Giving a NOD2 to Yao syndrome

By Warren R. Heymann, MD, FAAD
March 5, 2025
Vol. 7, No. 9

The 21st century has witnessed an expanding array of systemic autoinflammatory disorders (SAIDs) due to innate immunity dysfunction. SAIDs are characterized by recurrent attacks of fever, cutaneous signs, chest or abdominal pain, lymphadenopathy, vasculopathy, and musculoskeletal symptoms. Many SAIDs have been described (familial Mediterranean fever, TRAPS [tumor necrosis factor receptor-associated periodic syndrome], cryopyrin-associated periodic syndromes, NLRP12-associated disorder, hyperimmunoglobulin D syndrome, mevalonate kinase deficiency, haploinsufficiency A20, deficiency of ADA2 [adenosine deaminase 2], type I interferonopathy, adult-onset Still disease, idiopathic recurrent pericarditis, Schnitzler syndrome, PFAPA [periodic fever with aphthous stomatitis pharyngitis and adenitis] syndrome, and SAPHO [synovitis, acne, pustulosis, hyperostosis and osteitis] syndrome. Although the diagnosis of SAIDs is often established in childhood, based on clinical suspicion and genetic confirmation, an increasing number of adults are being recognized with SAIDs, including adult-onset disease. (1)

In 2011, Yao et al. described a “new” SAID associated with nucleotide-binding oligomerization domain 2 (NOD2) gene mutations. (2) This is now known as Yao syndrome (YAOS, OMIM #617321)

The nucleotide-binding oligomerization domain containing 2 (NOD2) gene is located in chromosome 16q12-21.According to Zhang et al., “NOD2 protein is composed of N-terminal caspase recruitment domains (CARDs), central nucleotide binding and oligomerization domain (NBD), and C-terminal leucine-rich repeats (LRRs). NOD2 recognizes and combines with pathogen-associated molecular patterns (PAMPs), then receptor interaction protein-2 (RIP2) and nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinases (MAPKs) inflammatory signaling are activated, which leads to the overproduction of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and antimicrobial peptides.” In addition to YAOS, NOD2 variants have also been linked to Blau syndrome (BS) and Crohn’s disease (CD). (3) BS is an autosomal dominant disorder typically presenting in childhood, characterized by noncaseating granulomatous arthritis, a granulomatous skin eruption, uveitis, synovial cysts, and camptodactyly occurring in the absence of lung or other visceral involvement. (4)

The following is the abstract of the seminal article by Yao et al. (2) This commentary expands on the abstract (in italics) — the additions from more current literature are not italicized and are individually referenced within the abstract.

Introduction: Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations.

Methods: Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed.

Results: All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. A follow-up study of 22 patients showed a female predominance (13 women, 8 men). (5) These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. In their review of 164 patients with YAOS, Shakhashiro et al documented cutaneous manifestations in 87.1% (143/164). Rashes typically consisted of minimally pruritic erythematous macules, papules, patches and plaques distributed on the face, trunk, abdomen, and extremities. Of the 45 patients who underwent skin biopsies, 31 had dermatitis, including 16 with spongiotic dermatitis, 9 with perivascular dermatitis, and 7 with other dermatitides. There were 9 cases of granulomatous dermatitis or poorly formed granulomatous changes. One patient had biopsy findings consistent with a pigmented pruritic dermatitis, and one patient had leukocytoclastic vasculitis. (6) Esse et al described a case of a 16-year-old woman with YAOS presenting with a cyclical suppurative folliculitis. (7) There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation. Patients with YAOS often carry NOD2 IVS8+158/R702W, NOD2 IVS8+158/L1007fs, NOD2 IVS8+158/V955I or other NOD2 variants. (8)

Conclusions: Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau’s syndrome. To offer perspective, 167 patients with confirmed SAIDs who underwent screening using next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied — 24 rare NOD2 variants in 23/167 patients (14%) were detected. The candidate clinical diagnosis was YAOS in 12 patients (7% of the entire SAID cohort). (9)

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Yao syndrome may be diagnosed by 2 major criteria (periodic occurrence of at least 2 flares, recurrent fevers, or dermatitis), at least 2 minor criteria (arthralgia, arthritis, or distal extremity swelling, gastrointestinal symptoms, sicca-like symptoms, pericarditis, pleuritis), molecular criterion (NOD2 or R702W mutations), and exclusion criteria (negative autoimmune work-up, exclusion of other autoinflammatory diseases). (7)

Therapeutically, systemic corticosteroids and sulfasalazine are first-line, although limited reports of hydroxychloroquine, methotrexate, TNF-alpha inhibitors, anakinra, canankinumab, and tocilizumab have shown efficacy. (6)

In conclusion, SAIDs should be considered in patients with episodic fever, rashes, and other systemic symptoms. YAOS should be in the differential diagnosis musculoskeletal, gastrointestinal, and sicca-like symptoms accompany these features.

Point to Remember: There are several autoinflammatory disorders that may present in adults. The number of cases of Yao syndrome due to mutations in NOD2 has been increasing. It should be in the differential diagnosis of patients manifesting recurrent fever, rashes, musculoskeletal, gastrointestinal, and sicca-like symptoms.

Our experts’ viewpoint

Qingping Yao, MD, PhD
Chief, Division of Rheumatology, Allergy, and Immunology
Director, Center of Autoinflammatory Diseases
Department of Medicine
Stony Brook University, Renaissance School of Medicine

John M. Davis III, MD, MS, RhMSUS
Chair, Division of Rheumatology
Enterprise Chair, Rheumatology Specialty Council
Professor of Medicine, Mayo Clinic College of Medicine and Science

Yao syndrome is a recurrent, chronic inflammatory disease with high morbidity and disability. It is a disease affecting multi-organs and systems, such as cutaneous, musculoskeletal, digestive, lymphoreticular and respiratory, among others. Cases are encountered in rheumatology, dermatology, allergy, immunology, gastroenterology, infectious disease, pulmonology, and other disciplines. Despite an unclear prevalence, an increasing number of cases and case series has been reported in the U.S., Europe, and Asia. The disease appears to be more common than initially thought. Patients present with a constellation of characteristic clinical features, such as erythematous patches, eyelid swelling, distal lower extremity swelling, and nonspecific symptoms like fever, arthralgia, myalgia, abdominal pain, bloating, diarrhea, and sicca symptoms. Serologic testing of autoantibodies for lupus, rheumatoid arthritis, Sjogren syndrome, and vasculitis is negative, except occasionally positive for low-titer antinuclear antibodies. Gastrointestinal workup does not show convincing evidence of inflammatory bowel disease, though most patients must be evaluated by gastroenterologists due to the shared NOD2 mutations identified in 40% of Caucasian patients with Crohn disease (notably NOD2 R702W, L1007Fs, and G908R). Patients usually experience a long diagnostic odyssey prior to recognition of YAOS. Certain NOD2 mutations are required for diagnosis. Based on the constellation of the clinical phenotype and exclusion of relevant known diseases, an autoinflammatory gene panel including whole NOD2 DNA sequencing may be obtained by an experienced specialist. Unlike classical Mendelian disorders, where gene mutations are highly penetrant and deterministic, patients with YAOS often carry low penetrance NOD2 variants, for which most large molecular laboratories currently do not give a full report of these NOD2 variants. Individual patients commonly carry NOD2 IVS8+158, often being compounded with NOD2 R702W or L1007fs. These NOD2 variants or other variants, including rare NOD2 variants, can serve as a diagnostic criterion for the disease singly or in combination. YAOS is considered a Genetically Transitional Disease, a new concept in genomic medicine, where a gene mutation is necessary but insufficient to cause disease alone. Disease may result from the interactions of candidate genes, genetic background, and environment. This concept is important to discuss as part of genomic counseling for these patients. Therapeutically, IL-1 inhibitors are effective treatment for up to 65% of cases based on our experience and reports by others, although clinical trials are warranted. IL-1 inhibitors may serve as a mainstay of treatment for recurrent active disease or persistent disease until more effective drugs are identified or developed. About 15% of patients may eventually develop chronic pain syndrome, poor physical and mental functioning, and inability to attend schools or to do regular work so that patients may file for disability. (10,11)

1. Betrains A, Staels F, Schrijvers R, Meyts I, Humblet-Baron S, De Langhe E, Wouters C, Blockmans D, Vanderschueren S. Systemic autoinflammatory disease in adults. Autoimmun Rev. 2021 Apr;20(4):102774. doi: 10.1016/j.autrev.2021.102774. Epub 2021 Feb 17. PMID: 33609798.

2. Yao Q, Zhou L, Cusumano P, Bose N, Piliang M, Jayakar B, Su LC, Shen B. A new category of autoinflammatory disease associated with NOD2 gene mutations. Arthritis Res Ther. 2011;13(5):R148. doi: 10.1186/ar3462. Epub 2011 Sep 14. PMID: 21914217; PMCID: PMC3308076.

3. Zhang J, Luo Y, Wu B, Huang X, Zhao M, Wu N, Miao J, Li J, Zhu L, Wu D, Shen M. Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome. Arthritis Res Ther. 2024 Feb 23;26(1):58. doi: 10.1186/s13075-024-03286-w. PMID: 38395960; PMCID: PMC10885518.

4. Alonso D, Elgart GW, Schachner LA. Blau syndrome: a new kindred. J Am Acad Dermatol. 2003 Aug;49(2):299-302. doi: 10.1067/s0190-9622(02)61772-4. PMID: 12894082.

5. Yao Q, Su LC, Tomecki KJ, Zhou L, Jayakar B, Shen B. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. J Am Acad Dermatol. 2013 Apr;68(4):624-631. doi: 10.1016/j.jaad.2012.09.025. Epub 2012 Oct 24. PMID: 23102769.

6. Shakhashiro M, Sadeghian S, Newcomer J, Marzano AV, Maronese CA, Davis JM 3rd, Alavi A. Yao syndrome: a novel systemic autoinflammatory disease with cutaneous manifestations. Int J Dermatol. 2024 Jul 4. doi: 10.1111/ijd.17350. Epub ahead of print. PMID: 38965064.

7. Esse I, Kincaid C, Horton L, Arnold JD, Mesinkovska NA. Yao syndrome: Cyclical folliculitis, fevers, and abdominal pain. JAAD Case Rep. 2023 Mar 12;35:71-73. doi: 10.1016/j.jdcr.2023.01.039. PMID: 37124443; PMCID: PMC10139879.

8. Nomani H, Deng Z, Navetta-Modrov B, Yang J, Yun M, Aroniadis O, Gorevic P, Aksentijevich I, Yao Q. Implications of combined NOD2 and other gene mutations in autoinflammatory diseases. Front Immunol. 2023 Oct 19;14:1265404. doi: 10.3389/fimmu.2023.1265404. PMID: 37928541; PMCID: PMC10620916.

9. Karamanakos A, Vougiouka O, Sapountzi E, Venetsanopoulou AI, Tektonidou MG, Germenis AE, Sfikakis PP, Laskari K. The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review. Front Immunol. 2024 Jan 29;15:1342668. doi: 10.3389/fimmu.2024.1342668. PMID: 38348033; PMCID: PMC10859468.

10. Nomani H, Wu S, Ashmia S, Hwang F, Metzger J, Navetta-Modrov B, Gorevic P, Aksentijevich I, Yao Q. Comprehensive clinical phenotype, genotype and therapy in Yao syndrome. Front Immunol. Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1458118

11. Willaimson KA, Samec MJ, Patel JA, Orandi AB, Wang B, Crowson CS, Loftus EB, Alavi A, Moyer AM, Davis JM. Clinical Phenotype, NOD2 Genotypes, and Treatment Observations in Yao Syndrome: A Retrospective Case Series. Front Immunol Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1304792

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