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Hindawi Case Reports in Immunology Volume 2020, Article ID 8846827, 5 pages https://doi.org/10.1155/2020/8846827 Case Report Interleukin-1 Receptor-Associated Kinase 4 Deficiency in a Greek Teenager Panagiota Karananou, Anastasia Alataki, and Eﬁmia Papadopoulou-Alataki 4th Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of essaloniki, Papageorgiou General Hospital, essaloniki, Greece Correspondence should be addressed to Eﬁmia Papadopoulou-Alataki; eﬁala@otenet.gr Received 25 May 2020; Revised 15 September 2020; Accepted 24 September 2020; Published 8 October 2020 Academic Editor: Rajni Rani Copyright©2020PanagiotaKarananouetal.*isisanopenaccessarticledistributedundertheCreativeCommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Human interleukin- (IL-) 1 receptor-associated kinase 4 (IRAK-4) deﬁciency is a recently described primary immunodeﬁciency. It is a rare, autosomal recessive immunodeﬁciency that impairs toll/IL-1R immunity, except for the toll-like receptor (TLR) 3- and TLR4-interferon alpha (IFNA)/beta (IFNB) pathways. Case Report. We report the ﬁrst patient in Greece withIRAK-4deﬁciency.Fromtheageof8months,shepresentedwithrecurrentinfectionsoftheupperandlowerrespiratorytract and skin abscesses. For this, she had been repeatedly hospitalized and treated empirically with intravenous antibiotics. No severe viral, mycobacterial, or fungal infections were noted. Her immunological laboratory evaluation revealed low serum IgA and restored in subsequent measurements; normal IgG, IgM, and IgE; and normal serum IgG subclasses. Peripheral blood immunophenotyping by ﬂow cytometry and dihydrorhodamine (DHR) test revealed normal counts. She was able to make functional antibodies against vaccine antigens, including tetanus and diphtheria. She was administered with empirical IgG substitution for 5 years until the age of 12 years, and she has never experienced invasive bacterial infections so far. DNA analysis revealed a heterozygous variant in the patient: c.823delT (p.S275fs 13 at protein level) in the IRAK4 gene. Conclusions. *e importance of clinical suspicion is emphasized in order to conﬁrm the diagnosis by IRAK4 gene sequencing and provide the appropriate treatment for this rare primary immunodeﬁciency, as soon as possible. Union of Immunological Societies Committee in the major 1. Introduction PIDgroup:defectsinintrinsicandinnateimmunityasaTIR Human interleukin- (IL-) 1 receptor-associated kinase 4 signaling pathway deﬁciency with bacterial infections . (IRAK-4) deﬁciency is a recently described primary im- Until now, more than 50 patients were studied and reported munodeﬁciency (PID) . It is a rare, autosomal recessive to suﬀer from IRAK-4 deﬁciency worldwide . immunedeﬁciencythatimpairstoll/IL-1Rimmunity,except forthetoll-likereceptor(TLR)3-andTLR4-interferonalpha 2. Clinical Case (IFNA)/beta (IFNB) pathways . Toll-like receptors and interleukin-1 receptors are essential for the recognition of We report the case of a 17-year-old female patient, the only microbes and signaling pathway through MyD88 (myeloid child of healthy unrelated parents with no family history of diﬀerentiation molecule) that recruits IRAK-4. IRAK-4 recurrent or severe infections, autoimmune disease, or deﬁciency highly predisposes to bacterial infections . lymphoma. She had an uncomplicated perinatal history, Picardetal.,in2003,wastheﬁrsttodescribeacaseseries withanormalintervalforumbilicalcordseparation(7days). of3unrelatedchildrenwithrecurrentinfectionscausedonly *e girl was fully immunized, including the conjugated by extracellular pyogenic bacteria and poor inﬂammatory pneumococcal vaccine, as well as measles, mumps, rubella, response . IRAK-4 deﬁciency (OMIM gene606883 and and varicella, and BCG live vaccinations with no adverse OMIM phenotype 607676) is described by the International eﬀects. 2 Case Reports in Immunology Attheageof8months,shepresentedtothehospitalwith variant of the IRAK4 gene in this patient and has been bronchiolitis. Since then, she suﬀered from recurrent re- previously reported . spiratory tract infections (sinusitis, mastoiditis, otitis, and pharyngitis) every 1–6 months until the age of 3 years. 4. Discussion *ereafter,shealsodevelopedskinabscesses(Staphylococcus aureus was detected) treated by appropriate antibiotic IRAK-4 protein is the fourth member of the IRAK family therapy within the hospital. From 3 years until 5 years, she (IRAK-1, IRAK-2, and IRAK-3/M) that, together with had been hospitalized twice per year and treated empirically MyD88(akeycytosolicadaptermolecule),isfoundtoplaya with intravenous antibiotics (ampicillin and/or cephalo- pivotal role in the signaling pathway that is involved in the sporins). At the age of 5 years, she underwent adenoidec- early recognition of pathogens and the initiation of the tomy and tonsillectomy and received antibiotic prophylaxis cascade of the inﬂammatory response . for 6 months without recession of the infections (Table 1). *e TIR superfamily (TLRs/IL-1Rs) depends on MyD88 No severe viral, mycobacterial, or fungal infections were and IRAK-4 signaling for its regulation of gene transcription. noted. She was also diagnosed with intellectual disability After MyD88 is activated, it provides a bridge using its TIR within autism spectrum. domain from TLRs and interleukin-1 receptors (IL-1Rs) to Her immunological laboratory evaluation performed at the IRAK complex. MyD88 forms an oligomer and then 6yearsofagerevealedlowserumIgA,thathasbeenrestored recruits IRAK-4 to the receptor, triggering the activation of in subsequent measurements; normal IgG, IgM, and IgE; the IκB kinase (IKK) complex. *e activation of the IKK and normal serum IgG subclasses (except from IgG4, also complex promotes the phosphorylation and degradation of restored in subsequent measurements). Peripheral blood IκBαandthetranslocationofNF-κBtothenucleusleadingto immunophenotyping by ﬂow cytometry revealed normal the production of inﬂammatory cytokines [9, 10] (Figure 2). counts. *e circulating monocyte counts and neutrophil Human IRAK4 gene maps to chromosome 12q12, counts are normal. *e dihydrorhodamine (DHR) test for contains 13 exons, and provides instructions for making a theestimationofthephagocyticfunctionwasnormalforher proteinthatplaysanimportantroleinstimulatingtheinnate age (Table 2). She was able to make functional antibodies immune response against infections. IRAK-4 deﬁciency is against vaccine antigens, including tetanus and diphtheria. caused by mutations in the IRAK4 gene that lead to the At the age of 7 years, she started being treated with production of a nonfunctional protein . prophylactic subcutaneous immunoglobulin therapy. *e Clinically, aﬀected IRAK-4-deﬁcient patients suﬀer from treatment lasted 5 years resulting in signiﬁcant reduction of recurrent infections caused by pyogenic bacteria, mainly infections (Table 1). *e patient was studied by genetic Gram-positive, and tend to develop weak or delayedsystemic analysis (sequencing of genomic DNA). *e parents could signs of inﬂammation (e.g., fever) and minimal change in notbeinvestigated.Sincetheageof12years,sheisnolonger inﬂammatory markers (e.g., C-reactive protein) . Most of suﬀering from infections, she is free of treatment, but she these patients develop their ﬁrst invasive infection before the still presents with learning diﬃculties and behavioral ageof2yearsandpresentwithperipheral(e.g.,skininfection, problems. cellulitis,furuncles,andotitismedia)and/orinvasivebacterial diseases (e.g., meningitis, arthritis, septicemia, and visceral abscess) . Τhe most common Gram-positive bacteria 3. Genetic Analyses associated with IRAK-4 deﬁciency are Streptococcus pneu- Whole exome sequencing (WES) was performed. DNA- moniaeand Staphylococcus aureusfollowedbyGram-negative bacteria, such as Pseudomonas aeruginosa, Neisseria, and analysis was done using Otogenetics Corporation (USA), and identiﬁcation of pathogenic and disease-causing vari- Shigella in a less frequent rate . None of the patients ants was conducted using the Ingenuity Variant Analysis reported had severe viral, parasitic, or fungal disease. It is software (Qiagen). Sequencing of IRAK4 showed that a remarkable that all life-threatening infections occur during changeinasinglenucleotidebase occurredinﬁvetranscript early infancy and that there is an overall trend towards im- variantsofthegene.Inparticular,twoofthemRNAvariants provement of their severity and frequency after the teenage had a heterozygous deletion of thymidine 823 of IRAK4 years. Prophylactic antibiotic treatment and vaccinations against pyogenic bacteria, as well as immunoglobulin re- (c.823delT), and three variants had a heterozygous deletion of thymidine 451 of IRAK4 (c.451delT) (Table 3). *e ﬁrst placement starting early in life until teenage, are suggested as supportive treatment . two transcript variants encode isoform A of the IRAK-4 protein, whilst the other three encode isoform B (based on Our patient is the ﬁrst patient in Greece who has been NCBI). identiﬁedwithIRAK-4 deﬁciency,andwereportthiscaseto Isoform A (IRAK4-long) induces the activation of NF- point out the diagnosischallenge that can raise. *eonset of κB through MyD88 binding, and it is associated with dis- her infections was before the age of 2 years as previously eases, such as primary immunodeﬁciency diseases and reported [1, 10, 12]. She presented with recurrent nonin- cancer [7, 8]. In contrast, isoform B (IRAK4-short) is less vasive pyogenic bacterial infections of the respiratory tract eﬃcient at activating NF-κB and the innate immune and skin which were successfully and promptly treated with pathwayandispreferentiallyexpressedinnormaltissues intravenous or oral antibiotics, that comes in accordance with the existing literature . Her immunological inves- (Figure 1). As such, c.823delT (p.S275fs 13 at protein level) is considered a heterozygous mutated disease-causing tigations were normal, and she produced adequate Case Reports in Immunology 3 Table 1: Summary of the patient’s infections and therapy. Age Infection Treatment 8 months old Bronchiolitis Intravenous ampicillin-nebulized salbutamol-O 9 months old Laryngitis Nebulised adrenaline 12 months old Bronchiolitis Nebulised salbutamol-ipratropium bromide 14 months old Acute otitis media Intravenous ampicillin-sulbactam 17 months old Bronchiolitis Nebulised salbutamol-ﬂuticasone 19 months old Pharyngitis Oral amoxycillin 21 months old Acute otitis media Intravenous cephalosporin 2 years old Pharyngitis Oral cephalosporin 2.5 years old Sinusitis-mastoiditis Intravenous cephalosporin 3 years old Skin abscesses-MSSA Intravenous oxacillin 3.5 years old Sinusitis Intravenous cephalosporin 4 years old Tonsilitis Intravenous cephalosporin 4.5 years old Skin abscess-MRSA Intravenous vancomycin 5 years old Adenoidectomy-tonsillectomy 6 years old Acute otitis media Intravenous ampicillin-sulbactam 7 years old Subcutaneous immunoglobulin treatment Table 2: Summary of the patient’s immunological proﬁle. Parameter Normal range Baseline 17 years old Blood hemoglobin (g/dL) 12–15.4 13 13.5 Blood platelets (G/L) 150–400 219 357 Blood leukocytes (mm ) 3900–11.000 10.400 10.200 Blood neutrophils (%) 40–75 68.6 59.8 Blood lymphocytes (%) 19–48 23.7 30.2 Monocytes (%) 3.4–9 5.3 6.97 Eosinophils (%) 0–7 1.9 2.12 Basophils (%) 0–1.5 0 0.8 IgA (mg/dl) 26.50 (NR: 60–220) 72.40 (NR: 70–400) IgG (mg/dl) 717 (NR: 600–1300) 784 (NR: 700–1600) IgM, (mg/dl) 50.80 (NR: 40–160) 61.60 (NR: 40–230) IgE (IU/ml) 61.30 (NR: <52) 54.20 (NR: <378) IgG1 (mg/dl) 633 (NR: 561–1100) 556 (NR: 405–1011) IgG2 (mg/dl) 89.80 (NR: 86–355) 164 (NR: 169–426) IgG3 (mg/dl) 53 (NR: 31–100) 27 (NR: 11–85) IgG4 (mg/dl) 15.60 (NR: 20–117) 42.30 (NR: 3–201) CD2 T cells (%) 75.9–84.9 75.3 75.9 CD3 T cells (%) 55–78 69 71.1 + + CD3 /CD4 (%) 27–53 52 49.1 + + CD3 /CD8 (%) 19–34 12.5 15.9 − + + CD3 /CD16 CD56 NK (%) 4–26 18.9 4.6 CD19 B cells (%) 10–31 10.2 20.1 CD23 (%) N/D 13.4 + + CD4 /CD8 ratio 0.9–2.6 4.2 3.08 CD3 /cδ 18.5 N/D CD3 /αβ 76.1 N/D DHR (%) 97.3 97.5 1,2,3 Baseline,ﬁrstinvestigationofthepatient.NR,normalranges,DHR ,Dihydrorhodaminetest.*eIgAandIgG4valuesareinboldtosuggestthattheyare 1,2,3 below the normal range. Table 3: Whole exome sequencing analysis. Genomic Protein Variant RS Gene c-DNA nucleotide change Disease Inheritance Status location change classiﬁcation number NM_001114182.2: c.823delT, NM_016123.3: c.823delT, IRAK4 IRAK4 NM_001145256.1: p.S275fs 13, Autosomal chr12: g Pathogenic deﬁciency (OMIM c451delT, p.S151fs 13 — recessive Heterozygous 44171539 (ingenuity) (OMIM 606883) NM_001145257.1: (ingenuity) (AR) 607676) c451delT, NM_001145258.1: c.451delT (ingenuity) 4 Case Reports in Immunology p.S275fs 13 IRAK4-long: 1 DD Kinase domain 460 IRAK4-short: Kinase domain 1 336 p.S151fs 13 Figure 1: Schematic representation of two protein isoforms of IRAK-4 with the reported protein changes. *e IRAK-4 protein contains an N-terminaldeathdomain(DD),ahingedomain(labelledinwhite),andthekinasedomain.*efull-lengthDNAoftheIRAK4geneencodes the IRAK4-long protein consisting of 460 amino acids, while the alternative spliced gene encodes the IRAK4-short protein of 336 amino acids. TLR2 TLR5 TLR6 TLR10 TLR1 TLR4 IL-1Rs Extracellular TLR3 TLR7 TLR8 TLR9 MyD88 IRAK4 (IKK complex) ΙΚΚα ΙΚΚβ NEMO NF-κB P IκΒα IκΒα P65 P50 P50 P65 Intracellular Nucleus Gene transcription Inﬂammatory cytokines Figure 2: MyD88 and IRAK-4-mediated signaling pathway. antibodies against speciﬁc vaccines antigens. As recom- protein resulting in crucial impairment of IRAK-4 signaling mended by Picard et al., our patient was administered with pathway,leadingtodisease.*erefore,theheterozygous empirical IgG substitution until the age of 12 years, a mutation could result in the phenotype of our patient. Although the prognosis of IRAK-4 deﬁciency is poor in prophylaxis that seems to have been beneﬁcial, since she has never experienced bacterial infections so far . earlychildhood,withamortalityrateof30%–43%beforethe *e patient’s DNA analysis revealed the change of ageof8years,itimprovessubstantiallywithage[1,2,12,13]. c.823delTandp.S275fsat the protein level inheterozygosity. *is ﬁnding is remarkable in the ﬁeld of primary immu- *is change aﬀecting isoform A of IRAK-4 could alter the nodeﬁciencies,thatalwaysdeterioratewithtime,andmaybe kinase activity since it is located in the kinase domain of the due to the acquisition of humoral immunity and Case Reports in Immunology 5  H.Al-Mousa, M. Abouelhoda,D. M.Monies et al., “Unbiased immunologicmemorywithage(adaptiveantigenspeciﬁcT- targeted next-generation sequencing molecular approach for and B- lymphocyte responses) [5, 9, 10]. primary immunodeﬁciency diseases,” Journal of Allergy and In conclusion, IRAK-4 deﬁciency should be considered Clinical Immunology, vol. 137, no. 6, pp. 1780–1787, 2016. in diﬀerential diagnosis of children presenting with severe  M. A. Smith, K. Choi, N. Salomonis, M. J. Walter, infections whose immunological evaluations, including K. Komurov, and D. T. Starczynowski, “Alternative splice those for innate immunity, are unremarkable. *e impor- variants of IRAK4 that activate innate immune signaling are tance of clinical suspicion is emphasized in order to conﬁrm associated with U2AF1 mutations in myelodysplastic syn- thediagnosisbytheIRAK4genesequencingandprovidethe drome and acute myeloid leukemia,” Blood, vol. 128, no. 22, appropriate treatment for this rare primary immunodeﬁ- p. 1531, 2016. ciency, as soon as possible.  H. Von Bernuth, C. Picard, A. Puel, and J.-L. Casanova, “ExperimentalandnaturalinfectionsinMyD88-andIRAK-4- deﬁcient mice and humans,” European Journal of Immunol- Data Availability ogy, vol. 42, no. 12, pp. 3126–3135, 2012.  C. Picard, J.-L. Casanova, and A. Puel, “Infectious diseases in *e data used to support the ﬁndings of this study are patients with IRAK-4, MyD88, NEMO, or I B deﬁciency,” available from the corresponding author upon request. Clinical Microbiology Reviews, vol. 24, no. 3, pp. 490–497, Consent  H. Chapel, A. Puel, H. Von Bernuth, C. Picard, and J.-L.Casanova,“Shigellasonneimeningitisduetointerleukin- Written informed consent was obtained from the teenager’s 1 receptor--associated kinase-4 deﬁciency: ﬁrst association parents prior to preparation and submission of this with a primary immune deﬁciency,” Clinical Infectious Dis- eases, vol. 40, no. 9, pp. 1227–1231, 2005. manuscript.  S. Grazioli, S. J. Hamilton, M. L. McKinnon et al., “IRAK-4 deﬁciency as a cause for familial fatal invasive infection by Conflicts of Interest Streptococcus pneumoniae,” Clinical Immunology, vol. 163, pp. 14–16, 2016. *e authors declare that they have no conﬂicts of interest.  K. Gobin, M. Hintermeyer, B. Boisson et al., “IRAK4 deﬁ- ciency in a patient with recurrent pneumococcal infections: case report and review of the literature,” Frontiers in Pedi- Authors’ Contributions atrics, vol. 5, p. 83, 2017. 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Published: Oct 8, 2020
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