Skip to content


  • Poster presentation
  • Open Access

Clinical presentation and cytokine production abnormalities in a cohort of patients carrying NLRP12 gene variants

  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 2,
  • 2,
  • 1,
  • 1,
  • 3,
  • 1,
  • 4,
  • 1 and
  • 1
Pediatric Rheumatology201412 (Suppl 1) :P71

  • Published:


  • Juvenile Idiopathic Arthritis
  • Conjunctivitis
  • Tocilizumab
  • Anakinra
  • Autosomal Dominant Disease


The NLRP12 related autoinflammatory disorder (NLRP12-RD) is a rare autosomal dominant disease,caused by mutations in the NLRP12 gene.Clinical manifestations are extremely heterogeneous.At present,only few cases have been described.Patients occasionally required treatment with steroids and NSAIDS for short periods.Treatment with Anakinra induced an initial good response,that appears to decrease over time.


To describe clinical features and inflammatory response of a cohort of patients carrying different NLRP12 variants,some of which not yet described as being associated with NLRP12-RD.


Twelve caucasian patients(6 males)carrying NLRP12 variants were identified.Blood samples obtained from 9/12 NLRP12 patients and from 7 active Juvenile idiopathic arthritis(JIA) patients were stimulated ex vivo with 1 mg/ml of Zymosan for 22h.Whole blood RNA analysis was also performed,using a human immune array(TaqMan® Human Immune Array from Applied Biosystems),containing 92 genes typically involved in the immune response.


The median age at symptoms onset was 11,4 months(IQR 4,6–35,2)and the median of disease duration was 6,8 years(IQR 4,1–11).Sequencing of NLRP12 gene in the 12 patients revealed 5 heterozygous mutations:F402L(n=6),G448A(n=1),H304Y(n=1),R1030G(n=1) and G39V(n=1).Two patients were homozygous for NLRP12 variants:F402L and G39V.In 6/12 variants of NLRP3 were also found:Q703K(n=4) and V198M(n=2).All patients had symptoms consistent with a recurrent inflammatory syndrome:11/12 presented recurrent episodes of skin lesions,11/12 arthralgia,10/12 recurrent fever episodes,8/12 arthritis,10/12 headache,11/12 fatigue,5/12 conjunctivitis,7/12 recurrent abdominal pain and lymphadenopathy,5/12 oral aphthosis,4/12 thoracic pain and 2/12 sensorineural deafness. During the attacks 5/12 patients showed increased acute phase reactants.In 5/12 patients anakinra was administered because of the severity of phenotype and the persistence of elevated acute phase reactants.In 2 of these 5 patients lack of efficacy led withdrawal of anakinra and introduction of tocilizumab with good response.In vitro cytokine release studies,performed in 9 patients,showed that the production of IL-6 and TNF-a was significantly higher in patients carrying the NLRP12 variants compared to patients with JIA (IL-6:2841±1682 ng/ml and 1496±982.4 ng/ml versus 498.8±338.7 ng/ml and 226.6±111.8 ng/ml respectively;p=0.0002 and p=0.007)and even higher in homozygous patients;no significant difference in IL-1β production was found(2134 ± 1026 ng/ml versus 1527±930.3 ng/ml, p=0.29).Whole blood RNA samples collected from 5 NLRP12 patients were compared to 6 whole blood RNA samples collected from healthy controls comparable for age.At basal level,we did not find significant differences in the expression of 92 genes evaluated.


Our data in vitro and in vivo suggest that these NLRP12 variants are pathogenic.The role played by the concomitant presence of the NLRP3 variants remains to be clarified,though an effect in modifying the disease phenotype cannot be excluded.Our data also confirm the clinical and functional heterogeneity of NLRP12 related disorder,a condition often misunderstood.Furthermore,although the small number of patients treated,our data suggest that inhibition of IL-6 may be effective in NLRP12-related disorder.

Disclosure of interest

None declared.

Authors’ Affiliations

Division of Rheumatology, Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesù, Italy
Cytogenetics, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
Pediatric Rheumatology Unit, Department of Rheumatology, Istituto Ortopedico G.Pini University of Milan, Milan, Italy
Division of Pediatric, Santa Maria della Stella Hospital, Orvieto, Italy


© Insalaco et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. 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 work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.