PID

The term "primary immunodeficiency diseases" (synonym: immunodeficiency syndromes) covers various diseases of the immune system that are characterized by a temporary or irreversible disturbance of the immune function. Congenital or primary immunodeficiencies (PID) are diseases in which the immunodeficiency is congenital, occurs in families and/or can be inherited. The PID group is contrasted with diseases in which the immunodeficiency is acquired, which are referred to by the generic term "secondary immunodeficiencies". The best-known example of this is AIDS (acquired immune deficiency syndrome).

In the group of PIDs with associated syndromes or well-defined immunodeficiencies, all well-defined PIDs with almost pathognomic clinical phenotype can be found, e.g. ataxia teleangiectatica (ataxia + telangiectasias) or Wiskott-Aldrich syndrome (thrombocytopenia with microplatelets and petechiae).

PID with congenital thrombocytopenia

• Wiskott-Aldrich syndrome (WAS): LOF mutations in the WAS gene (cytoskeletal defect affecting hematopoiesis/progressive loss of anti-CD3 induced proliferation/deficiency of IgM and polysaccharide antibodies with elevated IgA and IgE.
• XL thrombocytopenia (mild variant of WAS): small functionally defective platelets; eczematous skin lesions; lymphoma; autoimmune disease/ IgA nephropathy/ bacterial and viral infections. Note: XL thrombocytopenia is a mild variant of Wiskott-Aldrich syndrome (WAS), which later manifests as WAS.
• WIP (WAS interacting protein) defect: AR/ LOF mutations in WIPF1 gene/ disruption in cytoskeleton and immunological synapse/ thrombocytopenia and WAS-like symptoms/ absent WAS protein.
• Defect of Arp2/3-mediated filament branching: AR/mutation in ARPC1B gene/mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies -ANA, ANCA-, eosinophilia/high IgA and IgE.

Other combined immunodeficiencies (CID) less severe than SCID/ DNA repair defects.

• Ataxia teleangiectatica (Louis Bar syndrome): AR/mutation in AT gene (the mutated gene is called ATM gene )/disruption of cell cycle leads to chromosomal instability/ variable disorders in IgG subclasses, IgA and IgE/specific antibodies. Proliferation of monomeric IgM/rare hyper-IgM/low TRECs possible.
• Nijmegen-breakage syndrome : defect in NBS1 gene (NBS stands for nibrin) (disruption of cell cycle and DNA repair. Often IgA, IgE and IgG subclasses decreased, IgM possibly increased (AR; microcephaly, bird-like face, lymphomas; radiosensitive; chromosomal instability).
• Bloom syndrome: AR/mutation in BLM gene: RecQ-like helicase. Ig possibly decreased/chromosomal instability, radiosensitive, bone marrow insufficiency, leukemia, lymphoma, short stature, bird's head face, photosensitivity, telangiectasia.
• ICF1 syndrome (immunodeficiency with centromere instability and facial abnormalities): Mutation in DNA methyltransferase DNMT3B results in defective DNA methylation (B/T cells and function normal to decreased, AR; facial dysmorphia, macroglossia, bacterial and opportunistic infections, malabsorption. Hypogammaglobulinemia, low antibodies in some cases, T-cell function usually decreased. Multi-radial configurations of chromosomes 1, 9 and 16).
• ICF2 syndrome (immunodeficiency with centromere instability and facial abnormalities): Mutation at ZBTB24. (B/T cells and function normal to decreased; AR; facial dysmorphia, hypogammaglobulinemia, macroglossia, bacterial and opportunistic infections, malabsorption. Multi-radial configurations of chromosomes 1, 9, and 16).
• ICF3 syndrome (immunodeficiency with centromere instability and facial abnormalities) mutation at CDCA7. (B/T cells and function normal to decreased; AR; facial dysmorphia, hypogammaglobulinemia, macroglossia, bacterial and opportunistic infections, malabsorption. Multi-radial configurations of chromosomes 1, 9, and 16).
• ICF4 syndrome (immunodeficiency with centromere instability and facial abnormalities): Mutation in HELLS. B/T cells and function normal to decreased (AR; Facial dysmorphia, hypogammaglobulinemia, macroglossia, bacterial and opportunistic infections, malabsorption. Multi-radial configurations of chromosomes 1, 9 and 16).
• PMS2 (PMS1 homolog 2) defect: Mutation in PMS2 resulting in defects in class switch-induced DNA double-strand break repairs (IgG, IgA decreased; IgM possibly increased; AR; hyper IgM phenotype possible. B cells decreased; recurrent infections, café-au-lait spots, lymphomas and other malignant tumors).
• RNF168 defect (RNF stands for: ring finger protein 168); clinically also called RIDDLE syndrome = Radiosensitivity, Immune Deficiency, Dysmorphic features, Learning difficulties): AR/ mutation in RNF168 gene resulting in impaired repair of DNA strand breaks/mild decrease in IgG and IgA/ short stature, mild neurological disorders, microcephaly, mild facial dysmorphia/radiosensitivity.
• MCM4 defect (MCM4 stands for: minichromosome maintenance complex component 4):AR/ mutations in MCM4 gene involved in DNA replication and repair/ infections with various herpes viruses, short stature, adrenal insufficiency. Low NK cells, B, T cells normal, Ig normal.
• POLE1 defect (POLE1 stands for: polymerase ε subunit 1; = FILS syndrome) AR/defect in POLE1 gene/recurrent respiratory infections, meningitis, facial dysmorphia, livedo, short stature/ T cell proliferation decreased; memory B cells decreased, IgG2 and IgM decreased.
• POLE2 defect (POLE2 stands for polymerase ε subunit 1): Defect in POLE2 gene (AR; recurrent infections, disseminated BCG infection, autoimmunity disorder: type 1 diabetes/ hypothyroidism; facial dysmorphia. B and T cells severely decreased Tregs decreased, severely decreased T cell function, Ig decreased).
• Ligase I defe ct: AR/defect in LIG1 gene/recurrent respiratory infections, short stature,photosensitivity, radiosensitivity, lymphoma. Erythrocytes enlarged, T lymphopenia, Ig decreased.
• NSMCE3 defect: AR/mutation in NSMCE3 gene/severe(viral?) lung disease, thymic hypoplasia, chromosomal fragility increased; radiosensitivity increased. T cells and function decreased; Ig largely normal (see OMIM: 617241/LICS ) .
• ERCC6L2 (Hebo defect): AR/defect in ERCC6L2 gene/facial dysmorphia, microcephaly/bone marrow failure. B and T cells decreased.
• GINS1 defect: AR/mutation in GINS gene/neutropenia, intrauterine growth retardation, B and T cells N/decreased, NK cells very low. IgA increased, IgM and IgG decreased.

Other combined immunodeficiencies (CID) less severe than SCID/thymic defects with additional abnormalities.

• DiGeorge syndrome (velocardiofacial syndrome, chromosome 22q11.2 microdeletion syndrome): AD/defect affecting 90% thymic development triggered by 3 Mb microdeletion 22q11.2. Possible. TRECs decreased/hypoparathyroidism, conotruncal malformations, velopalatal disorders, conspicuous facies, developmental deficits/ severe T-cell defect only in < 5% of pat (note: DiGeorge syndrome is nowadays grouped with other phenotypically different but genotypically identical syndromes (CATCH 22; Cayler cardiofacial syndrome; DiGeorge sequence; Sedlackova syndrome; Sphrintzen syndrome; Takao syndrome; velocardiofacial syndrome et al.et al.) are grouped under the nonprejudicial neutral name"microdeletion syndrome 22q11(DS)."
• DiGeorge syndrome (velocardiofacial syndrome; genetic defect is unknown): sporadic/ hypoparathyroidism, conotruncal malformations, velopalatal disorders, prominent facies, developmental deficits. T cells normal to decreased.
• TBX1 defect:AD/ heterozygous mutation in transcription factor TBX1, localized within the above deletion region. Possibly TRECs decreased/ hypoparathyroidism, conotruncal malformations, velopalatal disorders, conspicuous facies, developmental deficits. T cells normal/ decreased.
• CHARGE association (syndrome) in CHD7 defect: AD/mutations in transcriptional regulator CHD7/ coloboma, cardiac defects, choanal atresia, retardation, genital and ear abnormalities/individual patients with T lymphopenia/ SCID-like picture and low Tregs.
• CHARGE association (syndrome) in SEMA3E defect: AD/mutations in transcriptional regulator SEMA3E/coloboma, cardiac defects, choanal atresia, retardation, genital and ear abnormalities/individual patients with T-lymphopenia/SCID-like picture and low Tregs.
• CHARGE association (syndrome): AD/gene defect unknown/coloboma, cardiac defects, choanal atresia, retardation, genital and ear abnormalities. Individual patients with T lymphopenia, SCID-like picture and low Tregs).
• FOXN1 defect(syn: winged helix (nude) defect = syndromic SCID): AD/defect in transcription factor FOXN1/ recurrent bacterial and viral infections, alopecia, nail dystrophy . T cells decreased, abnormal thymic epithelium with immature T cells.
• Chromosome 10p13-p14 deletion syndrome: AD/mutation in: 10p13-p14DS/hypoparathyroidism, renal disease, deafness, growth retardation, facial dysmorphia, less common are: heart defects and recurrent infections. B/T cells mostly normal, T lymphopenia with decreased function.
• Chromosome 11q deletion(Jacobsen syndrome): AD/mutation in 11q23del /immune deficiency/recurrent respiratory infections/warts, facial dysmorphia, growth retardation.

Other combined immunodeficiencies (CID) less severe than SCID/immunoosseous dysplasias.

• Cartilage hair hypoplasia: AR/mutation in the RMRP gene (RMRP stands for: component of mitochondrial RNA processing endoribonuclease) involved in processing ribosomal RNA and mitochondrial DNA/variably expressed T cell defect from largely normal to SCID-like findings/recurrent infections, short-limbed dwarfism, metaphyseal dysostoses, hypotrichosis; anemia, neutropenia. Autoimmunity, increased susceptibility to malignancies, reduced spermatogenesis, intestinal neuronal dysplasia.
• Schimke immunoosseous dysplasia: mutation in the SMARCAL 1 gene involved in chromatin remodeling (SMARCAL1 stands for: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1)/gene product is part of a multiprotein complex closely related to chromatin function and structure/ewa 30 mutations in the SMARCAL1 gene (2q34-q35; 18 exons) are known/ AR/ short stature, spondyloepiphyseal bone dysplasias, nephropathy/ recurrent infections/possible symptoms as in SCID with corresponding infections, T-lymphopenia, bone marrow failure.
• MYSM1 defect: mutation in MYSM1 gene: AR/small stature, recurrent infections, congenital bone marrow failure, myelodysplasia, skeletal abnormalities, cataract, developmental delay/immune defect in B cells and granulocytes, B, T, NK lymphopenia.
• MOPD1 defect: AR/mutation in RNU4ATAC gene (RNU4ATAC stands for: RNA, U4atac Small Nuclear /U12-Dependent Splicing)/recurrent bacterial infections, lymphadenopathei, spondyloepiphyseal bone dysplasias, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphia, microcephaly possible/ immunoglobulins and antibody production decreased/NK function decreased.
• EXTL3 defect: AR/ mutation in EXTL3 gene/ variable skeletal abnormalities, cervical spinal stenosis, developmental delay. T cells decreased.

Other combined immunodeficiencies (CID) less severe than SCID/ hyper IgE syndromes.

• STAT3 gene defect (HIES 1/s.u. Hyper-IgE syndrome 1) AD/ heterozygous LOF mutations in STAT3 gene/diminished TH17 cells, follicular TH cells, MAIT cells and NKT cells. Decreased memory B cells, increased BAFF expression. Deficient production of STAT3-dependent cytokines/ IGE increased, recurrent eosinophilia; often de novo defect; including candidiasis of nails/cold staphylococcal abscesses/eczema, pneumatoceles and lung abscesses/typical facies, osteoporosis, scoliosis, dentition abnormalities (delayed tooth change), hypermobility, premature aneurysm formation (coronary, cerebral).
• IL6 receptor defect: AR/ mutation in the gene encoding the IL6R receptor/recurrent purulent infections, cold abscesses/very high IgE, switched memory B cells and specific Ak are decreased (see below Hyper IgE syndrome 5).
• IL-6 signal transducer defect: AR/mutation in IL6ST gene/bacterial infections, eczema, lung abscesses with pneumatoceles formation, skeletal abnormalities, delayed dentition. Very high IgE, TH17 cells (see hyper IgE syndrome 4 below).
• ZNF431 defect: AR/mutation in the ZNF431 gene (zinc finger 431 gene). Associated with Hyper-IgE syndrome 3 (see below Hyper-IgE syndrome).
• DOCK8 defect: AR/mutation in the DOCK8 gene (Dedicator of cytogenesis 8 proteins). Associated with hyper IgE syndrome 2.
• ERBIN defect: AR/mutation in ERBIN gene/recurrent respiratory infections, including Staph. aureus/eczema, hyperextensible joints, some with arterial aneurysms/circulating Tregs increased.
• Loeys-Dietz syndrome: AD/mutations in TGFBR1 or TGFBR2 genes/recurrent respiratory infections, atopic dermatitis, NM allergies, hyperextensible joints, delayed dentition, some with aortic aneurysms (see also under hyper-IgE syndrome).
• Comel-Netherton syndrome: AR/mutation in the SPINK5 gene. The encoded protein, the serine protease LEKTI is missing or functionally impaired/ congenital ichthyosis, bamboo hair, atopic diathesis, bacterial infections, failure to thrive. IgE increased, Ak formation variably impaired, B cells decreased.
• PGM3 defect: AR/mutation in the PGM3 gene (PGM3 stands for phosphoglucomutase 3)/mutation leads to disturbances in glycosylations. The disease can therefore also be included in the family of CDG syndromes/ severe atopy, autoimmunity, bacterial and viral infections, cognitive impairment, hypomyelination, short stature, brachydactyly, facial dysmorphia. IgE increased; eosinophilia, possibly B and T cells decreased (see also hyper IgE syndrome).
• CARD11 defect (heterozygous): Mutation in CARD11 gene/ AD, recurrent respiratory and cutaneous viral infections, atopic diathesis, eosinophilia, food-middle-gel allergies, lymphoma. TH2 dominance, disruption of T-cell activation as well as activation of signaling pathways via NFkB and mTORC1).

Disorders of vitamin B12 and folic acid metabolism

• Transcobalamin 2 defect: AR/mutation in TCN2/megaloblastic anemia, pancytopenia/without therapy neurological damage. Ig Decreased.
• SLC46A1/PCFT defect: AR/ hereditary folate malabsorption: mutation in SLC46A1/megaloblastic anemia, failure to thrive. Without therapy neurological damage.
• MTHFD1 -defect: AR/MTHFD1 stands for methylene tetrahydrofolate dehydrogenase 1/mutation in MTHFD1 gene lead to recurrent bacterial infections/ PCP, failure to thrive, megaloblastic anemia, neutropenia. Intellectual deficits, convulsions. Folate-responsive. RTE and B cells decreased.

Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

• NEMO/IKBKG defect (NEMO stands for NFkB essential modulator): Mutations in the IKBKG gene (NEMO) causes disruption of NFkB activation in various cells, such as in T cells via the T cell receptor/XL/ reduced sweat production, ectodermal dysplasia (not obligate)/ partially conical teeth/ absence of polysaccharide specific antibodies/ increased susceptibility to infection with increased susceptibility to bacteria especially mycobacteria, viruses/ colitis.
• IKBA (NFKBIA) defect/anhidroticectodermal dysplasia with immunodeficiency 2 (EDA-ID): An IkBa gain-of-function (GOF) mutation in the NFKBIA gene/disruption of NFkB activation, so in T cells/reduced sweat production/ectodermal dysplasia (partial conical teeth), absence of polysaccharide-specific antibodies/hyper-IgM phenotype possible/increased susceptibility to infection, increased susceptibility to mycobacteria, viruses and bacteria, colitis.
• IKBKB GOF mutation (EDA-ID): Mutation in the IKB gene. This hemotype is characterized by decreased T cells; decreased TZR activation; hypogammaglobulinemia. An autosomal dominant genotype is characterized by recurrent bacterial, viral and fungal infections. Additionally, possibly ectodermal defects.

Calcium channel defects

• ORAI1 (ORAI stands for OTAI calcium release-activated calcium modulator 1) defect (seeImmunodeficiency 9; OMIM:612782): AR/mutation in the Orai1 gene, a component of the Ca channel activated by Ca release results in the following clinic: normal T-cell count, defective activation via the TZR/autoimmunity, non-progressive myopathy.
• STIM-1 (STIM-1 = stromal interaction molecule 1) defect: AR/ mutation in STIM-1 involved in Orai1 activation. Normal T cell number but defective activation via the TZR /autoimmunity, anhidrotic ectodermal dysplasia, non-progressive myopathy.

Combined immunodeficiencies (CID) less severe than SCID /Other defects.

• Purine nucleoside phosphorylase (PNP) deficiency: AR/mutation in PNP. T cell defect due to toxic metabolites (e.g. dGTP) as a result of enzyme deficiency/uric acid decreased/autoimmune hemolytic anemia, neurological disorders. Sometimes SCID-like picture (PNP-SCID).
• Immunodeficiency with multiple intestinal atresias: AR/mutation in TTC7A gene (TTC7A stands for tetratricopeptide repeat (TPR) domain 7A)/variable immunodeficiency of B and T cells/bacterial (sepsis), mycotic and viral infections/multiple intestinal atresias, often with intrauterine polyhydramnios. Partial SCID phenotype. TTC7A mutation may also manifest as inflammatory bowel disease.
• Tricho-hepato-enteral syndrome (trichohepatoenteric syndrome): AR/mutations in TTC37 or SKIV2L genes/memory B cells decreased; Ig and Ak decreased; AR; respiratory infections/inconsistent: growth retardation, facial dysmorphia, woolly hair, early untreatable diarrhea, liver cirrhosis, platelet abnormalities.
• Veno-occlusive disease of the liver with immunodeficiency (VODI): AR/mutation in SP110 gene/ hypogammaglobulinemia, functional disorders in B and T cells, veno-occlusive disease of liver, hepatosplenomegaly, thrombocytopenia, PCP, Candida and CMV infections, cerebrospinal leukodystrophy.
• BCL11B defect: AD/mutation in BCL11B gene/neonatal teeth, dysmorphia, abnormal corpus callosum, neurocognitive deficits. T cells decreased, T cell proliferation decreased.
• Vici syndrome: mutation in the EPG5 gene. AR/the EPG5 gene encodes the ectopic P-granule autophagy protein 5/ mutation leads to a disturbance of the autophagy process/ CD4 cells strongly decreased; their proliferation is markedly reduced/Ig low, especially IgG2; furthermore agenesis of the corpus callosum, cataract, cardiomyopathy, albinism, cleft palate, microcephaly, intellectual deficits, infections, CMC.
• HOIL1 (heme-oxidized IRP2 ubiquitin ligase-1, RBCK1) defect: AR/ mutation in HOIL1/RBCK1, a component of LUBAC. Disruption of NFkappaB activation/bacterial infections, autoinflammation, amylopectinosis. Decreased memory B cells, PS antibodies decreased.
• HOIL1 (heme-oxidized IRP2 ubiquitin ligase-1, RBCK1) defect; AR/mutation in HOIL1/RBCK1, a component of LUBAC. Disruption of NFkB activation/bacterial infections, autoinflammation, amylopectinosis. Memory B cells decreased, PS antibodies decreased.
• Hennekam lymphangiectasia-lymphoedema syndrome type 1: mutation in CCBE1 (facial and other dysmorphias, hypogammaglobulinemia, variable decrease in B and T cells).
• Hennekam lymphangiectasia/lymphoedema syndrome type 2: mutation at FAT4 (facial and other dysmorphias, hypogammaglobulinemia, variable reduction of B and T cells)
• NFE2L2 defect (nuclear factor, erythroid 2- like): Activating de novo mutation (respiratory and skin infections, growth retardation, developmental delay, cerebral white matter lesions, homocysteine. Geswitche Memory B cells/ facial and other dysmorphia/hypogammaglobulinemia, variable decrease in B and T cells decreased; Ig decreased; Ak formation decreased.
• STAT5b deficiency: AR/defect in STAT5b gene/disruption of T and NK cell function. STAT5b is necessary for signaling via IL-2 and IL-15/STH-refractory short stature, dysmorphia, eczema, lymphoid interstitial pneumonia, autoimmunity.
• STAT5b deficiency: AD/defect in STAT5b gene/disruption of T and NK cell function/STH-refractory short stature, eczema, high IgE. No ID compared to AR variant.
• Kabuki syndrome type 1: AD/mutation in KMT2D/MLL2/typical facies, cleft formation/high palate, skeletal abnormalities, short stature, intellectual deficits, congenital vitias, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity possible/IgA usually, IgG occasionally decreased.
• Kabuki syndrome type 2: AD/ mutation in KDM6A XL (also affects wbl)/ syndrome with multiple congenital anomalies/characterized by typical facial features, skeletal anomalies, mild to moderate intellectual disability and postnatal short stature/OMIM: 147920 300867).
• KMT2A defect (Wiedemann-Steiner syndrome): AD/mutation in KMT2A gene /respiratory infections, short stature, hypertelorism, hypertrichosis of elbows/developmental delay, intellectual deficits. Switched memory B cells decreased/ Ig and antibody formation decreased.