Open Access

Heterogeneity in combined immunodeficiencies with associated or syndromic features (Review)

  • Authors:
    • Lavinia Caba
    • Cristina Gug
    • Eusebiu Vlad Gorduza
  • View Affiliations

  • Published online on: November 26, 2020     https://doi.org/10.3892/etm.2020.9517
  • Article Number: 84
  • Copyright: © Caba et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Primary immunodeficiencies are genetic diseases, mainly monogenic, that affect various components of the immune system and stages of the immune response. The category of combined immunodeficiencies with associated or syndromic features comprises over 70 clinical entities, characterized by heterogeneity of clinical presentation, mode of transmission, molecular, biological, mutational and immunological aspects. The mutational spectrum is wide, ranging from structural chromosomal abnormalities to gene mutations. The impact on the function of the proteins encoded by the genes involved is different; loss of function is most common, but situations with gain of function are also described. Most proteins have multiple functions and are components of several protein interaction networks. The pathophysiological mechanisms mainly involve: Missing enzymes, absent or non‑functional proteins, abnormal DNA repair pathways, altered signal transduction, developmental arrest in immune differentiation, impairment of cell‑to‑cell and intracellular communications. Allelic heterogeneity, reduced penetrance and variable expressivity are genetic phenomena that cause diagnostic difficulties, especially since most are rare/very rare diseases, which is equivalent to delaying proper case management. Most primary immunodeficiencies are Mendelian diseases with X‑linked or recessive inheritance, and molecular diagnosis allows the identification of family members at risk and the application of appropriate primary and secondary prevention measures in addition to the specific curative ones. In conclusion, recognizing heterogeneity and its sources is extremely important for current medical practice, but also for the theoretical value of improving biological and biomedical applications.

1. Introduction

Primary immunodeficiencies (PIDs) are rare, mostly monogenic genetic diseases that affect various components of the immune system and are characterized by pathological, clinical, and immunological diversity (1,2). The prevalence of PIDs is approximately 4-10 per 105 live births (3).

The International Union of Immunological Societies (IUIS) recognizes the existence of 430 entities and 408 different genes involved. It classifies diseases into 9 categories: Immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocyte number or function, defects in intrinsic and innate immunity, autoinflammatory disorders, complement deficiencies and phenocopies of inborn errors of immunity (4-6). Of these, combined immunodeficiencies with associated or syndromic features present high heterogeneity manifested at the molecular and mutational level. Biological processes involve different gene expression products, ‘extraimmune’ clinical symptoms characteristic of each syndrome, and many diseases present incomplete penetrance and variable expressivity. This combined immunodeficiencies are classified into 10 types: Immunodeficiency with congenital thrombocytopenia; DNA repair defects (immunodeficiencies affecting cellular and humoral immunity); thymic defects with additional congenital anomalies; immuno-osseous dysplasias; hyper IgE syndromes (hyperimmunoglobulin E syndromes or HIES); dyskeratosis congenita (DKC), myelodysplasia, short telomeres; defects of vitamin B12 and folate metabolism; ectodermal anhidrotic dysplasia with immunodeficiency (EDA-ID); and calcium channel defects (4).

Correct and early diagnosis is necessary to prevent complications and reduce mortality (7). The molecular diagnosis can be followed by early protective and curative interventions, but also by avoiding the usual interventions which in the case of certain PIDs can bring additional complications (for example use of DNA-radiomimetic drugs in radiosensitive PIDs) (8). It is estimated that 70-90% of patients with PID remain undiagnosed worldwide (9). The onset can be at any age, but early onset correlates negatively with the severity of the manifestations (7). In many cases, patients are consulted for recurrent infections, but the etiological diagnosis is delayed. There are studies that show that in the US the etiological diagnosis is delayed by up to 12.4 years (10). During all this time, negative consequences can appear in personal, social and professional life, so that the quality of life is profoundly altered (3,7,11). In some cases, patients also have a predisposition to autoimmune diseases, autoinflammatory diseases or lymphoproliferative phenomena (4,8,12-16).

2. Molecular heterogeneity and biological processes

The vast majority of genes involved are genes that encode proteins. In combined immunodeficiencies with syndromic features a double heterogeneity is present: A specific protein presents multiple and diverse molecular functions while several different proteins have the same molecular function. Table I summarizes the molecular functions of these proteins and the biological processes in which they intervene according to UniProt Knowledgebase https://www.uniprot.org/ (4-6,17-23).

Table I

Heterogeneity of molecular and biological processes in combined immunodeficiencies with associated or syndromic features (4-6,17,19-23).

Table I

Heterogeneity of molecular and biological processes in combined immunodeficiencies with associated or syndromic features (4-6,17,19-23).

DiseaseGene (MOI)Molecular functionBiological process
Immunodeficiency with congenital thrombocytopenia
Wiskott-Aldrich syndrome (WAS LOF)WAS (XL)GTPase regulator and binding activity; protein binding (actin, protein kinase); phospholipase bindingFc-gamma receptor signaling pathway involved in phagocytosis; immune response; regulation of T cell antigen processing and presentation; T cell activation; T cell receptor signaling pathway
WIP deficiencyWIPF1 (AR)Actin binding; profilin binding; SH3 domain bindingFc-gamma receptor signaling pathway involved in phagocytosis; regulation of cell shape, immune response against microorganisms
ARPC1B deficiencyARPC1B (AR)Actin filament and binding; structural constituent of cytoskeletonFc-gamma receptor signaling pathway involved in phagocytosis
DNA repair defects other than those listed in the 1st category
Ataxia-telangiectasiaATM (AR)ATP, protein and DNA binding; DNA-dependent protein kinase activityCell cycle; DNA damage
Nijmegen breakage syndromeNBN (AR)Damaged DNA and protein binding;Cell cycle; DNA damage; DNA repair; host-virus interaction;
Bloom syndromeBLM (RECQL3) (AR)3'-5' DNA helicase activity; DNA and ATP bindingDNA damage; DNA repair; DNA replication
ICF1DNMT3B (AR)Chromatin, DNA and metal binding; DNA-methyltransferase activity; histone deacetylase bindingDNA methylation; regulation of histone methylation and transcription
ICF2ZBTB24 (AR)DNA-binding transcription factor activityTranscription; transcription regulation
ICF3CDCA7 (AR)MYC-mediated cell transformation and apoptosisApoptosis; transcription
ICF4HELLS (AR)Developmental protein; helicase activity; hydrolase; ATP bindingCell cycle; transcription; multicellular organism development
PMS2 deficiencyPMS2 (AR)Endonuclease activity; ATPase activity; ATP and DNA bindingDNA damage; DNA repair
RNF168 deficiency (Riddle syndrome)RNF168 (AR)Chromatin, histone and metal binding; ubiquitin-protein transferase activityDNA damage; DNA repair; ubiquitin conjugation pathway
MCM4 deficiencyMCM4 (AR)ATP binding, DNA helicase activityCell cycle; DNA replication
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome)POLE (AR)DNA and metal binding; DNA-directed DNA polymeraseDNA damage; DNA repair; DNA replication
POLE2 (polymerase ε subunit 2) deficiencyPOLE2 (AR)DNA-binding; DNA-directed DNA polymerase activityDNA replication
Ligase I deficiencyLIG1 (AR)DNA ligase activity; ATP, DNA and metal bindingCell cycle; DNA damage, recombination, repair and replication
DNA repair defects other than those listed in the 1st category
NSMCE3 deficiencyNSMCE3 (AR)Tumor antigenDNA damage, recombination and repair; growth regulation
ERCC6L2 (Hebo deficiency)ERCC6L2 (AR)DNA, ATP and protein kinase binding; helicase activityDNA damage; DNA repair
GINS1 deficiencyGINS1 (AR)DNA-binding (single-stranded DNA)DNA replication; inner cell mass cell proliferation
Thymic defects with additional congenital anomalies
DiGeorge/velocardiofacial syndrome (22q11.2DS)Deletion in chromosome 22 (AD)  
TBX1 deficiencyTBX1 (AD)Developmental protein; DNA and transcription activator binding; RNA polymerase IITranscription; angiogenesis; thymus development; morphogenesis
CHARGE syndromeCHD7 (AD)ATP and chromatin binding; DNA helicase activity;rRNA processing; transcription
CHARGE syndromeSEMA3E (AD)Developmental protein;Angiogenesis; differentiation; neurogenesis
Winged helix nude FOXN1 deficiencyFOXN1 (AR)Developmental protein; DNA-binding transcription activatorDifferentiation; transcription; thymus epithelium morphogenesis; lymphoid lineage cell migration into thymus; regulation of thymic T cell selection; T cell homeostasis; T cell lineage commitment
Chromosome 10p13-p14 deletionDel10p13-p14 (AD)  
Chromosome 11q deletion (Jacobsen syndrome)Del11q23 (AD)  
Immuno-osseous dysplasias
Cartilage hair hypoplasia (CHH)RMRP (AR)Noncoding RNAProcessing of ribosomal RNA; cell cycle control
Schimke immuno-osseous dysplasiaSMARCAL1 (AR)Helicase activity; ATP bindingCellular response to DNA damage stimulus
MYSM1 deficiencyMYSM1 (AR)DNA histone and metal ion bindingTranscription
MOPD1 deficiencyRNU4ATAC (AR)Small nuclear RNA (snRNA)Part of spliceosome complex
EXTL3 deficiencyEXTL3 (AR)Metal ion binding; transferase activityProteoglycan biosynthetic process; regulation of cell growth
Hyper-IgE syndromes (HIES)
STAT3 deficiency (Job syndrome)STAT3 (AD)DNA, enzyme and chromatin binding; RNA polymerase activityHost-virus interaction; transcription
IL6 receptor deficiencyIL6R (AR)Cytokine and enzyme binding, cytokine receptor activityRegulation of the immune response, acute-phase reactions and hematopoiesis
Hyper-IgE syndromes (HIES)
IL6 signal transducer (IL6ST) deficiencyIL6ST (AR)Cytokine and growth factor binding, cytokine receptor activity, bindingHost-virus interaction
ZNF341 deficiency AR-HIESZNF341 (AR)DNA and metal ion binding; DNA-binding transcription activator activityTranscription, transcription regulation
ERBIN deficiencyERBIN (AD)Signaling receptor binding; structural constituent of cytoskeletonCell adhesion; cellular response to tumor necrosis factor; epidermal growth factor receptor signaling pathway
Loeys-Dietz syndrome (TGFBR deficiency)TGFBR1 (AD)Activin, ATP and metal ion binding; protein kinase activityApoptosis, differentiation, growth regulation
Loeys-Dietz syndrome (TGFBR deficiency)TGFBR2 (AD)Activin-activated receptor activity; activin, ATP and metal ion bindingApoptosis, differentiation, growth regulation
Comel-Netherton syndromeSPINK5 (AR)Serine-type endopeptidase inhibitor activityCell differentiation; central nervous system development; regulation of T cell differentiation
PGM3 deficiencyPGM3 (AR)Magnesium binding; enzymatic activityCarbohydrate metabolism; hemopoiesis
CARD11 deficiency (heterozygous)CARD11 (AD LOF dominant negative)CARD domain binding, guanylate kinase activityCostimulatory signal for T-cell receptor-mediated T-cell activation; NF-κB activation in a T-cell receptor/CD3-dependent manner
Dyskeratosis congenita (DKC), myelodysplasia, short telomeres
XL-DKCDKC1 (XL)RNA-binding; telomerase RNA bindingRibosome biogenesis; rRNA processing
AR-DKC with NHP2 deficiencyNHP2 (AR)RNA-binding; telomerase RNA bindingRibosome biogenesis; rRNA processing
AR-DKC with NHP3 or NOP10 deficiencyNOP10 (AR)RNA-binding; telomerase RNA bindingRibosome biogenesis; rRNA processing
AD/AR-DKC with RTEL1 deficiencyRTEL1 (AD or AR)DNA, ATP, DNA polymerase and metal ion binding; DNA helicase activityDNA damage; DNA repair
AD-DKC with TERC deficiencyTERC (AD)Telomerase RNA componentDNA replication
AD/AR-DKC with TERT deficiencyTERT (AD or AR)DNA, chaperone, protein and metal ion -bindingTranscription and replication
AD-DKC with TINF2 deficiencyTINF2 (AD)Telomeric DNA bindingTranscription of telomeres
AD/AR-DKC with TPP1 deficiencyTPP1 (AD or AR)Peptidase activity; metal and ion bindingDevelopment and cell differentiation; lipid and protein metabolic process
AR-DKC with DCLRE1B deficiency DCLRE1B/SNM1/ APOLLO (AR)5'-3' exonuclease activityDNA damage; DNA repair
AR-DKC with PARN deficiencyPARN (AR (AD?)) 3'-5'-Exoribonuclease activity; cation binding; metalion bindingNonsense-mediated mRNA decay
AR-DKC with WRAP53 deficiencyWRAP53 (AR)RNA chaperone histone protein bindingDNA damage; DNA repair; Host-virus interaction
Coats plus syndromeSTN1 (AR)DNA bindingDNA repair; DNA replication;
Coats plus syndromeCTC1 (AR)DNA bindingCell cycle control; multicellular organism growth
SAMD9SAMD9 ADInflammatory response to tissue injuryEndosomal vesicle fusion
Defects of vitamin B12 and folate metabolism
Transcobalamin 2 deficiencyTCN2 (AR)Cobalamin binding; metal ion bindingCobalt transport; ion transport;
SLC46A1/PCFT deficiencySLC46A1 (AR)Folic acid binding; folic acid, heme, methotrexate and transporter activityTransport of different cellular components
MTHFD1 deficiencyMTHFD1 (AR)ATP binding; enzymatic activityProtein biosynthesis
Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID)
EDA-ID with NEMO/IKBKG deficiencyIKBKG (NEMO) (XL)Protein and metal ion bindingDNA damage; host-virus interaction; transcription
EDA-ID with IKBA GOF mutationNFKBIA (IKBA) (XL)Protein and enzyme bindingHost-virus interaction
EDA-ID with IKBKB GOF mutationIKBKB (AD GOF)ATP and protein kinase binding, protein kinase activityHost-virus interaction
Calcium channel defects
ORAI-1 deficiencyORAI1 (AR)Calmodulin-binding; store-operated calcium channel activityAdaptive immunity; calcium transport;
STIM1 deficiencySTIM1 (AR)Calcium channel regulator activity; calcium ion bindingCalcium transport
Other defects
Purine nucleoside phosphorylase deficiencyPNP (AR)Drug protein nucleoside and phosphate bindingImmune response; interleukin-2 secretion; neutrophil degranulation; nucleotide biosynthetic process; regulation of T cell proliferation; response to drug; urate biosynthetic process
Immunodeficiency with multiple intestinal atresiasTTC7A (AR)Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membraneCellular iron ion homeostasis; hemopoiesis; phosphatidylinositol phosphorylation
Tricho-Hepato-Enteric Syndrome (THES)TTC37 (AR)Exosome-mediated RNA decayExonucleolytic catabolism of deadenylated mRNA
Tricho-Hepato-Enteric Syndrome (THES)SKIV2L (AR)ATP and RNA binding; RNA helicase activityRNA catabolic process
Hepatic veno-occlusive disease with immunodeficiencySP110 (AR)DNA, protein and metal ion binding; RNA polymerase II-specificHost-virus interaction; transcription
BCL11B deficiencyBCL11B (AD)DNA, metal binding; RNA polymeraseTranscription
Vici syndrome due to EPG5 deficiencyEPG5 (AR)Clearance of autophagosomal cargo innate and adaptive immune responseAutophagy; cellular response to dsDNA; nucleotide transport; toll-like receptor 9 signaling pathway
Other defects
HOIL1 deficiencyHOIL1 (RBCK1) (AR)Protein, enzyme and metal ion bindingHost-virus interaction
HOIP deficiencyRNF31 (AR)Protein, metal ion and ubiquitin bindingUbl conjugation pathway
Hennekam-lymphangiectasia-lymphedema syndromeCCBE1 (AR)Calcium ion collagen and protease bindingAngiogenesis and lymphangiogenesis
Hennekam-lymphangiectasia-lymphedema syndromeFAT4 (AR)Calcium ion bindingCell adhesion
De novo mutations in nuclear factor, erythroid 2- like (NFE2L2)NFE2L2 (AD)DNA and protein binding; RNA polymerase II-specificHost-virus interaction, transcription,
STAT5b deficiencySTAT5B (AR)Chromatin, protein and hormone binding; RNA polymerase IITranscription
STAT5b deficiencySTAT5B (AD)  
Kabuki syndrome 1 with KMT2D deficiencyKMT2D (MLL2) (AD)DNA histone and metal ion binding; histone methyltransferase activity transcription coactivator activityTranscription
Kabuki syndrome 2 with KDM6A deficiencyKDM6A (XL)DNA histone and metal ion binding; histoneChromatin remodeling and morphogenesis methyltransferase activity transcription coactivator activity
Wiedemann-Steiner syndromeKMT2A (AD)DNA and zinc ion binding; RNA polymerase II-specific; histone methyltransferase activityApoptosis; transcription;

[i] MOI, mode of inheritance; XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance. WAS, WASP actin nucleation promoting factor; WIPF1, WAS/WASL interacting protein family member 1; ARPC1B, actin related protein 2/3 complex subunit 1B; ATM, ATM serine/threonine kinase); NBN, nibrin; BLM (RECQL3), BLM RecQ like helicase; DNMT3B, DNA methyltransferase 3 β; ZBTB24, zinc finger and BTB domain containing 24; CDCA7, cell division cycle associated 7; HELLS, helicase, lymphoid specific; PMS2, PMS1 homolog 2, mismatch repair system component; RNF168, ring finger protein 168; MCM4, minichromosome maintenance complex component 4; POLE, DNA polymerase ε, catalytic subunit; POLE2, DNA polymerase ε 2, accessory subunit; LIG1, DNA ligase 1; NSMCE3, NSE3 homolog, SMC5-SMC6 complex component; ERCC6L2, ERCC excision repair 6 like 2; GINS1, GINS complex subunit 1; TBX1, T-box transcription factor 1; CHD7, chromodomain helicase DNA binding protein 7; SEMA3E, semaphorin 3E; FOXN1, forkhead box N1; RMRP, RNA component of mitochondrial RNA processing endoribonuclease; SMARCAL1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1; MYSM1, Myb like, SWIRM and MPN domains 1; RNU4ATAC, RNA, U4atac small nuclear (U12-dependent splicing); EXTL3, exostosin like glycosyltransferase 3; STAT3, signal transducer and activator of transcription 3; IL6R, interleukin 6 receptor; IL6ST, interleukin 6 signal transducer; ZNF341, zinc finger protein 341; ERBIN, erbb2 interacting protein; TGFBR1, transforming growth factor β receptor 1; TGFBR2, transforming growth factor β receptor 2; SPINK5, serine peptidase inhibitor Kazal type 5; PGM3, phosphoglucomutase 3; CARD11, caspase recruitment domain family member 11; DKC1, dyskerin pseudouridine synthase 1; NHP2, NHP2 ribonucleoprotein; NOP10, NOP10 ribonucleoprotein; RTEL1, regulator of telomere elongation helicase 1; TERC, telomerase RNA component; TERT, telomerase RNA component; TINF2, TERF1 interacting nuclear factor 2; TPP1, tripeptidyl peptidase 1; DCLRE1B/SNM1/APOLLO, DNA cross-link repair 1B; PARN, poly(A)-specific ribonuclease; WRAP53, WD repeat containing antisense to TP53; STN1, STN1 subunit of CST complex; CTC1, CST telomere replication complex component 1; SAMD9, sterile alpha motif domain containing 9; SAMD9L, sterile α motif domain containing 9 like; TCN2, transcobalamin 2; SLC46A1, solute carrier family 46 member 1; MTHFD1, methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1; KBKG (NEMO), inhibitor of nuclear factor κB kinase regulatory subunit γ; NFKBIA (IKBA), NFKB inhibitor α; IKBKB, inhibitor of nuclear factor κB kinase subunit β; ORAI1, ORAI calcium release-activated calcium modulator 1; STIM1, stromal interaction molecule 1; PNP, purine nucleoside phosphorylase; TTC7A, tetratricopeptide repeat domain 7A; SP110, SP110 nuclear body protein) BCL11B, BAF chromatin remodeling complex subunit BCL11B; TTC37, tetratricopeptide repeat domain 37; SKIV2L, Ski2 like RNA helicase; EPG5, ectopic P-granules autophagy protein 5 homolog; RBCK1(HOIL1), RANBP2-type and C3HC4-type zinc finger containing 1; RNF31, ring finger protein 31; CCBE1, collagen and calcium binding EGF domains 1; FAT4, FAT atypical cadherin 4; NFE2L2, nuclear factor, erythroid 2 like 2; STAT5B, signal transducer and activator of transcription 5B; KMT2D (MLL2), lysine methyltransferase 2D; KDM6A, lysine demethylase 6A; KMT2A, lysine methyltransferase 2A.

Some genes encode proteins that interact with chromatin, being implied in chromatin binding (DNMT3B, RNF168, POLE, STAT5B and KDM6A), chromatin DNA binding (STAT3, KDM6A) or chromatin regulation (CHD7, MYSM1, KMT2D and KDM6A) (23).

Other proteins interact with histones and allow histone binding (RNF168, MYSM1, WRAP53 and KMT2D), histone deacetylase binding (DNMT3B), histone demethylase activity [H3-K27 specific] (KDM6A) or histone methyltransferase activity [H3-K4 specific] (KMT2D and KMT2A) (23).

A major category is represented by genes that encode proteins implied in interaction with DNA: DNA binding (ZNF341, ATM, BLM, NFE2L2, DNMT3B, PMS2, POLE, POLE2, LIG1, ERCC6L2, TBX1, CHD7, FOXN1, MYSM1, STAT3, RTEL1, TERT, SP110 and KMT2D), DNA replication origin binding (MCM4), single-stranded DNA binding (BLM, MCM4, STN1 and CTC1), or damaged DNA binding (NBN, DCLRE1B/SNM1/APOLLO) (23).

Other genes encode transcription factors implied in RNA polymerase II activity (TBX1, FOXN1, STAT3, STAT5B, NFE2L2, KMT2A and BCL11B), DNA-binding transcription factor activity [ZBTB24, FOXN1, MYSM1, STAT3, SP110, STAT5B, KMT2D (MLL2), TBX1, ZNF341 and NFE2L2, BCL11B] or transcription factor binding (NBN, TBX1, STAT3 and NFKBIA) (23).

The functions of telomeres are regulated by other genes that influence telomeric DNA binding (TERT, TINF2, STN1 and CTC1), telomerase RNA binding (DKC1, NHP2, NOP10, TERT, PARN and WRAP53) or telomerase activity (TERT and DKC1) (23).

In addition, in immunodeficiencies different enzymatic activity may be disturbed: GTPase regulator activity (WAS), small GTPase binding (WAS), phospholipase binding (WAS), protein kinase binding (WAS, ERCC6L2, STAT3, PARN and IKBKB), DNA-dependent protein kinase activity (ATM), helicase (BLM, HELLS, MCM4, ERCC6L2, CHD7, SMARCAL1, RTEL1, SKIV2L), hydrolase (HELLS, PMS2, MCM4, POLE, ERCC6L2, CHD7, SMARCAL1, MYSM1, RTEL1, TPP1, DCLRE1B/SNM1/APOLLO, PARN and MTHFD1), nuclease (PMS2, POLE, DCLRE1B/SNM1/APOLLO and PARN), metalloprotease (MYSM1), phosphoglucomutase activity (PGM3), DNA polymerase binding (RTEL1) (23).

Another process that is perturbed in immunodeficiencies is ion binding and the main genes implied are TGFBR1, TGFBR2, ZNF341, DNMT3B, ZBTB24, RNF168, LIG1, MYSM1, EXTL3, RTEL1, TERT, TPP1, PARN, TCN2, IKBKG (NEMO), SP110, HOIL1 (RBCK1), RNF31, KMT2D (MLL2), KMT2D (MLL2), KDM6A, BCL11B, STIM1, FAT4 and CCBE1 (23).

The connection with RNA could be abnormal in immunodeficiencies because of an abnormal ribonucleoprotein (DKC1, NHP2, NOP10, TERT), RNA binding (DKC1, NHP2, NOP10 and WRAP53) or box H/ACA snoRNA binding (DKC1, NHP2 and NOP10) (23).

Other processes are disturbed because of gene mutations implied in protein binding (WAS, ATM, BLM, STAT3, TERT, IKBKB, WRAP53, IKBKG (NEMO), NFKBIA, ORAI1, STIM1, PNP, HOIL1, KDM6A,KMT2A and IL6ST), Rac GTPase (WAS), SH3 domain binding (WAS, WIPF1), profilin binding (WIPF1), ATP binding [IKBKB, TGFBR1, TGFBR2, ATM, BLM (RECQL3), HELLS, PMS2, MCM4, LIG1, ERCC6L2,SKIV2L, CHD7, SMARCAL1, RTEL1 and MTHFD1], chaperone binding (TERT and WRAP53), actin (actin filament) binding (WAS, WIPF1 and ARPC1B) (23).

Other genes, such as RMRP, RNU4ATAC or TERC, encode noncoding RNA (part of RNase MRP), small nuclear RNA and telomerase RNA component (Table I). Mutations in these genes cause alterations in processing of ribosomal RNA. RMRP gene mutations disturb mitochondrial DNA replication and cell cycle control. RNU4ATAC gene mutations produce defects of spliceosome complex. Mutations in the TERC gene are implied in dysfunctions of telomere length (19,22,24-26).

Genes including HELLS, TBX1, SEMA3E, FOXN1, CCBE1 or KDM6A encode proteins involved in development of one or more organs. The most illustrative example is the TBX1 gene that is involved in multiple biological processes: Angiogenesis, morphogenesis of cranial region, heart, parathyroid gland, pharyngeal system, soft palate, thymus or thyroid gland (23). Thus, deficiency in the TBX1 gene, characteristic to velo-cardio-facial syndrome, explains the association of abnormalities in multiple systems. The TBX1 gene allows thymus epithelium morphogenesis, lymphoid lineage cell migration into the thymus, regulation of positive thymic T cell selection and T cell homeostasis. Other developmental proteins are also involved in the genesis of various organs/components of the immune system. For example, the FOXN1 gene allows thymus epithelium morphogenesis, lymphoid lineage cell migration into the thymus, regulation of positive thymic T cell selection, T cell homeostasis and T cell lineage commitment (Table I) (19,22,24-26).

The pathogenic complexity of combined immunodeficiencies associated with syndromic features could be explained by the multiple interactions between the mentioned genes and important cell processes, such as the cell cycle, DNA damage, DNA repair process, DNA replication, apoptosis, transcription, cell division, multicellular organism development, ribosome biogenesis and processing, immune response, autophagy and cell adhesion. The pathophysiological mechanisms mainly involved are: Missing enzymes, absent or non-functional proteins, abnormal DNA repair, altered signal transduction, developmental arrest in immune differentiation, impairment of cell-to-cell and intracellular communications (Table I) (19,22,24-26).

3. Mutational heterogeneity

The majority of combined immunodeficiencies with syndromic features are monogenic diseases caused by mutations in a pair of nuclear genes and only few diseases are caused by chromosomal microdeletions.

Most mutations are loss-of-function (LOF) mutations with a recessive pattern of transmission. Other mutations produce a gain of function (GOF). GOF mutations are almost always dominant (27). In some situations, for the same gene, distinct missense mutations may cause either LOF or GOF. An example of this is the STAT3 gene (28). STAT3 LOF mutation causes Job syndrome while STAT3 GOF mutation causes a form of immunodeficiency characterized by an immune deregulation. Thus, in such situations it is absolutely necessary to perform genetic testing to detect the mutation and its effect on the protein (29). All of these can influence also the treatment strategy. In STAT3 GOF the efficient treatment includes monoclonal antibody (mAb) against IL-6R and HSCRT, while in STAT3 LOF the most efficient treatment is the long term use of antibiotics and humanized recombinant monoclonal against IgE (30-32).

4. Clinical heterogeneity and mode of inheritance

Clinical heterogeneity is even greater as in the case of combined immunodeficiencies with syndromic features when it presents an interindividual and interfamilial variable expressivity, in correlation with the type of mutation. In such cases, identification of a specific association of abnormalities allows an early diagnosis, sometimes even before the onset of immune manifestations (33). In the majority of cases, immunodeficiency clinical signs are not specific such as infections, skin inflammation, hematologic autoimmune/autoinflammatory disorders, and different types of malignancy. Thus discovery of a particular non-immune feature becomes very helpful for a precocious diagnosis (33-35).

Usually, the onset of disease occurs in childhood, but retarded manifestations could be found in the case of a hypomorphic mutations or a random X-chromosome inactivation in women heterozygote for a X-linked recessive mutation (33,36,37).

Infections observed in various primary immunodeficiency diseases can be bacterial, viral or fungal. Each infection has certain particularities. For example non-tuberculosis mycobacteria infections are found in IKBKG, IKBKB, GOF NFKBIA/IKBA deficiency; pyogenic pneumonia with pneumatocele formation and empyema/abscess and visceral abscess with S. aureus in childhood are specific for STAT3 deficiency; recurrent pyogenic sepsis is found in NEMO deficiency (33).

Viral infections with EBV (Epstein-Barr virus) and HHV8 (human herpes virus 8) - Kaposi sarcoma in young subjects are associated with STIM1 deficiency, AT (ATM), WAS (WASP), CHH (RMRP). Infection with HPV (human papilloma virus) with severe/recalcitrant warts, flat or verruca (often on trunk, face, neck, extremities, genital regions) are found in Netherton syndrome (SPINK5), WAS (WASP), NEMO deficiency (IKBKG), AT (ATM). Widespread molluscum contagiosum is associated with WAS, NEMO deficiency (IKBKG). Pneumonia with Pneumocystis jirovecii is present in WAS (WASP), NEMO deficiency (IKBKG), VODI (SP110), CARD11. Chronic mucocutaneous infection with Candida spp. is found in IKBG, IKBA, IKBB, NEMO deficiency, VODI (SP110) and infection with Aspergillus spp. is specific for STAT3 deficiency (33).

In combined immunodeficiencies, various inflammatory skin conditions are found: Generalized exfoliative erythroderma of infancy in Comèl-Netherton syndrome (SPINK5); diffuse early-onset eczema and erythroderma and muscle amylopectinosis in HOIL-1 deficiency; severe early-onset atopic eczema in WAS, Comèl-Netherton syndrome, PGM3, STAT5b deficiencies, STAT3 deficiency; congenital livedo in FILS syndrome (POLE) (33).

Autoimmune/autoinflammatory disorders associated with primary immunodeficiencies include organ-specific autoimmunity (in 22q deletion syndrome, WASP, ATM, STAT5B mutations). Global hematologic autoimmunity changes have been observed in 22q deletion syndrome, PNP, STIM1, ORAI1, WASP, ATM and STAT5B mutations while hematologic autoimmunity with non-virally induced lymphoproliferation have been associated with STIM1 deficiency, 22q11 deletion, 10p deletion. Other changes have been associated with sterile arthritis (WASP or STAT5B mutations); early-onset inflammatory bowel disease (WASP and IKBKG mutations); trichohepatoenteric syndrome-SKIV2L and TTC37 mutations, Veno-occlusive disease with immunodeficiency (VODI) SP110 mutations; early-onset diarrhea and malabsorption from ICF-Immunodeficiency-centromeric instability-facial anomalies syndrome determined by mutations in DNMTB3, ZBTB24, CDCA7 and HELLS genes) (33,38).

An increased risk of certain malignancies has been found in certain immunodeficiency syndromes. Various DNA repair deficiencies (ATM, NBN, LIG1) are associated with mainly lymphomas. MCM4 deficiency predisposes to EBV-associated lymphomas; Wiskott-Aldrich syndrome with myelodysplasia, leukemias and lymphomas. HHV8 is associated with primary Kaposi sarcoma (TNFRSF4, IFNGR1, WAS and STIM1); CHH (RMRP) with an increased risk of basal cell carcinoma and of EBV-associated lymphoproliferation (25,33,39-45).

In combined immunodeficiencies with syndromic features all type of monogenic transmission have been identified. Pedigree analysis is an easy-to-use tool available to any practitioner to establish this fact. However, some genetic phenomena, such as low frequency of the disease (some of the immunodeficiencies are extremely rare diseases), incomplete penetrance of the disease, variable expressivity and de novo mutations, can complicate the process of identification of the type of transmission. A special situation is the allelic heterogeneity encountered for example in the case of Kabuki syndrome (KS): KMT2D-related KS is inherited in an autosomal dominant manner while KDM6A-related KS is inherited in an X-linked manner (45). There is also the variant in which mutations in a gene determine a condition that can be transmitted differently; STAT5b deficiency can be transmitted in an autosomal recessive or in an autosomal dominant model (33).

5. Conclusion

In conclusion, recognizing heterogeneity and its sources is extremely important for current medical practice, but also for the theoretical value of improving biological and biomedical applications.

Acknowledgements

Not applicable.

Funding

Not applicable.

Availability of data and materials

All data and materials supporting the results of the present study are available in the published article and supported by relevant references.

Authors' contributions

All three authors contributed equally to preparing the review and the data search and collection. LC carried out the writing of the original draft preparation and CG carried out the writing, review and editing of the manuscript. EVG conducted the validation and supervision of the literature review and writing. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Abraham RS and Aubert G: Flow cytometry, a versatile tool for diagnosis and monitoring of primary immunodeficiencies. Clin Vaccine Immunol. 23:254–271. 2016.PubMed/NCBI View Article : Google Scholar

2 

Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, et al: Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 136:1186–205.e1-78. 2015.PubMed/NCBI View Article : Google Scholar

3 

Fischer A, Provot J, Jais JP, Alcais A and Mahlaoui N: members of the CEREDIH French PID study group: Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 140:1388–1393.e8. 2017.PubMed/NCBI View Article : Google Scholar

4 

Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, et al: International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 38:96–128. 2018.PubMed/NCBI View Article : Google Scholar

5 

Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, et al: Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 40:66–81. 2020.PubMed/NCBI View Article : Google Scholar

6 

Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, et al: Human inborn errors of immunity: 2019 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. 40:24–64. 2020.PubMed/NCBI View Article : Google Scholar

7 

Condino-Neto A and Espinosa-Rosales FJ: Changing the lives of people with primary immunodeficiencies (PI) with early testing and diagnosis. Front Immunol. 9(1439)2018.PubMed/NCBI View Article : Google Scholar

8 

Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, Erichsen HC, Forbes LR, Gu S, Yuan B, et al: Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 139:232–245. 2017.PubMed/NCBI View Article : Google Scholar

9 

Primary Immunodeficiencies (PID) Driving Diagnosis for Optimal Care in Europe. European Reference Paper urihttp://worldpiweek.org/sites/default/files/basic_page_documents/PI_European_Reference_Paper.pdfsimplehttp://worldpiweek.org/sites/default/files/basic_page_documents/PI_European_Reference_Paper.pdf.(accessed on May 1, 2020).

10 

Immune Deficiency Foundation: Primary Immune Deficiency Diseases in America: 2007. The Third National Survey of Patients. Prepared by: Abt SRBI, Inc. May 1, 2009. urihttps://primaryimmune.org/wp-content/uploads/2011/04/Primary-Immunodeficiency-Diseases-in-America-2007The-Third-National-Survey-of-Patients.pdfsimplehttps://primaryimmune.org/wp-content/uploads/2011/04/Primary-Immunodeficiency-Diseases-in-America-2007The-Third-National-Survey-of-Patients.pdf.(accessed on 26 April 2020).

11 

Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L and Drabwell J: Editorial Board for Working Party on Principles of Care at IPOPI: Primary immune deficiencies-principles of care. Front Immunol. 5(627)2014.PubMed/NCBI View Article : Google Scholar

12 

Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, Jais JP, Fischer A, Hermine O and Stoppa-Lyonnet D: Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: A report from the French national registry of primary immune deficiencies. J Clin Oncol. 33:202–208. 2015.PubMed/NCBI View Article : Google Scholar

13 

Shapiro RS: Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists. Am J Hematol. 86:48–55. 2011.PubMed/NCBI View Article : Google Scholar

14 

Grimbacher B, Warnatz K, Yong PFK, Korganow AS and Peter HH: The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol. 137:3–17. 2016.PubMed/NCBI View Article : Google Scholar

15 

de Jesus AA, Canna SW, Liu Y and Goldbach-Mansky R: Molecular mechanisms in genetically defined autoinflammatory diseases: Disorders of amplified danger signaling. Annu Rev Immunol. 33:823–874. 2015.PubMed/NCBI View Article : Google Scholar

16 

Jonkman-Berk BM, van den Berg JM, Ten Berge IJ, Bredius RG, Driessen GJ, Dalm VA, van Dissel JT, van Deuren M, Ellerbroek PM, van der Flier M, et al: Primary immunodeficiencies in the Netherlands: National patient data demonstrate the increased risk of malignancy. Clin Immunol. 156:154–162. 2015.PubMed/NCBI View Article : Google Scholar

17 

Comrie WA and Lenardo MJ: Molecular classification of primary immunodeficiencies of T lymphocytes. Adv Immunol. 138:99–193. 2018.PubMed/NCBI View Article : Google Scholar

18 

Gug C, Gorduza EV, Lăcătuşu A, Vaida MA, Bîrsăşteanu F, Puiu M and Stoicănescu D: CHARGE syndrome associated with de novo (I1460Rfs*15) frameshift mutation of CHD7 gene in a patient with arteria lusoria and horseshoe kidney. Exp Ther Med. 20:479–485. 2020.PubMed/NCBI View Article : Google Scholar

19 

Mäkitie O and Vakkilainen S: Cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders. In: GeneReviews® [Internet]. Adam MP, Ardinger HH, Pagon RA, et al (eds). University of Washington, Seattle, WA, 1993-2020. 2012 Mar 15 [Updated 2020 Aug 6]. urihttps://www.ncbi.nlm.nih.gov/books/NBK84550/simplehttps://www.ncbi.nlm.nih.gov/books/NBK84550/ (accessed on 17 April 2020).

20 

Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, Meinecke P, de la Chapelle A and Westman JA: Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet. 82:140–146. 2012.PubMed/NCBI View Article : Google Scholar

21 

HGNC Database: HUGO Gene Nomenclature Committee (HGNC), European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom. Available online: urihttps://www.genenames.org/simplehttps://www.genenames.org/(accessed on April 2020).

22 

Savage SA: Dyskeratosis Congenita. In: GeneReviews® [Internet]. Adam MP, Ardinger HH, Pagon RA, et al (eds). University of Washington, Seattle, WA, 1993-2020. 2009 Nov 12 [Updated 2019 Nov 21]. Available from: urihttps://www.ncbi.nlm.nih.gov/books/NBK22301/simplehttps://www.ncbi.nlm.nih.gov/books/NBK22301/ Accessed April 17, 2020.

23 

The UniProt Consortium: UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res 47: D506-D515, 2019.

24 

Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, et al: Primary immunodeficiency diseases: An update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 5(162)2014.PubMed/NCBI View Article : Google Scholar

25 

Mäkitie O, Pukkala E, Teppo L and Kaitila I: Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr. 134:315–318. 1999.PubMed/NCBI View Article : Google Scholar

26 

Abdel-Salam GM, Abdel-Hamid MS, Issa M, Magdy A, El-Kotoury A and Amr K: Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet A. 158A:1455–1461. 2012.PubMed/NCBI View Article : Google Scholar

27 

Jung S, Lee S, Kim S and Nam H: Identification of genomic features in the classification of loss- and gain-of-function mutation. BMC Med Inform Decis Mak. 15 (Suppl 1)(S6)2015.PubMed/NCBI View Article : Google Scholar

28 

Notarangelo LD and Fleisher TA: Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders. J Allergy Clin Immunol. 139:715–723. 2017.PubMed/NCBI View Article : Google Scholar

29 

Weinreich MA, Vogel TP, Rao VK and Milner JD: Up, down, and all around: Diagnosis and treatment of novel STAT3 variant. Front Pediatr. 5(49)2017.PubMed/NCBI View Article : Google Scholar

30 

Alonso-Bello CD, Jiménez-Martínez MD, Vargas-Camaño ME, Hierro-Orozco S, Ynga-Durand MA, Berrón-Ruiz L, Alcántara-Montiel JC, Santos-Argumedo L, Herrera-Sánchez DA, Lozano-Patiño F and Castrejón-Vázquez MI: Partial and transient clinical response to omalizumab in IL-21-induced low STAT3-phosphorylation on Hyper-IgE syndrome. Case Reports Immunol. 2019(6357256)2019.PubMed/NCBI View Article : Google Scholar

31 

Hafsi W and Yarrarapu SNS: Job Syndrome (Hyperimmunoglobulin E). [Updated 2020 Jul 17] In: StatPearls. [Internet] StatPearls Publishing, Treasure Island, FL, 2020 Jan. Available from urihttps://www.ncbi.nlm.nih.gov/books/NBK525947/simplehttps://www.ncbi.nlm.nih.gov/books/NBK525947/ Accessed April 25, 2020.

32 

Jhamnani RD and Rosenzweig SD: An update on gain-of-function mutations in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 17:391–397. 2017.PubMed/NCBI View Article : Google Scholar

33 

Rezaei N, Bonilla FA, Sullivan KF, De Vries E, Bousfiha AA, Puck J and Orange J: An introduction to primary immunodeficiency diseases. In: Rezaei N, Aghamohammadi A, Luigi ND. (eds.). Primary Immunodeficiency Diseases. Springer, Berlin, Heidelberg, pp1-81, 2017.

34 

Arkwright PD and Gennery AR: Ten warning signs of primary immunodeficiency: A new paradigm is needed for the 21st century. Ann N Y Acad Sci. 1238:7–14. 2011.PubMed/NCBI View Article : Google Scholar

35 

Subbarayan A, Colarusso G, Hughes SM, Gennery AR, Slatter M, Cant AJ and Arkwright PD: Clinical features that identify children with primary immunodeficiency diseases. Pediatrics. 127:810–816. 2011.PubMed/NCBI View Article : Google Scholar

36 

Collin M, Bigley V, Haniffa M and Hambleton S: Human dendritic cell deficiency: The missing ID? Nat Rev Immunol. 11:575–583. 2011.PubMed/NCBI View Article : Google Scholar

37 

Nelson KS and Lewis DB: Adult-onset presentations of genetic immunodeficiencies: Genes can throw slow curves. Curr Opin Infect Dis. 23:359–364. 2010.PubMed/NCBI View Article : Google Scholar

38 

Gug C, Huțanu D, Vaida M, Doroş G, Popa C, Stroescu R, Furău G, Furău C, Grigoriță L and Mozos I: De novo unbalanced translocation t(15;22)(q26.2;q12) with velo-cardio-facial syndrome: A case report and review of the literature. Exp Ther Med. 16:3589–3595. 2018.PubMed/NCBI View Article : Google Scholar

39 

de Miranda NF, Björkman A and Pan-Hammarström Q: DNA repair: The link between primary immunodeficiency and cancer. Ann N Y Acad Sci. 1246:50–63. 2011.PubMed/NCBI View Article : Google Scholar

40 

Leechawengwongs E and Shearer WT: Lymphoma complicating primary immunodeficiency syndromes. Curr Opin Hematol. 19:305–312. 2012.PubMed/NCBI View Article : Google Scholar

41 

Casey JP, Nobbs M, McGettigan P, Lynch S and Ennis S: Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet. 49:242–245. 2012.PubMed/NCBI View Article : Google Scholar

42 

Karalis A, Tischkowitz M and Millington GW: Dermatological manifestations of inherited cancer syndromes in children. Br J Dermatol. 164:245–256. 2011.PubMed/NCBI View Article : Google Scholar

43 

Byun M, Ma CS, Akçay A, Pedergnana V, Palendira U, Myoung J, Avery DT, Liu Y, Abhyankar A, Lorenzo L, et al: Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J Exp Med. 210:1743–1759. 2013.PubMed/NCBI View Article : Google Scholar

44 

Leroy S, Moshous D, Cassar O, Reguerre Y, Byun M, Pedergnana V, Canioni D, Gessain A, Oksenhendler E, Fieschi C, et al: Multicentric Castleman disease in an HHV8-infected child born to consanguineous parents with systematic review. Pediatrics. 129:e199–e203. 2012.PubMed/NCBI View Article : Google Scholar

45 

Adam MP, Hudgins L and Hannibal M: Kabuki Syndrome. In: GeneReviews®. [Internet]. Adam MP, Ardinger HH, Pagon RA, et al (eds). GeneReviews, University of Washington, Seattle, Seattle, WA, pp1993-2020. 2011 Sep 1. [Updated 2019 Oct 21]. Available from urihttps://www.ncbi.nlm.nih.gov/sites/books/NBK62111/simplehttps://www.ncbi.nlm.nih.gov/sites/books/NBK62111/. Accessed April 26, 2020.

Related Articles

Journal Cover

January-2021
Volume 21 Issue 1

Print ISSN: 1792-0981
Online ISSN:1792-1015

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Caba L, Gug C and Gorduza EV: Heterogeneity in combined immunodeficiencies with associated or syndromic features (Review). Exp Ther Med 21: 84, 2021
APA
Caba, L., Gug, C., & Gorduza, E.V. (2021). Heterogeneity in combined immunodeficiencies with associated or syndromic features (Review). Experimental and Therapeutic Medicine, 21, 84. https://doi.org/10.3892/etm.2020.9517
MLA
Caba, L., Gug, C., Gorduza, E. V."Heterogeneity in combined immunodeficiencies with associated or syndromic features (Review)". Experimental and Therapeutic Medicine 21.1 (2021): 84.
Chicago
Caba, L., Gug, C., Gorduza, E. V."Heterogeneity in combined immunodeficiencies with associated or syndromic features (Review)". Experimental and Therapeutic Medicine 21, no. 1 (2021): 84. https://doi.org/10.3892/etm.2020.9517