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