Table 2.

Combined immunodeficiencies with associated or syndromic features.

Disease	Genetic defect/presumed pathogenesis	Inheritance	Circulating T cells	Circulating B cells	Serum Ig	Associated features	OMIM number
1. Congenital thrombocytopenia
(a) Wiskott– Aldrich syndrome (WAS)	Mutations in WAS; cytoskeletal, and immunologic synapse defect affecting hematopoietic stem cell derivatives	XL	Progressive decrease, abnormal lymphocyte responses to anti-CD3	Normal	Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE	Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP	301000
(b) WIP deficiencya	Mutations in WIPF1; cytoskeletal and immunologic synapse defect affecting hematopoietic stem cell derivatives	AR	Reduced, defective lymphocyte responses to anti-CD3	Low	Normal, except for increased IgE	Recurrent infections; eczema; thrombocytopenia. WAS-like phenotype	614493
2. DNA repair defects (other than those in Table 1)
(a) Ataxia–telangiectasia	Mutations in ATM; disorder of cell cycle checkpoint; and DNA double-strand break repair	AR	Progressive decrease	Normal	Often decreased IgA, IgE, and IgG subclasses; increased IgM monomers; antibodies variably decreased	Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability	208900
(b) Ataxia–telangiectasia-like disease (ATLD)a	Hypomorphic mutations in MRE11; disorder of cell cycle checkpoint and DNA double-strand break repair	AR	Progressive decrease	Normal	Antibodies variably decreased	Moderate ataxia; pulmonary infections; severely increased radiosensitivity	604391
(c) Nijmegen breakage syndrome	Hypomorphic mutations in NBS1 (Nibrin); disorder of cell cycle checkpoint and DNA double-strand break repair	AR	Progressive decrease	Variably reduced	Often decreased IgA, IgE, and IgG subclasses; increased IgM; antibodies variably decreased	Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability	251260
(d) Bloom syndrome	Mutations in BLM; RecQ-like helicase	AR	Normal	Normal	Reduced	Short stature; bird-like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability	210900
(e) Immunodeficiency with centromeric instability and facial anomalies (ICF)	Mutations in DNA methyltransferase DNMT3B (ICF1) resulting in defective DNA methylation	AR	Decreased or normal; responses to PHA may be decreased	Decreased or normal	Hypogamma globulinemia; variable antibody deficiency	Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks	242860
(f) Immunodeficiency with centromeric instability and facial anomalies (ICF)	Mutations in ZBTB24 (ICF2)	AR	Decreased or normal; responses to PHA may be decreased	Decreased or normal	Hypogamma globulinemia; variable antibody deficiency	Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16	242860
(g) PMS2 deficiency	Mutations in PMS2, resulting in class switch recombination deficiency due to impaired mismatch repair	AR	Normal	Switched and non-switched B cells are reduced	Low IgG and IgA, elevated IgM, abnormal antibody responses	Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor	600259
(h) RNF168 deficiencya	Mutations in RNF168, resulting in defective DNA double-strand break repair	AR	Normal	Normal	Low IgG or low IgA	Short stature; mild motor control to ataxia and normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity	611943
(i) MCM4 deficiency	Mutations in MCM4 (minichromosome maintenance complex component 4) gene involved in DNA replication and repair	AR	Normal	Normal	Normal	Viral infections (EBV, HSV, VZV) Adrenal failure Short stature	609981
3. Thymic defects with additional congenital anomalies
(a) DiGeorge anomaly	Contiguous gene defect in 90% affecting thymic development; may also be due to heterozygous mutation in TBX1 (chromosome 22q11.2 deletion or TBX1 haploinsufficient syndrome)	De novo defect (majority) or AD	Decreased or normal; 5% have <1500 CD3 T cells/μL	Normal	Normal or decreased	Hypoparathyroidism, conotruncal malformation; abnormal facies; large deletion (3 Mb) in 22q11.2 (or rarely a deletion in 10p)	188400
(b) CHARGE syndrome	Variable defects of the thymus and associated T cell abnormalities often due to deletions or mutations in CHD7, SEMA3E, or as yet unknown genes	De novo defect (majority) or AD	Decreased or normal; some have <1500 CD3 T cells/μL	Normal	Normal or decreased	Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies	214800 608892
4. Immune-osseous dysplasias
(a) Cartilage hair hypoplasia	Mutations in RMRP (RNase MRP RNA) involved in processing of mitochondrial RNA and cell cycle control	AR	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	250250
(b) Schimke syndrome	Mutations in SMARCAL1 involved in chromatin remodeling	AR	Decreased	Normal	Normal	Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, and fungal infections; may present as SCID; bone marrow failure	242900
5. Hyper-IgE syndromes (HIES)
(a) AD-HIES (Job’s syndrome)	Dominant-negative heterozygous mutations in STAT3	AD Often de novo defect	Normal Th-17 and T follicular helper cells decreased	Normal Switched and non-switched memory B cells are reduced; BAFF level increased	Elevated IgE; specific antibody production decreased	Distinctive facial features (broad nasal bridge), eczema, osteoporosis, and fractures, scoliosis, delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses, pneumatoceles) due to Staphylococcus aureus, candidiasis, aneurysm formation	147060
(i) Tyk2 deficiencya	Mutation in TYK2	AR	Normal, but multiple cytokine signaling defect	Normal	(±) Elevated IgE	Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi, and viruses	611521
(ii) DOCK8 deficiency	Mutations in DOCK8 – regulator of intracellular actin reorganization	AR	Decreased impaired T lymphocyte proliferation	Decreased, low CD27+ memory B cells	Low IgM, increased IgE	Low NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer	243700
6. Dyskeratosis congenital (DKC)
(a) XL-DKC	Mutations in dyskerin (DKC1) (Hoyeraal–Hreidarsson syndrome)	XL	Progressive decrease	Progressive decrease	Variable	Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells	305000
(b) AR-DKC due to NHP2 deficiency	Mutation in NOLA2 (NHP2)	AR	Decreased	Variable	Variable	Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails	613987
(c) AR-DKC due to NOP10 deficiency	Mutation in NOLA3 (NOP10 PCFT)	AR	Decreased	Variable	Variable	Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails	224230
(d) AR-DKC due to RTEL1 deficiency	Mutation in (RTEL1)	AR	Decreased	Variable	Variable	Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails	608833
(e) AD-DKC due to TERC deficiency	Mutation in TERC	AD	Variable	Variable	Variable	Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia	127550
(f) AD-DKC due to TERT deficiency	Mutation in TERT	AD	Variable	Variable	Variable	Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia	614742
(g) AD-DKC due to TINF2 deficiency	Mutation in TINF2	AD	Variable	Variable	Variable	Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia	613990
7. Defects of vitamin B12 and folate metabolism
(a) TCN2 deficiency	Mutation in TCN2; encodes transcobalamin, a transporter of cobalamin into blood cells	AR	Normal	Variable	Decreased	Megaloblastic anemia, pancytopenia, untreated for prolonged periods results in mental retardation	275350
(b) SLC46A1 deficiency	Mutation in SLC46A1; a proton coupled folate transporter	AR	Variable numbers and activation profile	Variable	Decreased	Megaloblastic anemia, failure to thrive untreated for prolonged periods results in mental retardation	229050
(c) MTHFD1a deficiency	Mutations in MTHFD1; essential for processing of single-carbon folate derivatives	AR	Low	Low	Decreased	Megaloblastic anemia, failure to thrive neutropenia, seizures, mental retardation
8. Comel–Netherton syndrome	Mutations in SPINK5 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells	AR	Normal	Switched and non-switched B cells are reduced	Elevated IgE and IgA	Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive	256500
					Antibody variably decreased
9. Winged helix deficiency (Nude)a	Defects in forkhead box N1 transcription factor encoded by FOXN1	AR	Markedly decreased	Normal	Decreased	Alopecia, abnormal thymic epithelium, impaired T cell maturation	600838
10. ORAI-I deficiencya	Mutation in ORAI1, a Ca++ release-activated channel (CRAC) modulatory component	AR	Normal number, but defective TCR-mediated activation	Normal	Normal	Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy defective TCR-mediated activation	610277
11. STIM1 deficiencya	Mutations in STIM1, a stromal interaction molecule 1	AR	Normal number, but defective TCR-mediated activation	Normal	Normal	Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy defective TCR-mediated activation	605921
12. STAT5b deficiencya	Mutations in STAT5B, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells	AR	Modestly decreased	Normal	Normal	Growth-hormone insensitive dwarfism	245590
						Dysmorphic features
						Eczema
						Lymphocytic interstitial pneumonitis, autoimmunity
13. Hepatic veno-occlusive disease with immunodeficiency (VODI)	Mutations in SP110	AR	Normal (decreased memory T cells)	Normal (decreased memory B cells)	Decreased IgG, IgA, IgM, absent germinal centers, absent tissue plasma cells	Hepatic veno-occlusive disease; Pneumocystis jiroveci pneumonia; susceptibility to CMV, Candida; thrombocytopenia; hepatosplenomegaly	235550
14. IKAROS deficiencya	Mutation in IKAROS	AD de novo	Normal, but impaired lymphocyte proliferation	Absent	Presumably decreased	Anemia, neutropenia, thrombocytopenia	Not assigned
15. FILS syndromea	Mutation in POLE1; defective DNA replication	AR	Low naïve T cells; decreased T cell proliferation	Low memory B cells	Decreased IgM and IgG; lack of antibodies to polysaccharide antigens	Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections, and recurrent meningitis	615139
16. Immunodeficiency with multiple intestinal atresias	Mutation in TTC7A [tetratricopeptide repeat (TPR) domain 7A] protein of unknown function	AR	Variable, but sometimes absent	Normal	Decreased	Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype	243150

SCID, severe combined immune deficiencies; XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; MSMD, Mendelian susceptibility of mycobacterial disease.

^aTen or fewer unrelated cases reported in the literature.

T and B cell number and function in these disorders exhibit a wide range of abnormality; the most severely affected cases meet diagnostic criteria for SCID or leaky SCID and require immune system restoring therapy such as allogeneic hematopoietic cell transplantation. While not all DOCK8-deficient patients have elevated serum IgE, most have recurrent viral infections and malignancies as a result of combined immunodeficiency. AR-HIES due to Tyk2 deficiency is also listed in Table 6, because of its association with atypical mycobacterial disease resulting in MSMD. Riddle syndrome is caused by mutations in a gene involved in DNA double-strand break repair and is associated with hypogammaglobulinemia. Autosomal dominant and autosomal recessive forms of dyskeratosis congenita are included in this table. IKAROS-deficiency represents a single prematurely born infant who died at the age of 87 days and who had absent B and NK cells and non-functional T cells.