NLRP12-associated systemic autoinflammatory disease L50.21

In 1997, the French Familial Mediterranean Fever Consortium (The International FMF Consortium 1997) first reported a monogenic disease characterized by fever and multisystem inflammation caused by MEFV mutations. In 1999, McDermott MF et al. demonstrated that TNFRSF1 mutations cause tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). They proposed the term "autoinflammation". With whole exome sequencing technologies, the spectrum of these diseases has rapidly and continuously expanded in clinical practice(hyperimmunoglobulin D syndrome (HIDS) induced by MVK mutations, cryopyrin-associated periodic syndrome (CAPS) induced by NLRP3 mutations). In the meantime, > 30 SAIDs (SAIDs stands for: systemic autoinflammatory diseases) have been published, all of which are associated with excessive inflammasome activation, increased reactive oxygen species, autophagy disorders and other pathological mechanisms (Lachmann HJ 2017).

NLRP12-associated systemic autoinflammatory disease (NLRP12-AID) is a newly identified, rare autosomal dominant autoinflammatory systemic disease (SAID) that usually occurs in childhood and is caused by mutations in the NLRP12 gene. An NLRP12-AID variant is also known as familial cold autoinflammatory syndrome 2 ( FCAS2). Data from <100 patients are available worldwide (Wang HF 2022). In NLRP12-AID, > 20 different mutation types are known. Clinically, the disease is characterized by periodic fever accompanied by inflammatory damage throughout the system. NLRP12-AID is diagnosed by early clinical identification and genetic detection.

To date, < 100 cases of NLRP12 AIDs have been reported worldwide. Well described are 33 pediatric cases (Wang HF 2022). Of these, 22% had a positive family history. Around 1/3 of the cases were clearly induced by cold stimulation.

To date, 21 different types of NLRP12 mutations have been discovered, including 16 missense mutations (76%), 2 nonsense mutations (10%) and 3 frameshift mutations (14%). Most of the mutation sites are located in its functional domains, which may impair the anti-inflammatory function of NLRP12 and lead to an undermined inflammatory pattern (Wang L et al. 2002). It is noteworthy that in several cases, NLRP12 mutations were also found in first-degree relatives who did not show clinical symptoms. This indicates that NLRP12 mutations are associated with other relational factors that trigger disease symptoms.

Although the specific pathogenic mechanism of NLRP12 in different mutation types needs further investigation, excessive production of IL-1β and other inflammatory cytokines due to imbalanced regulation of the innate immune system by NLRP12 undoubtedly plays an important role in the pathogenic process of NLRP12-AID . Certainly, the cross-interactions between pathogenic NLRP12 mutations in autoinflammatory and autoimmune diseases need further investigation.

In the pediatric cases, the age at diagnosis was between 2 months and 17 years. 35% of the patients were male and 65% female.

The most common clinical symptom was non-infectious periodic fever of varying duration (100%). Other symptoms were polyarthralgia/arthritis (55 %), abdominal pain/diarrhea (48 %), exanthema 45 % (about 1/3 of the exanthema was diagnosed as urticaria), lymphadenopathy/splenomegaly (33 %), headache (24 %), neurosensory numbness (21 %), aphthous stomatitis (12 %), elevated acute phase reactants such as C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR) at (55 %). Some patients suffered from concomitant diseases caused by acquired immune disorders, including Crohn's disease, C3 glomerulopathy, juvenile idiopathic arthritis, autoimmune hemolytic anemia and susceptibility to infections.

The main clinical symptom of NLRP12-AID is non-infectious recurrent fever. Fever may have a specific pattern lasting 2-10 days each time and has self-limiting characteristics with no particular manifestations at onset. Torreggiani S et al (2016) defined periodic or recurrent fever as 3 or more unexplained febrile episodes within 6 months, with an interval of at least 7 days between 2 febrile episodes. After exclusion of infectious and neoplastic factors, autoinflammatory diseases caused by disorders of the immune system should be considered.

The occurrence of most NLRP12-AID symptoms is related to cold stimulation (Jéru I et al. 2008). Due to the dominant genetic background, a positive family history is crucial information for the diagnosis of NLRP12-AID. In most SAIDs, the first onset occurs in childhood, even before the age of 10 years. Due to multisystemic inflammatory reactions, concomitant symptoms of NLRP12-AID may include polyarthralgia/arthritis, abdominal pain/diarrhea, lymphadenopathy/splenomegaly, headache, neurosensory numbness, aphthous stomatitis, etc. Exanthema associated with fever and systemic inflammatory reactions are also characteristic manifestations significantly associated with cold stimulation. Remarkably, depigmentation may occur after the skin lesions subside (Borghini S et al. 2011). The response of SAIDs to antibiotics and immunosuppressive therapy is usually poor, and in some cases corticosteroids may alleviate certain symptoms.

The goal of SAID treatment is to suppress the persistent hyperinflammatory state, restore the function of multiple systems and improve the patient's quality of life. Since the pathologic mechanism is still unclear, few treatment protocols are available. Many reports suggest that colchicine is ineffective (Yang X et al. 2020).

In terms of treatment, monotherapy or the combined use of corticosteroids, non-steroidal anti-inflammatory drugs and antihistamines may provide symptom relief in a small number of patients. New biologics that directly target IL-1-related inflammatory pathways have shown good efficacy, and targeted therapy has further deepened our understanding of the molecular mechanism of NLRP12-AID. The mechanism of anakinra resistance is still unclear. There may be imbalances or compensations through other signaling pathways. However, the disease can be subdivided according to its different responses to IL-1 inhibitors, and an in-depth study of the underlying mechanism of its pathogenesis and progression could facilitate the development of more direct and effective targeted drugs.

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