Table 1.

Sub classification of some PIDs Data from Refs ^{2, 3, 5, 6, 25-49}

Type of PID	Clinical features	Infections	Genetic Mutations (Other names) (OMIM numbers)
Antibody Deficiencies
Severely reduced serum immunoglobulins (Igs) with profoundly decreased or absent B cells (agammaglobulinemia)2,27,28	• Defect in early development of B cells in the bone marrow • Complete or near-total absence of B cells in peripheral blood. • Lack of peripheral lymphoid tissue like lymph nodes and tonsils. • Almost all of them (90%) present by preschool age, with over half presenting in infancy following the depletion of maternal immunoglobulins, and a few in adulthood	• Recurrent otitis media, pneumonia, and sinusitis • Chronic enteroviral meningoencepha litis and neutropenia have been reported in XLA	• BTK −85% (Bruton's or XLA) (300300) • Autosomal recessive Agam: deficiency of μ heavy chain (147020), λ5 (146770), CD79α(Igα) (112205) and CD79β (Igβ (147245), BLNK (604615), PIK3R1 (171833), and TCF3 (147141) • Other causes: myelodysplasia with hypogammaglobuline mia (monosomy 7, trisomy 8, or dyskeratosis congenita), and thymoma with immunodeficiency with unknown genetic defect
Severely reduced serum Ig isotypes (at least two) with normal or low numbers of B cells: Commonly classified as common variable immunodeficiency (CVID)2,29	• Present after two years of age with IgG 2SD below normal for age, low IgA and/ or IgM AND defective specific or functional antibodies • Other causes of hypogammaglobuline mia should be ruled out • Heterogeneous manifestations like autoimmunity, granulomatous disease, gastrointestinal disease, lymphoid hyperplasia, lymphoma, and other malignancies	• Recurrent infections: commonly sinopulmonary • Protozoal infections like Giardia	• ICOS (604558) , • CD19 (107265) , • CD81 (186845), • CD20 (112210) , • CD21 (614699), • TACI (604907) , • LRBA (606453) , BAFF-R (606269) , TWEAK (602695), NFKB2 (615577), and CXCR4 (WHIM syndrome) (193670) • Most patients do not have a causative gene identified • Once the causative gene is identified, it is appropriate to use the genetic name rather than CVID
Severe reduction in IgG and IgA, with normal or elevated IgM, and normal number of B cells (commonly termed as Hyper IgM Syndrome)	• AID/ UNG: 30 Patients present with lymphoid hyperplasia, and increased risk for autoimmunity	Bacterial infections	AID (605257) and UNG (191525) defects mainly affect class switch recombination and somatic hypermutation
	• CD40/CD40L30,31 lack secondary germinal centers in lymph nodes. They also have increased susceptibility to sclerosing cholangitis and hepatocellular carcinomas	Opportunistic infections (Cryptosporidium parvum, Histoplasma, Bartonella, Candida, and Cryptococcus sp)	CD40 (109535), CD40L (300386) affect T and B lymphocyte interaction and resulting signaling
			Other causes of high IgM: NEMO defect (300248) PI3K p110delta deficiency, Other diseases: PMS2, ataxia teleangiectasia (AT), and Nijmegen Breakage Syndrome (NBS).
Isotype or light chain deficiencies with generally normal number of B cells	• Selective IgA deficiency (SIgAD) can occur in isolation, with IgG subclass, or specific antibody, deficiency • SIgAD can be associated with autoimmunity, atopic diseases, and rarely lymphoid and gastrointestinal malignancies 3 • May evolve into CVID later in life	Most patients are asymptomatic and diagnosed incidentally, such as while testing for celiac disease but SIgAD can present with recurrent sinopulmonary infections,	The cause is not known but associated TACI mutations have been found
	• Isolated IgG subclass deficiency is mostly asymptomatic unless associated with other immune defect like specific antibody deficiency
	• PI3K p110delta deficiency 32 can be associated with lymphomas	CMV, EBV	• PIK3CD, PI3K-δ Other PIDs in this category include Ig heavy chain, kappa constant deficiency, PIK3CD, PRKCD mutations
Specific antibody deficiencies (SAD) with normal number of B cells	• Inability to produce sufficient antibodies to specific microbes, commonly those with protective polysaccharide capsules such as pneumococcus and hemophilus influenzae	Recurrent sinopulmonary infections or as per the specific antibody that is defective
Transient hypogammaglobulinemia of infancy (THI) with normal number of B cells	• Decreased IgG (2SD lower than normal level for age), low IgA and/ or IgM once the transplacentally transferred maternal IgG wanes • Typically resolves during toddlerhood but can persist till 5 years of age 27, and rarely, evolve into lasting PID.	While THI can be asymptomatic, the toddler can have recurrent sinopulmonary infections, or less commonly, severe invasive infections, triggering evaluation.
Combined Immunodeficiencies
Low CD8 subset:	• Severe ZAP70 33 deficiency can present with features of SCID • Hypomorphic mutations cause low CD8 counts and elevated IgE	Recurrent bacterial (sinopulmonary), fungal, and viral infections	ZAP70 (269840)
	• CD8 deficiency 34 and those with MHC Class I deficiency can present during childhood or adulthood • Vasculitis and pyoderma gangrenosum noted in MHC Class I deficiency • Bronchiectasis, and skin granulomas are noted 35	Chronic sinusitis and respiratory infections	CD8 (186910), TAP1, TAP2, TAPBP (604571)
Low CD4 T cell subset:	MHC Class II deficiency, 36 also known as bare lymphocyte syndrome, presents with protracted diarrhea, failure to thrive, and autoimmunity	Recurrent bacterial, fungal, viral, protozoal infections	CIITA, RFX5, RFXAP, RFXANK (209920)
	• MAGT1 deficiency 37 can present with chronic EBV infection and related malignancies. • Also called X-linked EBV associated neoplasia (XMEN)	Chronic EBV infection	MAGT1 (300715)
	LCK 38 and LRBA 39 deficiency can present with autoimmunity and inflammatory manifestations	Recurrent infections	LCK (153390) and LRBA (606453)
	UNC119 deficiency 40 can present with bronchiectasis	Recurrent infections (viral, fungal, and bacterial)	UNC119 (604011)
Low CD27+ B cells	CD27 deficiency 41 is associated with hypogammaglobulinemia.	Persistent EBV viremia	CD27 (615122)
Progressive decrease in T cell numbers, with normal B cell numbers, and normal or decreased serum Igs	• ITK (IL2 inducible T cell kinase) deficiency42 have lymphadenopathy, hepatosplenomegaly, cytopenias, EBV associated malignancies, and other viral and fungal infections • Neurological impairment and autoimmune hemolytic anemia are noted in purine nucleoside phosphorylase (PNP) deficiency 2		ITK (613011), PNP (164050)
Combined Immunodeficiencies with associated Syndromic Features
Congenital thrombocytopenia and eczema	• Seen in Wiskott Aldrich Syndrome/WAS 43 or WASP interacting protein (WIP) deficiency 44 • Can present with autoimmunity and malignancy
DNA repair defects 45	• AT presents with progressive neurological impairment, later onset of teleangiectasia • AT patients can develop malignancies like leukemia and lymphoma • Immune defects noted are low IgG and IgA with high IgM • Alpha feto protein level is elevated		Ataxia teleangiectasia (AT) (604391), Nijmegen breakage syndrome (NBS) (251260), and Bloom syndrome (210900)
	• NBS patients present with growth retardation, microcephaly, and have increased risk of malignancy like lymphoma • Alpha feto protein level is normal in NBS
Thymic defects	• Chromosome 22qll.2 deletion syndrome25,26 (congenital heart defect, hypocalcemia, cleft lip/ palate, behavioral problems) • Immune system can range from completely normal, or partial combined deficiency causing recurrent sinopulmonary infections to profound T cell deficiency leading to SCID- like features		Chromosome 22qll.2 deletion (188400)
	• CHARGE syndrome 25 presents with coloboma, heart defect, choanal atresia, growth and developmental retardation, genital anomalies, and ear anomalies • Varying degrees of immune defects ranging from normal immune system to complete absence of T cells		CHD7(608892), SEMA3E (2l4800)
Osseous dysplasias 46	• Cartilage hair hypoplasia: short-limbed short stature, joint laxity, metaphyseal chondrodysplasia, hair hypoplasia, neuronal dysplasia of intestine, and increased risk of malignancy • Both cellular and humoral immune defects are noted		RMRP (250250)
	• Schimke syndrome presents with dysmorphic facies, thin hair, spondyloepiphyseal dysplasia, short spine, renal failure and hyper pigmented macules along with cellular immune defects	Opportunistic infections	SMARCAL1 (242900)
Hyper IgE syndromes 47	• STAT3 deficiency eczema, pneumtoceles, coarse facies, skeletal anomalies like scoliosis	Recurrent skin abscesses	STAT3(147060), Tyk2 (611521), DOCK8 (243700), PGM3 (172100)
	• DOCK8 lacks the skeletal features but is more often associated with allergies • Impaired T cell (CD8) and NK cell function, low NK cell count and low CD27+ memory B cells	Viral infections like human papilloma virus (HPV), Varicella zoster, molluscum contagiosum, herpes simplex virus (HSV)	Other disorders like WAS, Omenn's syndrome, and can have high IgE levels
	• Tyk2 deficiency can present with severe eczema	Staphylococcus infections, intracellular infections like Mycobacteria, Salmonella, fungi, and viruses
	• PGM3 deficiency can present with impaired neurocognition, autoimmunity, and severe eczema
Phagocytic defects
Motility defects	Leukocyte adhesion deficiency present with poor wound healing, delayed separation of umbilical cord, and periodontitis, neutrophilia, and leukocytosis. • LAD1 presents with delayed separation of umbilical cord, poor wound healing with paucity of pus, in early infancy and is marked by lack of CD18 on flow cytometry 48 • LAD2 is characterized by psychomotor and growth retardation but decreasing infections with age. It is marked by the presence of Bombay blood group and lack of fucosylated glycoprotein moieties like Sialyl Lewis X 48. • LAD3 features bleeding tendency and sometimes osteopetrosis in early infancy 5,48		ITGB2 (116920), FUCT1 (266265), KINDLIN3 (612840) Other motility defect: RAC2 (602049)
Respiratory burst Defects: Chronic granulomatous disease(CGD) 5	• Defective NADPH oxidase system. • Associated with granulomatous disease of gastrointestinal, respiratory, or urinary tracts.	Catalase positive organisms like Staphylococcus aureus, Nocardia, Pseudomonas, Serratia species, Burkholderia cepacia Fungi like Candida, and Aspergillus	CYBB (306400), CYBA (233690), NCF1 (233700), NCF2 (233710), and NCF4 (601488)
Mendelian susceptibility to mycobacterial disease or MSMD 5	Defects in IL12/ IFN gamma pathway lead to susceptibility to specific organisms	Infection by Salmonella spp, Mycobacteria and Cryptococcus neoformans	IL12RB1 (209950), IL12B (161561), IFNGR1 (209950), IFNGR2 (147569), STAT1 (600555), CYBB (306400), IRF8 (601565), ISG15 (147571)
GATA2 deficiency 49	• Low B cell, NK cell, and monocyte counts. • CD4 and neutrophil counts can be low but are less remarkable. • Lymph edema, pulmonary alveolar proteinosis, warts, skin malignancies, sensorineural hearing loss, miscarriage, hypothyroidism myelodysplasia, and leukemias are other features	Severe viral infections, mycobacterial infections, fungal infections	GATA2 (137295)
Complement Defects 2,5,6
Early complement defects	• C1q ,C1r , C1s, C4, C2 deficiency present with SLE • C3, Factor I, H deficiency, CD46 deficiency can present with infections, glomerulonephritis, and atypical hemolytic-uremic syndrome (HUS)	Infections with encapsulated organisms	120550, 601269, 120575, 216950, 120580, 120810, 120820, 217000, 120700, 610984, 609814, 120920
Late complement and alternative pathway deficiency like	C5, C6, C7, C8 (C8A, C8G, C8B), C9 (mild), Factor D, Properdin deficiency	Present with infections caused by Neisserial species.	120900, 217050, 217070, 120950, 120960, 613825, 134350, 312060
Other complement defects	Inflammatory lung disease, and autoimmunity Ficolin 3 can present with necrotizing enterocolitis	• MASP2 deficiency: respiratory and pyogenic infections • Ficolin 3 deficiency (FCN3) can present with respiratory infections and abscesses.	605102, 604973