NOD2 Versus MEFV: Differential Diagnosis of Yao Syndrome and Familial Mediterranean Fever

Abstract

Objectives: Yao syndrome (YAOS, OMIM 617321) was formerly designated as nucleotide-binding oligomerization domain-containing protein-2 (NOD2)-associated autoinflammatory disease (NAID). This disorder shares similar clinical phenotypes with hereditary periodic fever syndromes (HPFS). This study aimed to compare YAOS with familial Mediterranean fever (FMF).

Methods: In this retrospective study, electronic medical records of a case series of YAOS were reviewed and data were analyzed. All patients underwent genetic testing for periodic fever syndrome 6-gene panel.

Results: A total of 6 cases were presented. These patients were initially thought to have MEditerranean FeVer (MEFV)-negative FMF and received treatment with colchicine. They were eventually diagnosed with YAOS. The differences between these diseases were illustrated. In addition, both MEFV and NOD2 mutations were detected in some patients and family members. Patients with carriage of both gene mutations may present with heterogeneous disease expression. A close correlation between phenotypes and genotypes is needed to make a diagnosis.

Conclusions: YAOS may mimic FMF. Molecular analysis should cover NOD2 whole gene sequencing to help distinguish these diseases. Both NOD2 and MEFV mutations may contribute to disease expression in an individual.

Keywords: MEFV; NOD2-associated autoinflammatory disease; Yao syndrome; familial Mediterranean fever; nucleotide-binding oligomerization domain-containing protein-2.

Figure 1

Schematic representation of the gene and protein structures of NOD2 and MEFV. (A) NOD2 gene and protein. (B) MEFV gene and protein. CARD, caspase activation recruitment domain; CC, coiled-coil; LRR, leucine-rich repeat; MEFV, MEditerranean FeVer; NBD, nucleotide-binding domain; NOD2, nucleotide-binding oligomerization domain-containing protein-2; PYD, pyrin domain; CC, coiled-coil; SPRY, Dictyostelium discoideum dual-specificity kinase SpIA and ryanodine receptor.

Figure 2

Signaling pathways and molecular interactions of NOD2 and pyrin. (1) Bacterial product, MDP, binds cytosolic NOD2 and, in turn, activates the Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RIP2). The phosphorylated RIP2 subsequently activates NF-kB and p38/ERK/JNK, leading to the inflammatory response. (2) By binding apoptosis-ASC, pyrin disrupts the cryopyrin-ASC interaction and specifically inhibits activation of caspase 1. Mutation in pyrin leads to apoptosis and NF-kB activation by reducing the inhibitory pathway. (3) NOD2 also interacts with other NLRs, leading to activation of caspase 1 with adaptor protein ASC. ASC, associated speck-like protein; CARD, caspase activation recruitment domain; CC, coiled-coil; ERK, extracellular-signal-regulated kinase; JNK, JUN aminoterminal kinase; LRR, leucine-rich repeat; MDP, muramyl dipeptide; NOD2, nucleotide-binding oligomerization domain-containing protein-2; NLRs, NOD-like receptors; NBD, nucleotide-binding domain.