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Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease.

Caso F, Galozzi P, Costa L, Sfriso P, Cantarini L, Punzi L - RMD Open (2015)

Bottom Line: Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non-caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum.The heightened nuclear factor-κB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms.We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine DIMED , University of Padova , Padova , Italy ; Rheumatology Unit, Department of Clinical Medicine and Surgery , University Federico II , Naples , Italy.

ABSTRACT
The recent identification of genetic mutations leading to dysfunction of inflammatory and apoptotic pathways, has allowed to characterise a group of diseases, recognised as monogenic autoinflammatory syndromes. Among those, Blau syndrome (BS) and early-onset sarcoidosis (EOS) have been identified as familial and sporadic phenotypes of the same non-caseating granulomatous form. Both the diseases are caused by mutations in the CARD15/NOD2 gene, encoding the cytosolic NOD2 protein, one of the key molecules in the regulation of innate immunity. Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non-caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum. The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD), a common polygenic inflammatory granulomatous bowel disease. The heightened nuclear factor-κB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms. Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease, which shares several clinical characteristics with BS and EOS. This review attempts to describe these diseases on the basis of the most recent evidences. We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the NOD2 protein (NP_071445.1) with the characteristic three domains structure and localisation of NOD2 mutations described in autoinflammatory granulomatous diseases. Red squares highlight mutations associated with BS, whereas the grey colour identifies EOS-related mutations, on the basis of the Infevers database data (CARD, caspase recruitment domain’ LRR, leucine rich repeat; NACHT, central nucleotide-binding and oligomerisation domain; http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php).
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RMDOPEN2015000097F1: Schematic representation of the NOD2 protein (NP_071445.1) with the characteristic three domains structure and localisation of NOD2 mutations described in autoinflammatory granulomatous diseases. Red squares highlight mutations associated with BS, whereas the grey colour identifies EOS-related mutations, on the basis of the Infevers database data (CARD, caspase recruitment domain’ LRR, leucine rich repeat; NACHT, central nucleotide-binding and oligomerisation domain; http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php).

Mentions: Improvement in the knowledge of pathogenic aspects of BS and EOS started with the identification of three missense mutations (p.R334Q, p.R334W and p.L469F) in four European families with BS.13 To date, on a total amount of almost 220 patients with BS and EOS carrying CARD15/NOD2 mutations, missense substitutions involving residue at position 334, p.R334Q/W, account for more than 80%.320–22 p.E383K has been found in almost 5% of cases, whereas other mutations have been described most rarely. Notably, in two patients with EOS, the concomitant presence of p.E338D and p.D390V mutations23 and a NOD2 six-base deletion (c.1493_1498delAACTGT, p.E498V, 499-500del) has been described.24 A schematic representation of the NOD2 protein and BS and EOS-related mutations are described in figure 1.


Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease.

Caso F, Galozzi P, Costa L, Sfriso P, Cantarini L, Punzi L - RMD Open (2015)

Schematic representation of the NOD2 protein (NP_071445.1) with the characteristic three domains structure and localisation of NOD2 mutations described in autoinflammatory granulomatous diseases. Red squares highlight mutations associated with BS, whereas the grey colour identifies EOS-related mutations, on the basis of the Infevers database data (CARD, caspase recruitment domain’ LRR, leucine rich repeat; NACHT, central nucleotide-binding and oligomerisation domain; http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612691&req=5

RMDOPEN2015000097F1: Schematic representation of the NOD2 protein (NP_071445.1) with the characteristic three domains structure and localisation of NOD2 mutations described in autoinflammatory granulomatous diseases. Red squares highlight mutations associated with BS, whereas the grey colour identifies EOS-related mutations, on the basis of the Infevers database data (CARD, caspase recruitment domain’ LRR, leucine rich repeat; NACHT, central nucleotide-binding and oligomerisation domain; http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php).
Mentions: Improvement in the knowledge of pathogenic aspects of BS and EOS started with the identification of three missense mutations (p.R334Q, p.R334W and p.L469F) in four European families with BS.13 To date, on a total amount of almost 220 patients with BS and EOS carrying CARD15/NOD2 mutations, missense substitutions involving residue at position 334, p.R334Q/W, account for more than 80%.320–22 p.E383K has been found in almost 5% of cases, whereas other mutations have been described most rarely. Notably, in two patients with EOS, the concomitant presence of p.E338D and p.D390V mutations23 and a NOD2 six-base deletion (c.1493_1498delAACTGT, p.E498V, 499-500del) has been described.24 A schematic representation of the NOD2 protein and BS and EOS-related mutations are described in figure 1.

Bottom Line: Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non-caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum.The heightened nuclear factor-κB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms.We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine DIMED , University of Padova , Padova , Italy ; Rheumatology Unit, Department of Clinical Medicine and Surgery , University Federico II , Naples , Italy.

ABSTRACT
The recent identification of genetic mutations leading to dysfunction of inflammatory and apoptotic pathways, has allowed to characterise a group of diseases, recognised as monogenic autoinflammatory syndromes. Among those, Blau syndrome (BS) and early-onset sarcoidosis (EOS) have been identified as familial and sporadic phenotypes of the same non-caseating granulomatous form. Both the diseases are caused by mutations in the CARD15/NOD2 gene, encoding the cytosolic NOD2 protein, one of the key molecules in the regulation of innate immunity. Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non-caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum. The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD), a common polygenic inflammatory granulomatous bowel disease. The heightened nuclear factor-κB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms. Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease, which shares several clinical characteristics with BS and EOS. This review attempts to describe these diseases on the basis of the most recent evidences. We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.

No MeSH data available.


Related in: MedlinePlus