Clinical IRAK4 deficiency caused by homozygosity for the novel IRAK4 (c.1049delG, p.Gly350Glufs*15) variant.

Alicia Jia,Elliot James,Mehul Sharma,Hasandeep Kular,Henry Y Lu,Stuart E Turvey,Kyla J Hildebrand,Stephanie Erdle,Bhavi P Modi,Alanna Chomyn,Catherine M Biggs

doi:10.1101/mcs.a005298

Abstract

The innate immune system allows for rapid recognition of pathogens. Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade. Each TLR recognizes a distinct set of pathogen-associated molecular patterns (PAMPs) that encompass conserved microbial components such as lipopolysaccharides and flagellin. Upon binding of PAMPs and TLR activation, TLR intracellular domains initiate the oligomerization of the myeloid differentiation primary response 88 (MyD88), IRAK1, IRAK2, and IRAK4 signaling platform known as the Myddosome complex while also triggering the Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway. The Myddosome complex initiates signal transduction pathways enabling the activation of NF-κB and mitogen-activated protein kinase (MAPK) transcription factors and the subsequent production of inflammatory cytokines. Human IRAK4 deficiency is an autosomal recessive inborn error of immunity that classically presents with blunted or delayed inflammatory response to infection and susceptibility to a narrow spectrum of pyogenic bacteria, particularly Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. We describe a case of IRAK4 deficiency in an 11-mo-old boy with concurrent S. pneumoniae bacteremia and S. aureus cervical lymphadenitis with a blunted inflammatory response to invasive infection. Although initial clinical immune profiling was unremarkable, a high degree of suspicion for an innate immune defect prompted genetic sequencing. Genetic testing revealed a novel variant in the IRAK4 gene (c.1049delG, p.(Gly350Glufs*15)) predicted to be likely pathogenic. Functional testing showed a loss of IRAK4 protein expression and abolished TLR signaling, confirming the pathogenicity of this novel IRAK4 variant.

Highlights

An 11-mo-old previously healthy boy who was born at term following an uncomplicated pregnancy presented with a 1-mo history of left-sided cervical lymphadenopathy
The presence of invasive pneumococcal infection concurrently with S. aureus adenitis and diminished clinical and laboratory response to these invasive infections prompted a further workup for inborn errors of immunity, with a particular focus on Toll-like receptor (TLR) signaling defects
We found that nonspecific chemical activation of the cells with phorbol 12-myristate 13-acetate (PMA) and ionomycin resulted in comparable levels of tumor necrosis factor-α (TNF-α) production in both interleukin-1 receptor-associated kinase 4 (IRAK4)-deficient and healthy control lymphoblastoid cell lines (LCLs)

Summary

Introduction

An 11-mo-old previously healthy boy who was born at term following an uncomplicated pregnancy presented with a 1-mo history of left-sided cervical lymphadenopathy. He lacked typical features of an infection such as fever and localized erythema, warmth, and tenderness; he was initially suspected of having a malignancy. The patient’s infections were treated with cefotaxime and the bacteremia resolved within 32 h; there were no further fevers He completed a 2-wk course of intravenous cefotaxime followed by a 2-wk course of oral cephalexin. Intravenous cefazolin was initiated and follow-up 4 wk later revealed minimal interval change clinically or sonographically, so he was brought to the operating room for left neck dissection and lymph node debulking with incision and drainage of the abscess. Cefazolin continued intravenously for another 4 wk totaling an 8-wk duration with near-complete resolution of the lymphadenitis

Methods

Conclusion