NLRC4 GOF Mutations, a Challenging Diagnosis from Neonatal Age to Adulthood.

Juliette Bardet,Sébastien Viel,Isabelle Durieu,Guillaume Mortamet,Noémie Laverdure,Jean-Marie De Guillebon,Alexandre Belot,Capucine Picard,Mathieu Fusaro,Lorna Garnier,Audrey Laurent,Clémence Casari-Thery,Sophie Collardeau-Frachon

doi:10.3390/jcm10194369

Abstract

The NLRC4 inflammasome is part of the human immune innate system. Its activation leads to the cleavage of pro-inflammatory cytokines IL-1β and IL-18, promoting inflammation. NLRC4 gain-of-function (GOF) mutations have been associated with early-onset recurrent fever, recurrent macrophagic activation syndrome and enterocolitis. Herein, we describe two new patients with NLRC4 mutations. The first case presented with recurrent fever and vasoplegic syndrome, gut symptoms and urticarial rashes initially misdiagnosed as a severe protein-induced enterocolitis syndrome. The second case had recurrent macrophage activation syndrome (MAS) and shock, suggesting severe infection. We identified two NLRC4 mutations, on exon 4, within the nucleotide-binding protein domain (NBD). After a systematic review of NLRC4 GOF mutations, we highlight the wide spectrum of this disease with a limited genotype–phenotype correlation. Vasoplegic shock was only reported in patients with mutation in the NBD. Diagnosing this new entity combined with gastrointestinal symptoms and vasoplegic shocks is challenging. It mimics severe allergic reaction or sepsis. The plasma IL-18 level and genetic screening are instrumental to make a final diagnosis.

Highlights

Patient 1 was a girl with no past familial medical history, who presented from 20 days of life with recurrent episodes of fever with vasoplegic shocks associated with gastrointestinal symptoms and urticarial rash (Figure 1a)
The hypothesis of a NLRC4 GOF mutation was evoked at 3 months of life in light of the sustained inflammation with the elevated plasmatic IL-18 cytokine and the focal enteritis
We conducted a literature review based on the PubMed database with the following keywords: inflammasome—NLRC4—gain of function—NLRC4 and autoinflammatory diseases up to 1 March 2021

Summary

Introduction

NLR-family CARD domain-containing protein 4 (NLRC4) acts as an innate sensor of the immune system. It is mainly expressed in macrophages and intestinal epithelial cells. Its transcription is activated by the tumor suppressor protein p53 or pro-inflammatory stimuli such as TNFα [2]. It encodes a protein of 1024 amino acids with a molecular weight of. Its oligomerization results in an exponential cascade of adapter recruitment and caspase-1 autoproteolysis known as inflammasome activation, resulting in the cleavage of the inflammatory substrates proIL-1β, pro-IL18, and gasdermin D. We report on two new cases of NLRC4 GOF expanding the spectrum of the disease and we discuss the clinical and immunological anomalies that are critical for the diagnosis

Patient 1

Patient 2

Literature Review

Discussion

Conclusions