Review Article
NLRP12-Associated Periodic Syndrome: An Analysis of Literature Data
Yuriy Nikirenkov*
Corresponding Author: Yuriy Nikirenkov, Rheumatologist, MVZ Outpatient Rheumatism Center Erfurt, Tschaikowskistrasse 22-24, 99096 Erfurt, Theuringen, Germany
Received: February 25, 2018; Accepted: March 18, 2019;
Citation: Nikirenkov Y. (2019) NLRP12-Associated Periodic Syndrome: An Analysis of Literature Data. J Cancer Sci Treatment, 1(3): 49-51.
Copyrights: ©2019 Nikirenkov Y. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Auto inflammatory diseases (AIDs) are a group of rare disorders characterized by persistent or recurrent inflammation caused by the hyper activation of mediators and innate immune cells (neutrophils, monocytes/macrophages). The paper describes the author reviews a series of cases of the similar disease, which are given in the literature.


Keywords: Auto inflammation, NLRP12, Inflammasome


Auto inflammatory diseases (AIDs) - a group of rare diseases characterized by persistent or recurrent inflammation, caused by the hyper activation of mediators and cells of congenital immunity (neutrophils, monocytes/macrophages). In contrast to autoimmune diseases in AVS, the involvement of T and B lymphocytes is only possible again, so there is no formation of autoantibodies and a connection with antigens of the main histocompatibility complex of HLA class II [1,2].

Innate immunity plays a crucial role in nonspecific protection of the body against infections using the system of recognizable receptors (pattern recognition receptors, PRRs). These receptors recognize the molecular sequences of pathogens and activate the immune response [3].

Interleukin 1 (IL1) is a key pro-inflammatory cytokine synthesized by monocytes, tissue macrophages and dendritic cells. Its formation is stimulated by the influence of microbial wall peptides, cytokines such as tumor necrosis factor (TNF), IL18, IL1 and IL1 itself [4]. Auto induction of IL1 synthesis is the main pathogenetic link of auto inflammation. IL1 is synthesized in an inactive form in the form of a precursor molecule of interleukin 1 (pro-IL1), which is activated by the enzyme caspase 1 (convertase IL1). Uncontrolled activation of the enzyme caspase 1 in patients with a mutation in the NLRP3 gene leads to the formation of a large amount of active IL1, which stimulates its own excess production.

This mechanism underlies cryopirin-associated periodic syndromes (CAPS), characterized by sterile multi-organ inflammation [5]. In AIDS, in contrast to autoimmune diseases, the use of IL1 blockers is effective, while blocking other cytokines does not produce a result [6].

CAPS is a group of hereditary diseases, represented by phenotypes, differing from each other in clinical manifestations and severity [7]. There are three forms of CAPS: Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and the neonatal Onset Multisystem Inflammatory Disease (NOMID), also known as chronic Infantile skin neurological and articular syndrome (Chronic Infantile Neurological Cutaneous Articular Syndrome, CINCA) [8]. All three diseases are associated with the presence of activating mutations in the gene NLRP3 (CIAS1), which encodes the cryopirin protein (a key component of the inflammosome activatingcaspase 1) and determines the production rate of IL1 [9-11].

All three forms of the disease are characterized by episodes of fever, accompanied by the appearance of urticaroid-like rash, joint pain and an increase in acute phase parameters. The easiest form is a family cold urticaria. This syndrome is characterized by episodes of fever, urtikaropodobnyh rashes against the background of joint pain and general malaise. Interestingly, for the development of an attack, adult patients with FCAS simply have, for example, in the department with cooling products in the store. As a rule, the disease worsens the quality of life, but does not significantly affect its duration and the development of irreversible organ changes.

In patients with MWS, in addition to the described manifestations, there are hearing impairments (sensorineural hearing loss), vision (uveitis, conjunctivitis), risk of amyloidosis (up to 25%), delay in physical and sexual development, and a decrease in life expectancy. Unlike FCAS, episodes of fever increase are often spontaneous and do not have a strict connection with hypothermia, acute phase parameters remain, as a rule, elevated even on days when fever and exanthema are absent [12].

CINCA/NOMID syndrome is the most severe form of CAPS, it manifests itself practically from the moment of birth, or in infancy, and is accompanied by multiple organ damage, high risk of amyloidosis, significant lag in physical and sexual development, influence on quality of life and a significant reduction in its duration [13-15]. In the clinical picture of the disease, fever, urtikaropodobnye rashes, an increased level of acute phase parameters of inflammation are constantly present. Patients with CINCA/NOMID syndrome have typical dysmorphic face changes, bone lesions in the form of local tumor-like hypertrophy [16,17]. Among organ manifestations, chronic meningitis should be noted, accompanied by signs of increased intracranial pressure (headache, morning vomiting, skull change, ventriculomegaly), as well as intellectual disorders of varying severity associated with brain tissue atrophy [14,17]. Also significant are hearing impairment (sensoneural hearing loss), vision (uveitis, conjunctivitis, papilloids), up to severe vision loss, if the disease is not diagnosed on time and the child does not receive adequate therapy [14].

CAPS has an autosomal dominant type of inheritance, respectively, similar symptoms or some of them may be present in the relatives of the patient. In most cases, in patients with typical CAMD Symptoms, mutations are localized in the 3 exon of the NLRP3 gene, responsible for the synthesis of the protein fragment necessary for the oligomerization process [18]. Approximately 16% of children with CAPD mutations are sporadic (de novo) and about 60% do not show any classical mutations. In patients with non-classical CAPS (for example, without exanthema) mutations can be localized in the 4 or 6 exon of the NLRP3 gene [19,20]. Up to 60% of patients with classical CASP phenotypes do not have mutations that can be identified by Sanger sequencing [21]. At present, this phenomenon can be explained by the presence of somatic mosaicism, when not all cells of the body have a mutation [22] or a genomic copy, when mutations in different genes can be manifested in a similar clinical picture.

Interest in the NLRP12 gene as a causative factor of fever arose due to the fact that individuals with undoubted syndrome FCAS did not show mutations in the NLRP3 gene. In 2008 I. Jeru et al. [23] reported three cases of NLRP12-associated disease in children. Two twin brothers who fell ill in the first month of life had episodes of fever, hearing loss, arthralgia and myalgia, while the level of CRP remained normal. They detected a mutation of p.Arg284X in exon 3 of the NLRP12 gene in the heterozygous state. In another case, in a 9 year old girl, fever arose at the age of 1 year, accompanied by abdominal pain, vomiting, lymphadenopathy and aphthous stomatitis, an increase in the level of CRP during the attack. The patient had a heterozygous mutation c.2072 + 3insT in the NLRP12 gene. Several members of the same family, especially those sensitive to cold, found the missense mutation p.D294E in the NLRP12 gene. In the carriers of this mutation, on contact with the cold, myalgia and arthralgia developed, whereas fever and exanthema were absent [24]. A mutation of p.Trp408X in the NLRP12 gene wasdetected in a family of 18 people who suffered very short attacks of fever and urticaroid-like rash of no more than 12-24 h [25]. Symptoms were stopped on their own, without the use of medication. In connection with the similarity of the clinical picture in patients with a mutation in the gene NLRP12 with that in patient with familial cold urticaria it is suggested to call this disease a family cold type II urticaria.

In most cases, NSAIDs and short courses of glucocorticoid therapy are effective in patients with NLPR12-associated syndrome. In the literature, I met a description of one case where a child with a family cold urticaria who did not have a mutation in the NLRP3 gene received an anakin therapy to stop seizures during the cold season. In another patient, the disease was accompanied by a delay in physical development, which was eliminated against the background of the use of the blocker IL1 kanakinumab, which indicates a significant effect of systemic inflammation on the child's body.


In some cases, NLRP12-periodic syndrome in the clinical picture resembles a family cold urticaria, in the presence of certain mutations - MWS. In other cases, it has the features of an undifferentiated autoimmune syndrome. The search for mutations in the NLRP12 gene should be performed in patients with a clinical picture of familial cold urticaria and MWS syndrome that do not have mutations in the NLRP3 gene, as well as in all other cases of non-classical AIDS flow.

1.       Hoffman HM, Wanderer AA, Broide DH (2001) Familial cold auto inflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever. J Allerg Clin Immunol 108: 615-620.

2.       Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, et al. (2004) NALP3 forms an IL-1b-processing inflammasome with increased activity in Muckle-Wells auto-inflammatory disorder. Immunity 20: 319-325.

3.       Goldbach-Mansky R (2011) Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep13: 123-131.

4.       Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50: 607-612.

5.       Prieur AM, Griscelli C (1981) Arthropathy with rash, chronic meningitis, eye lesions and mental retardation. J Pediatr 99: 79-83.

6.       Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, et al. (2006) Neonatal-onset multisystem inflammatory disease responsive to inter-leukin-1beta inhibition. N Engl J Med 355: 581-592.

7.       Lepore L, Paloni G, Caorsi R, Alessio M, Rigante D, et al. (2010) Follow-up and quality of life of patients with cryoprin-associated periodic syndromes treated with anakinra. J Pediatr 157: 310-315.e1.

8.       Kozlova AL, Mamzerova ES, Novichkova GA, Shcherbina AY (2014) Clinical manifestations and therapy of cryoprin-associated periodic syndromes. Voprosygematologii/onkologii I immunopatologii v pediatrii 13: 42-48.

9.       Kitley JL, Lachmann HJ, Pinto A, Ginsberg L (2010) Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology 74: 1267-1270.

10.    Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, et al. (2008) The infevers auto-inflammatory mutation online registry: Update with new genes and functions. Hum Mutat 29: 803-808.

11.    Jesus AA, Silva C, Segundo G, Aksentijevich I, Fujihira E, et al. (2011) Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): Description of a rare non-exon 3 and novel results of an International Multicenter Collaborative Study. Arthritis Rheum 63: 3625-3632.

12.    Jéru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, et al. (2008) Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A 105: 1614-1619.

13.    Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, et al. (2011) Clinical presentation and pathogenesis of cold-induced auto-inflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum 63: 830-839.

14.    Xia X, Dai C, Zhu X, Liao Q, Luo X, et al. (2016) Identification of a novel NLRP12 non-sense mutation (Trp408X) in the extremely rare disease FCAS by exome sequencing. PLoS One 11: e0156981.

15.    Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K (2014) An inherited mutation in NLRC4 causes auto-inflammation in human and mice. J Exp Med 211: 2385-2396.

16.    Tunca M, Ozdogan H (2005) Molecular and genetic characteristics of hereditary auto-inflammatory diseases. Curr DrugTargets Inflamm Allergy 4:77-80.

17.    Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, et al. (2002) PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem 277: 29874-29880.

18.    Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, et al. (2005) The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha- and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem 280: 39914-39924.

19.    Jеru I, Le Borgne G, Cochet E, Hayrapetyan H, Duquesnoy P, et al. (2011) Identification and functional consequences of a recurrent NLRP12 mis-sense mutation in periodic fever syndromes. Arthritis Rheum 63: 1459-1464.

20.    Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, et al. (2007) Monarch-1 suppresses non-canonical NF-kappa B activation and p52-dependent chemokine expression in monocytes. J Immunol 178: 1256-1260.


22.    hen M, Tang L, Shi X, Zeng X, Yao Q (2016) NLRP12 auto-inflammatory disease: A Chinese case series and literature review. Clin Rheumatol 36: 1661-1667.

23.    Rusmini M, Federici S, Caroli F, Grossi A, Baldi M, et al. (2016) Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis 75: 1550-1557.

24.    Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, et al. (2011) Clinical presentation and pathogenesis of cold-induced auto-inflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum 63: 830-839.

25.    Xia X, Dai C, Zhu X, Liao Q, Luo X, et al. (2016) Identification of a novel NLRP12 non-sense mutation (Trp408X) in the extremely rare disease FCAS by exome sequencing. PLoS One 11: e0156981.