The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review

Abstract

Objective: To assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece.

Methods: Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded.

Results: In total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment.

Conclusion: NOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.

Keywords: NGS; NOD2; Yao syndrome; coexisting gene variants; systemic autoinflammatory disease.

Figure 1

(A) Frequency of NOD2 variants, Yao syndrome or other diagnoses among 167 patients with systemic autoinflammatory diseases. (B) Disease diagnosis (blue bar), patients without variants (orange bar) or carrying only variants not influencing/causing disease (grey bar) in each disease. The y-axis indicates the absolute number of patients. Variants not influencing/causing disease are defined as non-contributory genotypes in MEFV, TNFRSF1A, MVK, NLRP3, NLRP12 (Eurofever criteria) (1), and/or variants in other genes not related to phenotype.Overlap diagnoses in 5 patients include the following: FMF/TRAPS11, n= 3; TRAPS/TRAPS11, n=1; HIDS/NLRP12RD, n=1. w/o, without; SAID, systemic autoinflammatory disease; YAOS, Yao syndrome; FMF, Familial Mediterranean Fever; PFAPA, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis; NLRP12 RD, NLRP12 related disease; CAPS, cryopyrin-associated periodic syndrome; HIDS, Hyperimmunoglobulinemia D with periodic fever syndrome; TRAPS, Tumor necrosis factor receptor-associated periodic syndrome; TRAPS11, TNFRSF11A associated hereditary fever disease; IRP, idiopathic relapsing pericarditis; SAPHO, Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis; periorb. swell, periorbital swelling.

Figure 2

(A) NOD2 gene variants reported in 12 patients with Yao syndrome in the present study and/or in literature. (B) NOD2 gene variants reported in patients with diagnoses other than Yao syndrome in 11 patients in the present study and/or in literature. In colored font are depicted variations found only in our series, in bold italics font those found both in our cohort and in literature, and the rest (regular font) are variants reported only in literature. The 12 exons of the gene are depicted as boxes, and the black line connecting the exons represents the intronic gene regions. ^#variants also found in patients with diagnoses other than Yao syndrome ^*variants also found in patients with Yao syndrome.

Figure 3

Coexisting variants in genes other than NOD2 in 8 out of 12 patients with Yao syndrome (YAOS) (67%) and 10 out of 11 patients with other diagnoses (91%). The y-axis indicates the absolute number of patients (dark blue bars)/variants (light blue bars).

Figure 4

Disease diagnoses among 23 patients with systemic autoinflammatory diseases and rare NOD2 variants. Twelve patients had Yao syndrome (52%) and 11 other diagnoses (48%). YAOS, Yao syndrome; FMF, Familial Mediterranean Fever; PFAPA, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis; TRAPS11, TNFRSF11A associated hereditary fever disease; SURF, syndrome of undifferentiated recurrent fever.