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Table 3 Other primary immune regulatory disorders (PIRD)

From: Rare diseases: What rheumatologists need to know?

Disease

Gene

Inheritance

Clinical features

Laboratory tests

Treatment

CVID

TNFRSF13; PIK3CD GOF; PIK3R1;

PTEN; among others

AR and AD

Severe recurrent infections, bronchiectasis, interstitial lung disease (GLILD), autoimmune manifestations (ITP, AIHA, rheumatoid arthritis, SLE)

Marked decrease of IgG and a marked decrease in at least one of the IgM or IgA, absent isohemagglutinins and/or poor response to vaccines; Molecular analysis#

Ig, antibiotic prophylaxis, immunosuppression in case of autoimmune features

ALPS¶

TNFRSF6;

TNFSF6;

CASP 8; CASP 10; FADD

AR and AD

Splenomegaly, lymphadenopathy, autoimmune cytopenia, increased lymphoma risk, bacterial and viral infections

IgG and IgA normal or increased, elevated serum FasL, IL-10, vitamin B12, increased TCR + CD4-CD8 double negative T cells; Molecular analysis#

mTORi, mycophenolate, rituximab, antibiotic prophylaxis in some cases

CTLA4 deficiency

CTLA4

AD (variable penetrance)

Autoimmune cytopenia, enteropathy, interstitial lung disease with lymphocytic infiltration, splenomegaly, lymphadenopathy recurrent infections, psoriasis, vitiligo

Cytopenia, Impaired function of Tregs, hypogammaglobulinemia, lymphocytic or granulomatous organ infiltration on biopsy; Molecular analysis#

Abatacept, Ig, antibiotic prophylaxis, HSCT

DADA2

ADA2

AR

Systemic vasculitis (polyarteritis nodosa), early-onset recurrent ischemic stroke and fever, livedo racemosus, recurrent infections, arthralgia, arthritis

Increased IM during disease flares, hypogammaglobulinemia, cytopenia in bone marrow failure (Diamond-Blackfan features), ANA positivity; Molecular analysis#

CS, TNFi, Ig, HSCT

HA20

TNFAIP3

AD

Oral and genital ulcers, GI manifestations, fever, arthritis, recurrent infections, uveitis, polyautoimmunity

Increased IM during disease flares, neutrophilia, pathergy positivity, positive ANA; Molecular analysis#

CS, TNFi, colchicine, cyclosporine, azathioprine

SAVI

STING

AD and AR GOF

Perniotic rash, small vessel vasculitis, severe interstitial lung disease, alveolar hemorrhage, arthritis, cerebral calcifications, nail clubbing

Increased IM during disease flares, lymphopenia, increased interferon signature and serum IgG, positive ANA, RF and ANCA; Molecular analysis#

CS, JAKi and IFNi, antifibrotic drugs, lung transplantation

COPA syndrome

COPA

AD

Arthritis, severe interstitial lung disease, alveolar hemorrhage, glomerulonephritis, autoimmune features

Increased IM during disease flares, increased interferon signature, positive ANA, RF and ANCA; Molecular analysis#

CS, JAKi and IFNi, antifibrotic drugs, lung transplantation

PLAID/ APLAID

PLCG2

AD GOF

Cold urticaria, atopic skin lesions granulomatous dermatitis, severe recurrent infections, autoimmune features, recurrent swelling of palms and feet

Increased IM during disease flares, hypogammaglobulinemia; Molecular analysis#

Antihistamines, CS, Ig, antibiotic prophylaxis

Type 1 interpheronopaties

TREX1;

DNASE2;

SAMHD1;

RNASEH2A.

IFIH1.

among others

AD GOF

AR LOF

Fever, encephalopathy, cerebral calcification, seizures, hydrocephalus, aortic and valvular calcifications, acro-osteolysis, dental abnormalities, joint contractures, cutaneous ulcers and perniotic lesions

Increased IM during disease flares, increased interferon signature, positive ANA, RF and ANCA; Molecular analysis#

CS, JAKi and IFNi

Proteasomopathies

PSMB8.

PSMB10;

POMP;

among others

AR and AD (dominant negative effect). Digenic inheritance.

Fever, joint contractures, myositis, hepatosplenomegaly, lipodystrophy, cerebral calcifications and perniotic lesions

Increased IM during disease flares, increased interferon signature, positive ANA, hypergammaglobulinemia. Molecular analysis#

CS, JAKi and IFNi

  1. AD autosomal dominant, ADA2 adenosine deaminase 2, AIHA autoimmune hemolytic anemia, ALPS¶ autoimmune lymphoproliferative syndrome, ANA antinuclear antibodies, APLAID autoinflammation, antibody deficiency, and immune dysregulation, AR autosomal recessive, CASP 8 caspase 8, apoptosis-related cysteine protease, CASP 10 caspase 10, apoptosis-related cysteine protease, COPA coatomer subunit alpha, CS corticosteroids, CTLA4 cytotoxic T-lymphocyte associated protein 4, CVID common variable immunodeficiency, CGD chronic granulomatous disease, CRP c-reactive protein, DADA2 deficiency of adenosine deaminase 2, DNASE2 deoxyribonuclease 2, lysosomal, ESR erythrocyte sedimentation rate, FADD fas-associating protein with death domain, FASL Fas ligand, GLILD granulomatous and lymphocytic interstitial lung diseases, GI gastrointestinal, GOF gain-of-function, HA20 haploinsufficiency A20, HSCT hematopoietic stem cell transplantation, IFIH1 interferon induced with helicase C domain 1, Ig immunoglobulin, IgA immunoglobulin A, IgG immunoglobulin G, IgM immunoglobulin M, IFN interferons, IFNi IFN inhibitors, IM inflammatory markers (erythrocyte sedimentation rate, c-reactive protein and serum amyloid A), ITP Immune thrombocytopenia, JAK janus kinase, JAKi JAK inhibitors, MTOR mammalian target of rapamycin, mTORi mTOR inhibitors, PIK3CD GOF phosphoinositide 3-kinase delta isoform deficiency gain-of-function, PLAID PLCG2 associated antibody deficiency and immune dysregulation, PLCG2 phospholipase C gamma 2, POMP proteasome maturation protein, PSMB8 proteasome 20S subunit beta 8, PSMB10 proteasome 20S subunit beta 10, PTEN phosphatase and tensin homologue gene, SAA serum amyloid A, RNASEH2A ribonuclease HI subunit A, SAMHD1 SAM domain and HD domain-containing protein 1, SAVI STING-associated vasculopathy with onset in infancy, SLE systemic lupus erythematosus, STING stimulator of interferon genes protein, TCR T-cell receptor, TMEM137 transmembrane protein 137, TNF tumor necrosis factor, TNFAIP3 tumor necrosis factor, alpha induced protein 3, TNFi TNF inhibitors, TNFSF6 tumor necrosis factor ligand superfamily member, TNFRSF6 tumor necrosis factor receptor superfamily, member 6, TNFRSF13B TNF receptor superfamily member 13B, TREG regulatory T cells, TREX1 three-prime repair exonuclease 1
  2. #Molecular analysis (sanger, next generation sequencing, whole exome sequencing)
  3. ----*no single gene or inheritance has been identified
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Advances in Rheumatology

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