR

172460

Low thymic output, normal in vitro proliferation

Low

Decreased/poor antibody responses to conjugated polysaccharide antigens

Recurrent bacterial infection, Pneumocystis jirovecii, megaloblastic anemia, neutropenia, seizures, intellectual disability, folate-responsive

8. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID))

 EDA-ID due to NEMO /IKBKG deficiency (ectodermal dysplasia, immune deficiency)

NEMO (IKBKG)

XL

300248

Normal or decreased, TCR activation impaired

Normal

Low memory and isotype switched B cells

Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibody to polysaccharide antigens

Anhidrotic ectodermal dysplasia (in some), various infections (bacteria, mycobacteria, viruses and fungi), colitis, conical teeth, variable defects of skin, hair and teeth, monocyte dysfunction

 EDA-ID due to IKBA GOF mutation

IKBA (NFKBIA)

AD GOF

164008

Normal total T cells, TCR activation impaired

Normal B cell numbers, impaired BCR activation, low memory and isotype switched B cells

Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens

Anhidrotic ectodermal dysplasia, various infections (bacteria, mycobacteria, viruses and fungi), colitis, variable defects of skin, hair and teeth, T cell and monocyte dysfunction

9. Calcium channel defects

 ORAI-1 deficiency

ORAI1

AR

610277

Normal, defective TCR mediated activation

Normal

Normal

Autoimmunity, EDA, non-progressive myopathy

 STIM1 deficiency

STIM1

AR

605921

Normal, defective TCR mediated activation

Normal

Normal

Autoimmunity, EDA, non-progressive myopathy

10. Other defects

 Purine nucleoside phosphorylase (PNP) deficiency

PNP

AR

164050

Progressive decrease

Normal

Normal or low

Autoimmune hemolytic anemia, neurological impairment

 Immunodeficiency with multiple intestinal atresias

TTC7A

AR

609332

Variable, but sometimes absent low TRECs

Normal or low

Markedly decreased IgG, IgM, IgA

Bacterial (sepsis), fungal, viral infections, multiple intestinal atresias, often with intrauterine polyhydramnios and early demise, some with SCID phenotype

 Hepatic veno-occlusive disease with immunodeficiency (VODI)

SP110

AR

604457

Normal (decreased memory T cells)

Normal (decreased memory B cells)

Decreased IgG, IgA, IgM, absent germinal centers and tissue plasma cells

Hepatic veno-occlusive disease, Susceptibility to Pneumocystis jirovecii pneumonia, CMV, candida, thrombocytopenia, hepatosplenomegaly, cerebrospinal leukodystrophy

 Vici syndrome due to EPG5 deficiency

EPG5

AR

615068

Profound depletion of CD4+ cells

Defective

Decreased (particularly IgG2)

Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, intellectual disability, microcephaly, recurrent infections, chronic mucocutaneous candidiasis

 HOIL1 deficiency

HOIL1 (RBCK1)

AR

610924

Normal numbers

Normal, decreased memory B cells

Poor antibody responses to polysaccharides

Bacterial infections, autoinflammation, amylopectinosis

 HOIP deficiency

RNF31

AR

612487

Normal numbers

Normal, decreased memory B cells

decreased

Bacterial infections, autoinflammation, amylopectinosis, lymphangiectasia

 Hennekam-lymphangiectasia-lymphedema syndrome due to CCBE1 deficiency

CCBE1

AR

612753

Low/variable

Low/variable

decreased

Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features

 Hennekam-lymphangiectasia-lymphedema syndrome due to FAT4 deficiency

FAT4

AR

612411

Low/variable

Low/variable

decreased

Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features

 STAT5b deficiency

STAT5B

AR

604260

Modestly decreased

Normal

Normal

Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity

 Kabuki syndrome 1 due to KMT2D deficiency

KMT2D (MLL2)

AD

602113

Normal

Normal

Low IgA and occasionally low IgG

Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present

 Kabuki syndrome 2 due to KDM6A deficiency

KDM6A

XL (females may be affected)

300128

Normal

Normal

Low IgA and occasionally IgG

 

Pure bone marrow failure syndromes have not been included. Total number of disorders in Table 2: 67. New disorders: 23, ARPC1B, CDCA7, HELLS, POLE2, LIG1, GINS1, NSMCE3, ERCC6L2, TBX1, MYSM1, MOPD1, STN1, CTC1, KMT2D, KDM6A, SAMD9, SAMD9L, EXTL3, WRAP53, FAT4. Unknown cause of DiGeorge syndrome, unknown cause CHARGE, 10p13-14 deletion

IUGR intrauterine growth retardation, HSV herpes simplex virus, VZV varicella zoster virus, BCG Bacillus Calmette-Guerin, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 3

Predominantly antibody deficiencies

Disease

Genetic defect

Inheritance

OMIM

Ig

Associated features

1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia

 BTK deficiency, X-linked agammaglobulinemia (XLA)

BTK

XL

300300

All isotypes decreased in majority of patients, some patients have detectable immunoglobulins

Severe bacterial infections, normal numbers of pro-B cells

 μ heavy chain deficiency

IGHM

AR

147020

All isotypes decreased

Severe bacterial infections, normal numbers of pro-B cells

 λ5 deficiency

IGLL1

AR

146770

All isotypes decreased

Severe bacterial infections, normal numbers of pro-B cells

 Igα deficiency

CD79A

AR

112205

All isotypes decreased

Severe bacterial infections, normal numbers of pro-B cells

 Igβ deficiency

CD79B

AR

147245

All isotypes decreased

Severe bacterial infections, normal numbers of pro-B cells

 BLNK deficiency

BLNK

AR

604515

All isotypes decreased

Severe bacterial infections, normal numbers of pro-B cells

 PIK3R1 deficiency

PIK3R1

AR

171833

All isotypes decreased

Severe bacterial infections, decreased or absent pro-B cells

 E47 transcription factor deficiency

TCF3

AD

147141

All isotypes decreased

Recurrent bacterial infections

2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype

 Common variable immune deficiency with no gene defect specified (CVID)

Unknown

Variable

 

Low IgG and IgA and/or IgM

Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease

 PIK3CD mutation (GOF)

PIK3CD GOF

AD

602839

All isotypes decreased

Severe bacterial infections; decreased or absent pro-B cells, EBV

 PIK3R1 deficiency (LOF)

PIK3R1

AD

616005

All isotypes decreased

Severe bacterial infections, pro-B cells present and low numbers of memory B cells, EBV

 PTEN Deficiency (LOF)

PTEN

AD

601728

Decreased

Lymphoproliferation, autoimmunity

 CD19 deficiency

CD19

AR

107265

Low IgG and IgA and/or IgM

Recurrent infections, may have glomerulonephritis

 CD81 deficiency

CD81

AR

186845

Low IgG, low or normal IgA and IgM

Recurrent infections, may have glomerulonephritis

 CD20 deficiency

MS4A1

AR

112210

Low IgG, normal or elevated IgM and IgA

Recurrent infections

 CD21 deficiency

CR2

AR

120650

Low IgG, impaired anti-pneumococcal response

Recurrent infections

 TACI deficiency

TNFRSF13B (TACI)

AD or AR

604907

Low IgG and IgA and/or IgM

Variable clinical expression

 BAFF receptor deficiency

TNFRSF13C (BAFF-R)

AR

606269

Low IgG and IgM,

Variable clinical expression

 TWEAK deficiency

TNFSF12

AD

602695

Low IgM and A, lack of anti-pneumococcal antibody

Pneumonia, bacterial infections, warts, thrombocytopenia. Neutropenia

 Mannosyl-oligosaccharide glucosidase deficiency (MOGS)

MOGS (GCS1)

AR

601336

Severe hypogammaglobulinemia,

Bacterial and viral infections, severe neurologic disease, also known as congenital disorder of glycosylation type IIb (CDG-IIb)

 TRNT1 deficiency

TRNT1

AR

612907

B cell deficiency and hypogammaglobulinemia

Congenital sideroblastic anemia, deafness, developmental delay

 TTC37 deficiency

TTC37

AR

614649

Poor antibody response to pneumococcal vaccine

Recurrent bacterial and viral infections, abnormal hair findings: trichorrhexis nodosa

 NFKB1 deficiency

NFKB1

AD

164011

Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells

Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis

 NFKB2 deficiency

NFKB2

AD

615577

Low serum IgG, A and M; low B cell numbers

Recurrent sinopulmonary infections, alopecia, and endorinopathies

 IKAROS deficiency

IKZF1

AD

603023

Low IgG, IgA, IgM, low or normal B cells, potentially reducing levels with age

Recurrent sinopulmonary infections

 IRF2BP2 deficiency

IRF2BP2

AD

615332

Hypogammaglobulenia, absent IgA

Recurrent infections, possible autoimmunity and inflammatory disease

 ATP6AP1 deficiency

ATP6AP1

XL

300197

Variable immunoglobulin findings

Hepatopathy, leukopenia, low copper

3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper IgM

 AID deficiency

AICDA

AR

605257

IgG and IgA decreased, IgM increased

Bacterial infections, enlarged lymph nodes and germinal centers

 UNG deficiency

UNG

AR

191525

IgG and IgA decreased, IgM increased

Enlarged lymph nodes and germinal centers

 INO80

INO80

AR

610169

IgG and IgA decreased, IgM increased

Severe bacterial infections

 MSH6

MSH6

AR

600678

Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig-class switch recombination and somatic hypermutation defects

Family or personal history of cancer

4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells

 Ig heavy chain mutations and deletions

Mutation or chromosomal deletion at 14q32

AR

 

One or more IgG and/or IgA subclasses as well as IgE may be absent

May be asymptomatic

 Kappa chain deficiency

IGKC

AR

147200

All immunoglobulins have lambda light chain

Asymptomatic

 Isolated IgG subclass deficiency

Unknown

?

 

Reduction in one or more IgG subclass

Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections

 IgG subclass deficiency with IgA deficiency

Unknown

?

 

Reduced IgA with decrease in one or more IgG subclass

Recurrent bacterial infections

 Selective IgA deficiency

Unknown

?

 

Very low to absent IgA with other isotypes normal, normal subclasses and specific antibodies

Bacterial infections, autoimmunity mildly increased

 Specific antibody deficiency with normal Ig levels and normal B cells

Unknown

?

 

Normal

Reduced ability to produce antibodies to specific antigens

 Transient hypogammaglobulinemia of infancy

Unknown

?

 

IgG and IgA decreased

Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections

 CARD11 GOF

CARD11

AD GOF

607210

High B cell numbers due to constitutive NF-κB activation

Splenomegaly, lymphadenopathy, poor vaccine response

 Selective IgM deficiency

Unknown

?

 

Absent serum IgM

Pneumococcal / bacterial infections

Common variable immunodeficiency disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VOD1 (Table 2), thymoma with immunodeficiency (Good syndrome) or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia and normal or reduced numbers of B cells. Total number of disorders in Table 3: 40. New disorders: 7, PTEN, NFKB1, IKZF1, IRF2BP2, ATP6AP1. Selective igA deficiency, selective IgM deficiency

EBV Epstein-Barr virus, COPD chronic obstructive pulmonary disease, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 4

Diseases of immune dysregulation

Disease

Genetic defect

Inheritance

OMIM

Circulating T cells

Circulating B cells

Functional defect

Associated features

1. Familial hemophagocytic lymphohistiocytosis (FHL syndromes)

Perforin deficiency (FHL2)

PRF1

AR

170280

Increased activated T cells

Normal

Decreased to absent NK and CTL activities cytotoxicity

Fever, (H)SM, hemophagocytic lymphohistiocytosis (HLH), cytopenias

UNC13D/Munc13-4 deficiency (FHL3)

UNC13D

AR

608897

Increased activated T cells

Normal

Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation)

Fever, (H)SM, HLH, cytopenias,

Syntaxin 11 deficiency (FHL4)

STX11

AR

605014

Increased activated T cells

Normal

Decreased NK activity (cytotoxicity and/or degranulation)

Fever, (H)SM, cHLH, cytopenias,

STXBP2/Munc18-2 deficiency (FHL5)

STXBP2

AR or AD

601717

Increased activated T cells

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Fever, (H)SM, cHLH, cytopenias, enteropathy

FAAP24 deficiency

FAAP24

AR

610884

Increased activated T cells

Normal

Failure to kill autologous EBV transformed B cells. Normal NK cell function

EBV infection-driven lymphoproliferative disease

2. FHL syndromes with hypopigmentation

Chediak-Higashi syndrome

LYST

AR

606897

Increased activated T cells

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction

Griscelli syndrome, type 2

RAB27A

AR

603868

Normal

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, fever, HSM, HLH, cytopenias

Hermansky-Pudlak syndrome, type 2

AP3B1

AR

603401

Normal

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH

Hermansky-Pudlak syndrome, type 10

AP3D1

AR

617050

Normal

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss, and neurodevelopmental delay

3. Regulatory T cell defects

IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked

FOXP3

XL

300292

Normal

Normal

Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs)

Autoimmune enteropathy, early-onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE, IgA

CD25 deficiency

IL2RA

AR

147730

Normal to decreased

Normal

No CD4 + C25+ cells with impaired function of Tregs cells

Lymphoproliferation, autoimmunity, impaired T cell proliferation

CTLA4 deficiency (ALPSV)

CTLA4

AD

123890

Decreased

Decreased

Impaired function of Tregs.

Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections

LRBA deficiency

LRBA

AR

606453

Normal or decreased CD4 numbers, T cell dysregulation

Low or normal numbers of B cells

Reduced I IgG and IgA in most

Recurrent infections, inflammatory bowel disease, autoimmunity, EBV infections

STAT3 GOF mutation

STAT3

AD (GOF)

102582

Decreased

Decreased

Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Tregs and impaired function

Lymphoproliferation, solid organ autoimmunity, recurrent infections

BACH2 deficiency

BACH2

AD

605394

Progressive T cell lymphopenia

Impaired memory B cell development

Haplosufficiency for a critical lineage specification transcription factor

Lymphocytic colitis, sinopulmonary infections

4. Autoimmunity with or without Lymphoproliferation

APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy

AIRE

AR or AD

607358

Normal

Normal

AIRE serves as check-point in the thymus for negative selection of autoreactive T cells and for generation of Tregs

Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia

ITCH deficiency

ITCH

AR

606409

Not assessed

Not assessed

Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs

Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features

ZAP-70 combined hypomorphic and activation mutations

ZAP70

AR (LOF/GOF)

176947

Decreased CD8, normal or decreased CD4 cells

Normal or decreased

Hyperactive Zap70 kinase

Severe autoimmunity

Tripeptidyl-peptidase II deficiency

TPP2

AR

190470

Decreased

Decreased

TPP2 deficiency results in premature immunosenescence and immune dysregulation

Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections

JAK1 GOF

JAK1

AD GOF

147795

Not assessed

Not assessed

Hyperactive JAK1

HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections

Prolidase deficiency

PEPD

AR

613230

Normal

Normal

Peptidase D

Autoantibodies common, chronic skin ulcers, eczema, infections

5. Autoimmune lymphoproliferative syndrome (ALPS, Canale-Smith syndrome)

ALPS-FAS

TNFRSF6

AD or AR

134637

Increased CD4CD8TCR α/β-double negative (DN) T cells

Normal, low memory B cells

Apoptosis defect FAS mediated

Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and A normal or increased, elevated serum FasL and IL-10, vitamin B12

ALPS-FASLG

FASLG

AR

134638

Increased DN T cells

Normal

Apoptosis defect FAS mediated

Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated

ALPS-caspase 10

CASP10

AD

601762

Increased DN T cells

Normal

Defective lymphocyte apoptosis

Adenopathies, splenomegaly, autoimmunity

ALPS-caspase 8

CASP8

AR

601763

Slightly increased DN T cells

Normal

Defective lymphocyte apoptosis and activation

Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia

FADD deficiency

FADD

AR

602457

Increased DN T cells

Normal

Defective lymphocyte apoptosis

Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction

6. Immune dysregulation with colitis

IL-10 deficiency

IL10

AR

124092

Normal

Normal

No functional IL-10 secretion

Inflammatory bowel disease (IBD), Folliculitis, recurrent respiratory diseases, arthritis,

IL-10Ra deficiency

IL10RA

AR

146933

Normal

Normal

Leukocytes unresponsive to IL-10

IBD, Folliculitis, recurrent respiratory diseases, arthritis, lymphoma

IL-10Rb deficiency

IL10RB

AR

123889

Normal

Normal

Leukocytes unresponsive to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29

IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma

NFAT5 haploinsufficiency

NFAT5

AD

604708

Normal

Normal

Decreased memory B cells and plasmablasts

IBD, recurrent sinopulmonary infections

7. Susceptibility to EBV and lymphoproliferative conditions

SH2D1A deficiency (XLP1)

SH2D1A

XL

300490

Normal or increased activated T cells

Reduced memory B cells

normal NK cell and CTL cytotoxic activity

Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, aplastic anemia, lymphoma. hypogammaglobulinemia, absent iNKT cells

XIAP deficiency (XLP2)

XIAP

XL

300079

Normal or Increased activated T cells; low/normal iNKT cells

Normal or reduced memory B cells

Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)

EBV infection, splenomegaly, lymphoproliferation HLH, colitis, IBD, hepatitis low iNKT cells, hypogammaglobulinemia

CD27 deficiency

CD27

AR

615122

Normal

No memory B cells

Low immunoglobulin after EBV infection

Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, lymphoma

CTPS1 deficiency

CTPS1

AR

615897

Nl to low, poor proliferation to antigen

Nl/low

Nl/high IgG

Recurrent/chronic bacterial and viral infections (EBV, VZV), lymphoproliferation, B cell non-Hodgkin lymphoma

RASGRP1 deficiency

RASGRP1

AR

603962

Poor activation, proliferation, motility

Poor activation, proliferation, motility

Normal IgM, IgG, increased IgA

Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma

CD70 deficiency

CD70 (TNFSF7)

AR

602840

Nl number, low Treg, poor activation and function

Nl number, poor antibody and memory responses

Reduced IgM, IgG, IgA (75%) and reduced Ag-specific Ab responses (50%)

EBV susceptibility, Hodgkin lymphoma

RLTPR (CARMIL2) deficiency

RLTPR

AR

610859

Nl number, low Treg, high CD4, poor function

Nl number

Nl to low, poor T dependent antibody response

Recurrent bacterial, fungal and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy

ITK deficiency

ITK

AR

186973

Progressive decrease

Normal

Nl to low

EBV associated B cell lymphoproliferation, lymphoma, Nl or low IgG

MAGT1 deficiency (XMEN)

MAGT1

XL

300853

Low CD4

Low recent thymic emigrant cells, poor proliferation to CD3

Normal

Normal

EBV infection, lymphoma, viral infections, respiratory and GI infections

PRKCD deficiency

PRKCD

AR

176977

Normal

Low memory B cells, high CD5 B cells

Apoptotic defect in B cells

Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG

Total number of disorders in Table 4: 40. New disorders: 9, FAAP24, RASGRP1, CD70, RLTPR, ZAP70 (GOF + LOF), AP3D1, BACH2, JAK1 GOF, PEPD. Removed gene: Hermansky-Pudlak syndrome type 9 was removed due to retraction of the defining publication

FHL familial hemophagocytic lymphohistiocytosis, HLH hemophagocytic lymphohistiocytosis, HSM hepatosplenomegaly ((H)SM indicating variable hepatomegaly), DN double negative, SLE systemic lupus erythematous, IBD inflammatory bowel disease, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 5

Congenital defects of phagocyte number or function

Disease

Genetic defect

Inheritance

OMIM

Affected cells

Affected function

Associated features

1. Congenital neutropenias

 Elastase deficiency (SCN1)

ELANE

AD

130130

N

Myeloid differentiation

Susceptibility to MDS/leukemia

Severe congenital neutropenia or cyclic neutropenia

 GFI 1 deficiency (SCN2)

GFI1

AD

600871

N

Myeloid differentiation

B/T lymphopenia

 HAX1 deficiency (Kostmann disease) (SCN3)

HAX1

AR

605998

N

Myeloid differentiation

Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia

 G6PC3 deficiency (SCN4)

G6PC3

AR

611045

N

Myeloid differentiation, chemotaxis, O2 production

Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs

 VPS45 deficiency (SCN5)

VPS45

AR

610035

N

Myeloid differentiation, migration

Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly

 Glycogen storage disease type 1b

G6PT1

AR

602671

N + M

Myeloid differentiation, chemotaxis, O2 production

Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly

 X-linked neutropenia/myelodysplasia WAS GOF

WAS

XL

300392

N

Differentiation, mitosis

Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies

 P14/LAMTOR2 deficiency

LAMTOR2

AR

610389

N + M

Endosomal biogenesis

Neutropenia

Hypogammaglobulinemia ↓CD8 cytotoxicity, partial albinism, growth failure

 Barth syndrome (3-methylglutaconic aciduria type II)

TAZ

XL

300394

N + L Mel

Mitochondrial function

Cardiomyopathy, myopathy, growth retardation, neutropenia

 Cohen syndrome

VPS13B

AR

607817

N

Myeloid differentiation

Dysmorphism, mental retardation, obesity, deafness, neutropenia

 Clericuzio syndrome (poikiloderma with neutropenia)

USB1

AR

613276

N

Myeloid differentiation

Retinopathy, developmental delay, facial dysmorphisms, poikiloderma

 JAGN1 deficiency

JAGN1

AR

616012

N

Myeloid differentiation

Myeloid maturation arrest, osteopenia

 3-Methylglutaconic aciduria

CLPB

AR

616254

N

Myeloid differentiation

Mitochondrial protein

Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR

 G-CSF receptor deficiency

CSF3R

AR

138971

N

Stress granulopoiesis disturbed

 

 SMARCD2 deficiency

SMARCD2

AR

601736

N

Chromatin remodeling, myeloid differentiation and neutrophil functional defect

Neutropenia, developmental aberrations, skeletal abnormalities, hematopoietic stem cells, myelodysplasia

 HYOU1 deficiency

HYOU1

AR

601746

N

Unfolded protein response

Hypoglycemia, inflammatory complications

2. Defects of motility

 Leukocyte adhesion deficiency type 1 (LAD1)

ITGB2

AR

600065

N + M +L + NK

Adherence, chemotaxis, endocytosis, T/NK cytotoxicity

Delayed cord separation, skin ulcers, periodontitis, leukocytosis

 Leukocyte adhesion deficiency type 2 (LAD2)

SLC35C1

AR

605881

N + M

Rolling, chemotaxis

Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay

 Leukocyte adhesion deficiency type 3 (LAD3)

FERMT3

AR

607901

N + M + L + NK

Adherence, chemotaxis

LAD type 1 plus bleeding tendency

 Rac 2 deficiency

RAC2

AD

602049

N

Adherence, chemotaxis O2 production

Poor wound healing, leukocytosis

 β actin deficiency

ACTB

AD

102630

N + M

Motility

Mental retardation, short stature

 Localized juvenile periodontitis

FPR1

AR

136537

N

Formylpeptide induced chemotaxis

Periodontitis only

 Papillon-Lefèvre syndrome

CTSC

AR

602365

N + M

Chemotaxis

Periodontitis, palmoplantar hyperkeratosis in some patients

 Specific granule deficiency

CEBPE

AR

189965

N

Chemotaxis

Neutrophils with bilobed nuclei

 Shwachman-Diamond syndrome

SBDS

AR

607444

N

Chemotaxis

Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia

 WDR1 deficiency

WDR1

AR

604734

N

Spreading, survival, chemotaxis

Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nuclei herniate

 Cystic fibrosis

CFTR

AR

602421

M only

Chemotaxis

Respiratory infections, pancreatic insufficiency, elevated sweat chloride

 Schwachman Diamond syndrome due to DNAJC21 deficiency

DNAJC21

AR

617048

N

Motility, ribosome biogenesis

Metaphyseal changes, short stature, developmental delay, pancreatic dysfunction, bone marrow failure

 Neutropenia with combined immune deficiency due to MKL1 deficiency

MKL1

AR

606078

N + M +L + NK

Impaired expression of cytoskeletal genes

Mild thrombocytopenia

3. Defects of respiratory burst

 X-linked chronic granulomatous disease (CGD), gp91phox

CYBB

XL

300481

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype, IBD

McLeod phenotype in patients with deletions extending into the contiguous Kell locus

 Autosomal recessive CGD p22phox

CYBA

AR

608508

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

 Autosomal recessive CGD p47phox

NCF1

AR

608,512

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

 Autosomal recessive CGD p67phox

NCF2

AR

608515

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

 Autosomal recessive CGD p40phox

NCF4

AR

601488

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

 G6PD deficiency class I

G6PD

XL

305900

N

Reduced O2 production

Infections

4. Other non-lymphoid defects

 GATA2 deficiency (MonoMac syndrome)

GATA2: loss of stem cells

AD

137295

Monocytes + peripheral DC

Multi lineage cytopenias

Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMMoL, lymphedema

 Congenital pulmonary alveolar proteinosis due to CSF2RB mutations

CSF2RB

AR

138981

Alveolar macrophages

GM-CSF signaling

Alveolar proteinosis

 Congenital pulmonary alveolar proteinosis due to CSF2RA mutations

CSF2RA

XL (pseudoautosomal)

306250

Alveolar macrophages

GM-CSF signaling

Alveolar proteinosis

Total number of disorders in Table 5: 39. New disorders: 9, WDR1, CFTR, SMARCD2, JAGN1, HYOU1, MKL1, DNAJC21, G6PD, CSF2RB. Removed: cyclic neutropenia was merged with elastase deficiency

MDS myelodysplastic syndrome, IUGR intrauterine growth retardation, LAD leukocyte adhesion deficiency, AML acute myelogenous leukemia, CMML chronic myelomonocytic leukemia, N neutrophil, M monocyte, MEL melanocyte, L lymphocyte, NK natural killer, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, GOF gain-of-function

Table 6

Defects in intrinsic and innate immunity

Disease

Genetic defect

Inheritance

OMIM

Affected cells

Affected function

Associated features

1. Mendelian susceptibility to mycobacterial disease (MSMD)

 IL-12 and IL-23 receptor β1 chain deficiency

IL12RB1

AR

601604

L + NK

IFN-γ secretion

Susceptibility to mycobacteria and Salmonella

 IL-12p40 (IL-12 and IL-23) deficiency

IL12B

AR

161561

M

IFN-γ secretion

Susceptibility to mycobacteria and Salmonella

 IFN-γ receptor 1 deficiency

IFNGR1

AR/AD

107470

M + L

IFN-γ binding and signaling

Susceptibility to mycobacteria and Salmonella

 IFN-γ receptor 2 deficiency

IFNGR2

AR

147569

M + L

IFN-γ signaling

Susceptibility to mycobacteria and Salmonella

 STAT1 deficiency (AD LOF)

STAT1

AD

600555

M + L

IFN-γsignaling

Susceptibility to mycobacteria, Salmonella

 Macrophage gp91 phox deficiency

CYBB

XL

300481

Macrophage only

Killing (faulty O2 production)

Isolated susceptibility to mycobacteria

 IRF8 deficiency (AD)

IRF8

AD

601565

CD1c+ MDC

Differentiation of CD1c+ MDC subgroup

Susceptibility to mycobacteria

 IRF8 deficiency (AR)

IRF8

AR

601565

CD1c+ MDC

Differentiation of CD1c+ MDC subgroup

Susceptibility to mycobacteria and multiple other infectious agents

 Tyk2 deficiency

TYK2

AR

176941

Normal, but multiple cytokine signaling defect

Normal

Susceptibility to intracellular bacteria (mycobacteria, Salmonella), viruses, +/− elevated IgE

 ISG15 deficiency

ISG15

AR

147571

 

IFNγ production defect

Susceptibility to mycobacteria (BCG), brain calcification

 RORc deficiency

RORC

AR

602943

L + NK

Lack of functional RORγT protein, IFNγ production defect, complete absence of IL-17A/F-producing T cells

Susceptibility to mycobacteria and candida

 JAK1 (LOF)

JAK1

AR

147795

N + L

IFNγ production

Susceptibility to mycobacteria and viruses, urothelial carcinoma

2. Epidermodysplasia verruciformis (HPV)

 EVER1 deficiency

TMC6

AR

605828

Keratinocytes and leukocytes

EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes

Human papillomavirus (HPV) (group B1) infections and cancer of the skin (typical EV)

 EVER2 deficiency

TMC8

AR

605829

Keratinocytes and leukocytes

EVER proteins may be involved in the regulation of cellular zinc homeostasis in Ly

HPV (group B1) infections and cancer of the skin (typical EV)

 WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome

CXCR4

AD GOF

162643

Granulocytes + lymphocytes

Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)

Warts, neutropenia, low B cell number, hypogammaglobulinemia

3. Predisposition to severe viral infection

 STAT1 deficiency (AR LOF)

STAT1

AR

600555

T and NK cells and monocytes

STAT1-dependent IFN-α, β, and γ response

Severe viral infections, mycobacterial infection

 STAT2 deficiency

STAT2

AR

600556

T and NK cells

STAT2-dependent IFN-α, β, and γ response

Severe viral infections (disseminated vaccine-strain measles)

 IRF7 deficiency

IRF7

AR

605047

Leukocytes, plasmacytoid dendritic cells, non-hematopoietic cells

IFN-α, β, and γ production and IFN-λ production

Severe influenza disease

 IFNAR2 deficiency

IFNAR2

AR

602376

Broadly expressed

No response to IFN-α

Severe viral infections (disseminated vaccine-strain measles, HHV6)

 CD16 deficiency

FCGR3A

AR

146740

NK cells

Altered NK cells function

Severe herpes viral infections, particularly VZV, Epstein-Barr virus (EBV), and (HPV)

 MDA5 deficiency (LOF)

IFIH1

AR

606951

Somatic and hematopoietic

Viral recognition

Rhinovirus and other RNA viruses

4. Herpes simplex encephalitis (HSE)

 TLR3 deficiency

TLR3

AD or AR

603029

Central nervous system (CNS) resident cells and fibroblasts

TLR3-dependent IFN-α, β, and γ response

Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)

 UNC93B1 deficiency

UNC93B1

AR

608204

CNS resident cells and fibroblasts

UNC-93B-dependent IFN-α, β, and γ response

Herpes simplex virus 1 encephalitis

 TRAF3 deficiency

TRAF3

AD

601896

CNS resident cells and fibroblasts

TRAF3-dependent IFN-α, β, and γ response

Herpes simplex virus 1 encephalitis

 TRIF deficiency

TICAM1

AD or AR

607601

CNS resident cells and fibroblasts

TRIF-dependent IFN-α, β, and γ response

Herpes simplex virus 1 encephalitis

 TBK1 deficiency

TBK1

AD

604834

CNS resident cells and fibroblasts

TBK1-dependent IFN-α, β, and γ response

Herpes simplex virus 1 encephalitis

 IRF3 deficiency

IRF3

AD

616532

CNS resident cells and fibroblasts

Low IFN-α/β production in response to HSV1 and decreased IRF3 phosphorylation

Herpes simplex virus 1 encephalitis

5. Predisposition to invasive fungal diseases

 CARD9 deficiency

CARD9

AR

607212

Mononuclear phagocytes

CARD9 signaling pathway

Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections

6. Predisposition to mucocutaneous candidiasis

 IL-17RA deficiency

IL17RA

AR

605461

Epithelial cells, fibroblasts, mononuclear phagocytes

IL-17RA signaling pathway

CMC, folliculitis

 IL-17RC deficiency

IL17RC

AR

610925

Epithelial cells, fibroblasts, mononuclear phagocytes

IL-17RC signaling pathway

CMC

 IL-17F deficiency

IL17F

AD

606496

T cells

IL-17F-containing dimers

CMC, folliculitis

 STAT1 GOF

STAT1

AD GOF

600555

T cells, B cells, monocytes

Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells

CMC, various fungal, bacterial and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy

 ACT1 deficiency

TRAF3IP2

AR

607043

T cells, fibroblasts

Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E

CMC, blepharitis, folliculitis and macroglossia

7. TLR signaling pathway deficiency with bacterial susceptibility

 IRAK-4 deficiency

IRAK4

AR

606883

Lymphocytes + granulocytes + monocytes

TIR-IRAK4 signaling pathway

Bacterial infections (pyogens)

 MyD88 deficiency

MYD88

AR

602170

Lymphocytes + granulocytes + monocytes

TIR-MyD88 signaling pathway

Bacterial infections (pyogens)

 IRAK1 deficiency

IRAK1

XL

Not yet attributed

Lymphocytes + granulocytes + monocytes

TIR-IRAK1 signaling pathway

Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1

 TIRAP deficiency

TIRAP

AR

614382

Lymphocytes + granulocytes+ monocytes

TIRAP- signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes

Staphylococcal disease during childhood

8. Other inborn errors of immunity related to non-hematopoietic tissues

 Isolated congenital asplenia (ICA) due to RPSA deficiency

RPSA

AD

271400

No spleen

RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome

Bacteremia (encapsulated bacteria)

 Isolated congenital asplenia (ICA) due to HMOX deficiency

HMOX

AR

141250

Macrophages

HO-1 regulates iron recycling and heme-dependent damage occurs

Hemolysis, nephritis, inflammation

 Trypanosomiasis

APOL1

AD

603743

Somatic

Lipid

Trypanosomiasis

 Acute liver failure due to NBAS deficiency

NBAS

AR

608025

Somatic and hematopoietic

ER stress

Fever induces liver failure

 Acute necrotizing encephalopathy

RANBP2

AD

601181

Ubiquitous expression

Nuclear pore

Fever induces acute encephalopathy

 CLCN7 deficiency associated osteopetrosis

CLCN7

AR

602727

Osteoclasts

Secretory lysosomes

Osteopetrosis with hypocalcemia, neurologic features

 SNX10 deficiency associated osteopetrosis

SNX10

AR

614780

Osteoclasts

Secretory lysosomes

Osteopetrosis with visual impairment

 OSTM1 deficiency associated osteopetrosis

OSTM1

AR

607649

Osteoclasts

Secretory lysosomes

Osteopetrosis with hypocalcemia, neurologic features

 PLEKHM1 deficiency associated osteopetrosis

PLEKHM1

AR

611466

Osteoclasts

Secretory lysosomes

Osteopetrosis

 TCIRG1 deficiency associated osteopetrosis

TCIRG1

AR

604592

Osteoclasts

Secretory lysosomes

Osteopetrosis with hypocalcemia

 TNFRSF11A deficiency associated osteopetrosis

TNFRSF11A

AR

603499

Osteoclasts

Osteoclastogenesis

Osteopetrosis

 TNFSF11 deficiency associated osteopetrosis

TNFSF11

AR

602642

Stromal

Osteoclastogenesis

Osteopetrosis with severe growth retardation

NCSTN deficiency hidradenitis suppurativa

NCSTN

AD

605254

Epidermis

Gamma-secretase in hair follicle regulates keratinization

Hidradenitis suppurativa with acne

 PSEN deficiency hidradenitis suppurativa

PSEN

AD

104311

Epidermis

Gamma-secretase in hair follicle regulates keratinization

Hidradenitis suppurative with cutaneous hyperpigmentation

 PSENEN deficiency hidradenitis suppurativa

PSENEN

AD

607632

Epidermis

Gamma-secretase in hair follicle regulates keratinization

Hidradenitis suppurativa

Total number of disorders in Table 6: 52. New genes: 19, IFNAR 2, IRF3, JAK1, IRAK1, TIRAP, IFIH1, HMOX, NBAS, RANBP2, CLCN7, SNX10, OSTM1, PLEKHM1, TCIRG1, TNFRSF11A, TNFSF11, NCSTN, PSEN, PSENEN

NF-κB nuclear factor kappa B, TIR Toll and interleukin-1 receptor, IFN interferon, TLR Toll-like receptor, MDC myeloid dendritic cell, CNS central nervous system, CMC chronic mucocutaneous candidiasis, HPV human papillomavirus, VZV varicella zoster virus, EBV Epstein-Barr virus, HHV6 human herpesvirus 6, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 7

Autoinflammatory disorders

1. Type 1 interferonopathies

Disease

Genetic defect

Inheritance

OMIM

T cells

B cells

Functional defect

Associated features

TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1)

TREX1

AR or AD

606609

Not assessed

Not assessed

Intracellular accumulation of abnormal ss DNA species leading to increased type I IFN production

Classical AGS, SLE, FCL

RNASEH2B deficiency, AGS2

RNASEH2B

AR

610326

Not assessed

Not assessed

Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production

Classical AGS, SP

RNASEH2C deficiency, AGS3

RNASEH2C

AR

610330

Not assessed

Not assessed

Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production

Classical AGS

RNASEH2A deficiency, AGS4

RNASEH2A

AR

606034

Not assessed

Not assessed

Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production

Classical AGS

SAMHD1 deficiency, AGS5

SAMHD1

AR

606754

Not assessed

Not assessed

Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production

Classical AGS, FCL

ADAR1 deficiency, AGS6

ADAR1

AR

146920

Not assessed

Not assessed

Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production

Classical AGS, BSN, SP

Aicardi-Goutieres syndrome 7 (AGS7)

IFIH1 (GOF)

AD

606951

Not assessed

Not assessed

IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule

Classical AGS, SLE, SP, SMS

Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)

ACP5

AR

171640

Not assessed

Not assessed

Upregulation of IFN through mechanism possibly relating to pDCS

Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections

STING-associated vasculopathy, infantile-onset

TMEM173

AR

612374

Not assessed

Not assessed

STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN

Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL

X-linked reticulate pigmentary disorder

POLA1

XL

301220

Not assessed

Not assessed

POLA1 is required for synthesis of cytosolic RNA:DNA and its deficiency leads to increase production of type I interferon

Hyperpigmentation, characteristic facies, lung and GI involvement

USP18 deficiency

USP18

AR

607057

Not assessed

Not assessed

Defective negative regulation of ISG15 leading to increased IFN

TORCH like syndrome

CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)

PSMB8 a

AR and AD

256040

Not assessed

Not assessed

Mutations cause increased IFN signaling through an undefined mechanism

Contractures, panniculitis, ICC, fevers

Singleton-Merten syndrome

DDX58

AD

609631

Not assessed

Not assessed

Recognizes double stranded RNA

Dental dysplasia), calcifications in the aorta, osteoporosis, especially in the hands and feet

2. Defects affecting the inflammasome

Disease

Genetic defect

Inheritance

OMIM

Affected cells

Functional defects

Associated features

 

Familial Mediterranean fever

MEFV

AR or AD

249100

134610

Mature granulocytes, cytokine-activated monocytes

Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury, macrophage apoptosis decreased

Recurrent fever, serositis and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease

 

Mevalonate kinase deficiency (Hyper IgD syndrome)

MVK

AR

260920

Somatic and hemaotpoietic

Affecting cholesterol synthesis, pathogenesis of disease unclear

Periodic fever and leukocytosis with high IgD levels

 

Muckle-Wells syndrome

NLRP3 (also called NALP3 CIAS1 or PYPAF1)

AD GOF

191900

PMNs Monocytes

Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing

Urticaria, SNHL, amyloidosis

 

Familial cold autoinflammatory syndrome 1

NLRP3

AD GOF

120100

PMNs, monocytes

As above

Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure

 

Familial cold autoinflammatory syndrome 2

NLRP12

AD GOF

611762

PMNs, monocytes

As above

Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure

 

Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)

NLRP3

AD GOF

607115

PMNs, chondrocytes

As above

Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation

 

NLRC4-MAS (macrophage activating syndrome) or familial cold autoinflammatory syndrome 4

NLRC4

AD GOF

616050

616115

PMNs monocytes macrophages

Gain-of-function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation

Severe enterocolitis and macrophage activation syndrome

 

PLAID (PLCγ2 associated antibody deficiency and immune dysregulation) or familial cold autoinflammatory syndrome 3 or APLAID (c2120A>C)

PLCG2

AD GOF

614468

B cells, NK, mast cells

Mutations cause activation of IL-1 pathways

Cold urticaria hypogammaglobulinemia, autoinflammation

 

NLRP1 deficiency

NLRP1

AR

606579

Leukocytes

Systemic elevation of IL-18 and caspase 1, suggesting involvement of NLRP1 inflammasome

Dyskeratosis, autoimmunity and arthritis

 

3. Non-inflammasome-related conditions

Disease

Genetic defect

Inheritance

OMIM

Affected cells

Functional defects

Associated Features

 

TNF receptor-associated periodic syndrome (TRAPS)

TNFRSF1A

AD

142680

PMNs, monocytes

Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF

Recurrent fever, serositis, rash, and ocular or joint inflammation

 

Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia

PSTPIP1 (also called C2BP1)

AD

604416

Hematopoietic tissues, upregulated in activated T cells

Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response

Destructive arthritis, inflammatory skin rash, myositis

 

Blau syndrome

NOD2 (also called CARD15)

AD

186580

Monocytes

Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-kB signaling

Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn colitis

 

ADAM17 deficiency

ADAM17

AR

614328

Leukocytes and epithelial cells

Defective TNFα production

Early-onset diarrhea and skin lesions

 

Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)

LPIN2

AR

609628

Neutrophils, bone marrow cells

Undefined

Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders

 

DIRA (deficiency of the interleukin-1 receptor antagonist)

IL1RN

AR

612852

PMNs, Monocytes

Mutations in the IL-1 receptor antagonist allow unopposed action of interleukin-1

Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis

 

DITRA (deficiency of IL-36 receptor antagonist)

IL36RN

AR

614204

Keratinocytes, leukocytes

Mutations in IL-36RN leads to increase IL-8 production

Pustular psoriasis

 

SLC29A3 mutation

SLC29A3

AR

602782

Leukocytes, bone cells

 

Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome

 

CAMPS (CARD14 mediated psoriasis)

CARD14

AD

602723

Mainly in keratinocytes

Mutations in CARD14 activate the NF-kB pathway and production of IL-8

Psoriasis

 

Cherubism

SH3BP2

AD

118400

Stroma cells, bone cells

Hyperactived macrophage and increase NF-kB

Bone degeneration in jaws

 

COPA defect

COPA

AD

6011924

PMN and tissue specific cells

Defective intracellular transport via the coat protein complex I (COPI)

Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production

 

Otulipenia/ORAS

OTULIN

AR

615712

Leukocytes

Increase LUBAC induction of NF-KB activation leading to high proinflammatory cytokines levels

Fever, diarrhea, dermatitis

 

A20 deficiency

TNFAIP3

AD LOF

616744

Lymphocytes

Defective inhibition of NF-KB signaling pathway

Arthralgia, mucosal ulcers, ocular inflammation

 

ADA2 deficiency

CECR1

AR

607575

Lymphocytes

ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors

Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever

 

AP1S3 deficiency

AP1S3

AR

615781

Keratinocytes

Disrupted TLR3 translocation

Pustular psoriasis

 

Total number of disorders in Table 7: 37. New disorders: 7, DDX58, POLA1, USP18, NLRP1, OTULIN, TNFAIP3, AP1S3

IFN interferon; HSM hepatosplenomegaly; CSF cerebrospinal fluid; SLE systemic lupus erythematosus; TORCH toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections; SNHL sensorineural hearing loss; AGS Aicardi-Goutières syndrome; BSN bilateral striatal necrosis; FCL familial chilblain lupus; ICC intracranial calcification; IFN interferon type I; pDCs plasmacytoid dendritic cells; SP spastic paraparesis; SMS Singleton-Merten syndrome; ss single-stranded DNA; XL X-linked inheritance; AR autosomal recessive inheritance; AD autosomal dominant inheritance; LOF loss-of-function; GOF gain-of-function

aVariants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in monogenic and digenic models

Table 8

Complement deficiencies

1. Complement deficiencies

Disease

Genetic defect

Inheritance

Gene OMIM

Laboratory features

Associated features

C1q deficiency due to defects in C1QA

C1QA

AR

120550

Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

C1q deficiency due to defects in C1QB

C1QB

AR

120570

Absent CH50 hemolytic activity, Defective activation of the classical pathway, diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

C1q deficiency due to defects in C1QC

C1QC

AR

120575

Absent CH50 hemolytic activity, Defective activation of the classical pathway, diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

C1r deficiency

C1R

AR

613785

Absent CH50 hemolytic activity, defective activation of the classical pathway

SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype

C1s deficiency

C1S

AR

120580

Absent CH50 hemolytic activity, defective activation of the classical pathway

SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype

Complete C4 deficiency

C4A + C4B

AR

120810

Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B

SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense

C2 deficiency

C2

AR

217000

Absent CH50 hemolytic activity, defective activation of the classical pathway

SLE, infections with encapsulated organisms, atherosclerosis

C3 deficiency (LOF)

C3

AR

120700

Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response

Infections, glomerulonephritis, atypical hemolytic-uremic syndrome with GOF mutations

C3 GOF

C3

AD

120700

Increased activation of complement

Atypical hemolytic-uremic syndrome

C5 deficiency

C5

AR

120900

Absent CH50 and AH50 hemolytic activity Defective bactericidal activity

Disseminated neisserial infections

C6 deficiency

C6

AR

217050

Absent CH50 and AH50 hemolytic activity, defective bactericidal activity

Disseminated neisserial infections

C7 deficiency

C7

AR

217070

Absent CH50 and AH50 hemolytic activity, defective bactericidal activity

Disseminated neisserial infections

C8α deficiency

C8A

AR

120950

Absent CH50 and AH50 hemolytic activity, defective bactericidal activity

Disseminated neisserial infections

C8γ deficiency

C8G

AR

120930

Absent CH50 and AH50 hemolytic activity, defective bactericidal activity

Disseminated neisserial infections

C8β-deficiency

C8B:

AR

120960

Absent CH50 and AH50 hemolytic activity, defective bactericidal activity

Disseminated neisserial infections

C9 deficiency

C9

AR

120940

Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity

Mild susceptibility to disseminated neisserial infections

MASP2 deficiency

MASP2

AR

605102

Deficient activation of the lectin activation pathway

Pyogenic infections, inflammatory lung disease, autoimmunity

Ficolin 3 deficiency

FCN3

AR

604973

Absence of complement activation by the Ficolin 3 pathway.

Respiratory infections, abscesses

C1 inhibitor deficiency

SERPING1

AD

606860

Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen

Hereditary angioedema

Factor B GOF

CFB

AD

138470

Gain-of-function mutation with increased spontaneous AH50

Atypical hemolytic-uremic syndrome

Factor B LOF

CFB

AR

138470

Deficient activation of the alternative pathway

Infections with encapsulated organisms

Factor D deficiency

CFD

AR

134350

Absent AH50 hemolytic activity

Neisserial infections

Properdin deficiency

CFP

XL

300383

Absent AH50 hemolytic activity

Neisserial infections

Factor I deficiency

CFI

AR

217030

Spontaneous activation of the alternative complement pathway with consumption of C3

Infections, disseminated neisserial infections, atypical hemolytic-uremic syndrome, preeclampsia

Factor H deficiency

CFH

AR or AD

134370

Spontaneous activation of the alternative complement pathway with consumption of C3

Infections, disseminated neisserial infections, atypical hemolytic-uremic syndrome, preeclampsia

Factor H-related protein deficiencies

CFHR1-5

AR or AD

134371, 600889, 605336, 605337, 608593

Normal CH50, AH50, autoantibodies to factor H, linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS

Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections

Thrombomodulin deficiency

THBD

AD

188040

Normal CH50, AH50

Atypical hemolytic-uremic syndrome

Membrane cofactor protein (CD46) deficiency

CD46

AD

120920

Inhibitor of complement alternate pathway, decreased C3b binding

Atypical hemolytic-uremic syndrome, infections, preeclampsia

Membrane attack Complex inhibitor (CD59) deficiency

CD59

AR

107271

Erythrocytes highly susceptible to complement-mediated lysis

Hemolytic anemia, polyneuropathy

CD55 deficiency (CHAPEL disease)

CD55

AR

125240

Hyperactivation of complement on endothelium

Protein losing enteropathy, thrombosis

Total number of disorders in Table 8: 30. New disorders: 1, CD55

MAC membrane attack complex, SLE systemic lupus erythematosus, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 9

Phenocopies of inborn errors of immunity

1. Phenocopies of inborn errors of immunity

Disease

Genetic defect/presumed pathogenesis

Circulating T cells

Circulating B cells

Serum Ig

Associated features/similar PID

Associated with somatic mutations

 Autoimmune lymphoproliferative syndrome (ALPS–SFAS)

Somatic mutation in TNFRSF6

Increased CD4−CD8− double negative (DN) T alpha/beta cells

Normal, but increased number of CD5+ B cells

Normal or increased

Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)

 RAS-associated autoimmune leukoproliferative disease (RALD)

Somatic mutation in KRAS (GOF)

Normal

B cell lymphocytosis

Normal or increased

Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like

 RAS-associated autoimmune leukoproliferative disease (RALD)

Somatic mutation in NRAS (GOF)

Increased CD4−CD8− double negative (DN) T alpha/beta cells

Lymphocytosis

Normal or increased

Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like

 Cryopyrinopathy, (Muckle-Wells/CINCA/NOMID-like syndrome)

Somatic mutation in NLRP3

Normal

Normal

Normal

Urticaria-like rash, arthropathy, neurological signs

 Hypereosinophilic syndrome due to somatic mutations in STAT5b

Somatic mutation in STAT5b (GOF)

Normal

Normal

Normal

Eosinophilia, atopic dermatitis, urticarial rash, diarrhea

 Large granular lymphocytosis

Somatic mutations in STAT3 (GOF)

Clonal expansion of large T cells

Normal

Normal

Anemia, neutropenia, splenomegaly

Associated with autoantibodies

 Chronic mucocutaneous candidiasis (isolated or with APECED syndrome)

Germline mutation in AIRE AutoAb to IL-17 and/or IL-22

Normal

Normal

Normal

Endocrinopathy, chronic mucocutaneous candidiasis/CMC

 Adult-onset immunodeficiency with susceptibility to mycobacteria

AutoAb to IFNγ

Decreased naive T cells

Normal

Normal

Mycobacterial, fungal, Salmonella VZV infections/MSMD, or CID

 Recurrent skin infection

AutoAb to IL-6

Normal

Normal

Normal

Staphylococcal infections/STAT3 deficiency

 Pulmonary alveolar proteinosis

AutoAb to GM-CSF

Normal

Normal

Normal

Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency

 Acquired angioedema

AutoAb to CI inhibitor

Normal

Normal

Normal

Angioedema/C1 INH deficiency (hereditary angioedema)

 Atypical hemolytic-uremic syndrome

AutoAb to complement factor H

Normal

Normal

Normal

aHUS = spontaneous activation of the alternative complement pathway

 Thymoma with hypogammaglobulinemia (Good syndrome)

AutoAb to various cytokines

Increased CD8+ T cells

No B cells

Decreased

Invasive bacterial, viral or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea

Total number of conditions for Table 9: 12

aHUS atypical hemolytic-uremic syndrome, GOF gain-of-function, PRCA pure red cell aplasia

The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of immune deficiency disorders. Thus, the “IUIS PID Committee Report on Inborn Errors of Immunity” and “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” publications are important resources for clinicians and researchers. In addition, these tables form the basis of lists used for sequencing panels and are used to monitor health utilization which will influence health services funding by federal or state governments and/or insurance companies in various global settings. The addition of ICD10 codes for the online version will promote a harmonization between the diagnostic tables and coding items that will facilitate bioinformatics research going forward.

Notes

Acknowledgements

The authors wish to thank Dawn Westerfer for the expert secretarial support and Ulrika Smrekova for the administrative support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Fudenberg H, Good RA, Goodman HC, Hitzig W, Kunkel HG, Roitt IM, et al. Primary immunodeficiencies. Report of a World Health Organization Committee. Pediatrics. 1971;47:927–46.PubMedGoogle Scholar
  2. 2.
    Fudenberg HH, Good RA, Hitzig W, Kunkel HG, Roitt IM, Rosen FS, et al. Classification of the primary immune deficiencies: WHO recommendation. N Engl J Med. 1970;283:656–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35:696–726.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Anonymous. Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol. 1997;109(Suppl 1):1–28.Google Scholar
  5. 5.
    Chandra R, Cooper M, Hitzig W, Rosen F, Seligmann M, Soothill JF, et al. WHO scientific group on immunodeficiencies. Clin Immunol Immunopathol. 1979;13:296–359.CrossRefGoogle Scholar
  6. 6.
    Gatti R. On the classification of patients with primary immunodeficiency disorders. Clin Immunol Immunopathol. 1974;3:243–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Cooper M, Faulk W, Fudenberg H, Good R, Hitzig W, Kunkel H, et al. Meeting report of the second international workshop on primary immunodeficiency diseases in man. Clin Immunol Immunopathol. 1974;2:416–45.CrossRefPubMedGoogle Scholar
  8. 8.
    Anonymous. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999;118(Suppl 1):1–28.Google Scholar
  9. 9.
    Immunodeficiency WSGo: meeting report primary immunodeficiency diseases. Clinical Immunology and Immunopathology 28: 450–475, 1983.Google Scholar
  10. 10.
    Rosen F, Wedgewood R, Eibl M. Primary immunodeficiency diseases. Clin Immunol Immunopathol. 1986;40:166–96.CrossRefGoogle Scholar
  11. 11.
    Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35:727–38.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;33:1078–87.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol 118 Suppl 1: 1–28, 1999.Google Scholar
  14. 14.
    Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R, et al. Primary immunodeficiency diseases: an update. J Allergy Clin Immunol. 2004;114:677–87.CrossRefPubMedGoogle Scholar
  15. 15.
    Notarangelo L, Casanova JL, Conley ME, Chapel H, Fischer A, Puck J, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol. 2006;117:883–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007;120:776–94.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    International Union of Immunological Societies Expert Committee on Primary I, Notarangelo LD, Fischer A, Geha RS, Casanova JL, Chapel H, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009;124:1161–78.CrossRefGoogle Scholar
  18. 18.
    Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Primary immunodeficiency diseases. Report of a WHO Scientific Group. Clin Exp Immunol 99 Suppl 1: 1–24, 1995.Google Scholar
  20. 20.
    Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139:232–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Casanova JL, Conley ME, Seligman SJ, Abel L, Notarangelo LD. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J Exp Med. 2014;211:2137–49.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Boufiha A, Phenotypical classification of PIDD. 2017. https://play.google.com/store/apps/details?id=com.horiyasoft.pidclassification.
  23. 23.
    Bousfiha A, Phenotypical classification of PIDD, iTunes. 2017. https://itunes.apple.com/us/app/pid-phenotypical-diagnosis/id1160729399?mt=8.
  24. 24.
    OMIM Online Mendelian Inheritance in Man. https://www.ncbi.nlm.nih.gov/omim.

Copyright information

© The Author(s) 2017

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Capucine Picard
    • 1
    • 2
  • H. Bobby Gaspar
    • 3
  • Waleed Al-Herz
    • 4
  • Aziz Bousfiha
    • 5
  • Jean-Laurent Casanova
    • 6
    • 7
    • 8
    • 9
  • Talal Chatila
    • 10
  • Yanick J. Crow
    • 11
    • 12
  • Charlotte Cunningham-Rundles
    • 13
  • Amos Etzioni
    • 14
  • Jose Luis Franco
    • 15
  • Steven M. Holland
    • 16
  • Christoph Klein
    • 17
  • Tomohiro Morio
    • 18
  • Hans D. Ochs
    • 19
  • Eric Oksenhendler
    • 20
  • Jennifer Puck
    • 21
  • Mimi L. K. Tang
    • 22
    • 23
    • 24
  • Stuart G. Tangye
    • 25
    • 26
  • Troy R. Torgerson
    • 19
  • Kathleen E. Sullivan
    • 27
    Email author
  1. 1.Center for the Study of Immunodeficiencies, Necker Hospital for Sick ChildrenAssistance Publique-Hôpitaux de Paris (APHP)ParisFrance
  2. 2.Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick ChildrenParis Descartes UniversityParisFrance
  3. 3.UCL Great Ormond Street Institute of Child HealthLondonUK
  4. 4.Department of Pediatrics, Faculty of MedicineKuwait UniversityKuwait CityKuwait
  5. 5.Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy LICIA Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical SchoolKing Hassan II UniversityCasablancaMorocco
  6. 6.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  7. 7.Howard Hughes Medical InstituteNew YorkUSA
  8. 8.Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick ChildrenUniversity Paris DescartesParisFrance
  9. 9.Pediatric Hematology-Immunology UnitNecker Hospital for Sick Children APHPParisFrance
  10. 10.Division of ImmunologyChildren’s Hospital BostonBostonUSA
  11. 11.Laboratory of Neuroinflammation and Neurogenetics, Necker BranchINSERM UMR1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut ImagineParisFrance
  12. 12.Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and HealthUniversity of Manchester, Manchester Academic Health Science CentreManchesterUK
  13. 13.Departments of Medicine and PediatricsMount Sinai School of MedicineNewYorkUSA
  14. 14.Ruth’s Children’s Hospital-TechnionHaifaIsrael
  15. 15.Grupo de Inmunodeficiencias Primarias, Facultad de MedicinaUniversidad de Antioquia UdeAMedellinColombia
  16. 16.Laboratory of Clinical Infectious DiseasesNational Institute of Allergy and Infectious DiseasesBethesdaUSA
  17. 17.Dr von Hauner Children’s HospitalLudwig-Maximilians-University MunichMunichGermany
  18. 18.Department of Pediatrics and Developmental BiologyTokyo Medical and Dental University (TMDU)TokyoJapan
  19. 19.Department of PediatricsUniversity of Washington and Seattle Children’s Research InstituteSeattleUSA
  20. 20.Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de ParisUniversity Paris Diderot, Sorbonne Paris CitéParisFrance
  21. 21.Department of PediatricsUniversity of California San Francisco and UCSF Benioff Children’s HospitalSan FranciscoUSA
  22. 22.Murdoch Children’s Research InstituteMelbourneAustralia
  23. 23.Department of PaediatricsUniversity of MelbourneMelbourneAustralia
  24. 24.Department of Allergy and ImmunologyRoyal Children’s HospitalMelbourneAustralia
  25. 25.Immunology DivisionGarvan Institute of Medical ResearchDarlinghurstAustralia
  26. 26.St Vincent’s Clinical SchoolUniversity of NSWSydneyAustralia
  27. 27.Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

Personalised recommendations