The Diagnostic Criteria for Yao Syndrome
Yao syndrome is diagnosed if 2 major criteria, at least one minor criterion, the molecular criterion, and exclusion criteria are fulfilled.
Major Criteria
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Periodic Occurrence ≥ 2 Flares
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Recurrent Fevers OR Dermatitis OR Both
Important Note: Fever does not have to be 100.4°F, low-grade temperature elevations should also be taken into account
Minor Criteria
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Oligo- or polyarthralgia/inflammatory arthritis, or distal extremity swelling
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Abdominal Pain OR Diarrhea OR Both
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Sicca-like Symptoms
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Pericarditis OR Pleuritis OR Both
Molecular Criteria
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NOD2 IVS8+158 or R702W or both, or other rare variants
Exclusion Criteria
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High titer antibodies
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Inflammatory Bowel Disease (eg. Crohn's), Blau Syndrome, Adult Scardosis, Primary Sjogren Syndrome, and Monogenic Autoinflammatory Diseases
Symptoms of Yao Syndrome
Periorbital Edema
Fever
Urticaria/Dermatitis
Fatigue
Oligo- or Polyarthralgias
Sicca-like Symptoms
Gastrointestinal Symptoms
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Distal Extremity Swelling
Lymphadenopathy
Cervical Lymph Nodes are most common
Other Symptoms can include, but are not limited to:
Facial Erythema, Malar Rash, Skin Biopsy (Spongiotic Dermatitis, Perivascular Lymphocytic Inflammation, Other Dermatitis), Oral Ulceration, Myalgia, Abdominal Pain, Abdominal Bloating, Diarrhea, Nausea, Vomiting, Constipation, Pericarditis, Pleurisy, Asthma, Dizziness (Dysautonomia - Orthostatic Intolerance, Postural Orthostatic Tachycardia Syndrome), Headaches, Nephrolithiasis, Leukocytosis, Anemia, Elevated CRP/ESR, Hearing Loss, Weight Loss, Proteinuria/Hematuria, Hypogammaglobulinemia, Night Sweats, Flushing, Livedo Reticularis, Gastrointestinal Dysmotility, etc
Related Health Issues
These are just a few of the commonly seen diagnoses among patients diagnosed with Yao Syndrome - this list is neither complete nor exhaustive.
Asthma
Immunodeficiency
Gastroparesis
Dysautonomia
Polycythemia
Mast cell activation Syndrome
Pericarditis
Connective tissue disorders
Kidney Stones
pancreatic and biliary disease
Pleurisy
Intercranial Hypertension
neuropathy
Hypertension
Differential Diagnosis
The differential diagnosis for autoinflammatory diseases in general is extensive. Listed below are a few common differentials for Yao Syndrome:
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Crohn's Disease
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Blau Syndrome
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Ulcerative Colitis
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Systemic Lupus Erythematosus
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Sarcoidosis
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Sjögren's Syndrome
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Rheumatoid Arthritis
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Persisting Infection
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Immunodeficiencies
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Malignancy
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Pre-malignant states
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Angioedema
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Urticaria
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Neoplastic Fever
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Psoriasis
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Uveitis
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Multi-system Inflammatory Syndrome
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Organ-specific Inflammatory Syndromes
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Cyclic Neutropenia
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Acute Intermittent Porphyria
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Primary Mast Cell Activation Syndrome
References
Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med. 2017 Mar;130(3):365.e13-365.e18.
Yao Q, Center of Autoinflammatory Diseases [Internet]. Stony Brook (NY): Renaissance School of Medicine, Stony Brook University; c2025 [cited 2025 Oct 28].
Williamson KA, Samec MJ, Patel JA, Orandi AB, Wang B, Crowson CS, Loftus EV Jr., Alavi A, Moyer AM and Davis JM III (2024)
Clinical phenotype, NOD2 genotypes, and treatment observations in Yao syndrome: a retrospective case series.
Front. Immunol. 15:1304792.
Damianos, John & Nehra, Avinash & Murray, Joseph & Loftus, Edward & Davis, John & Nehra, Vandana. (2025).
Gastrointestinal Manifestations of Yao Syndrome (NOD2-Associated Autoinflammatory Disease). Digestive Diseases and Sciences. 70. 3453-3464.
Verbsky JW.
When to Suspect Autoinflammatory/Recurrent Fever Syndromes. Pediatr Clin North Am. 2017 Feb;64(1):111-125.
doi: 10.1016/j.pcl.2016.08.008. PMID: 27894439.
Karamanakos A, Vougiouka O, Sapountzi E, Venetsanopoulou AI, Tektonidou MG, Germenis AE, Sfikakis PP and Laskari K (2024)
The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review.
Front. Immunol. 15:1342668.
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD.
MIM Number: #617321 Updated: 06/27/2023
Nomani H, Wu S, Saif A, Hwang F, Metzger J, Navetta-Modrov B, Gorevic PD, Aksentijevich I and Yao Q (2024)
Comprehensive clinical phenotype, genotype and therapy in Yao syndrome.
Front. Immunol. 15:1458118.
Zhang J, Huang X and Shen M (2024)
Expanding clinical characteristics and genotypic profiling of Yao syndrome in Chinese patients.
Front. Immunol. 15:1444542.
Natale, Marco & Celani, Camilla & Federici, Silvia & Passarelli, Chiara & Perrone, Chiara & Marasco, Emiliano & De Benedetti, Fabrizio & Insalaco, Antonella. (2025).
Genotype-phenotype correlation in a cohort of pediatric patients with autoinflammatory diseases carrying NOD2 variants.
Frontiers in Immunology. 16.
Davis JM III, McDonald C and Yao Q (2024) Editorial: Basic, clinical, and translational studies of Yao syndrome and other NOD2 related diseases.
Frontiers in Immunology, 15:1521815.
Rheumatology Advisor. (2022, November 13). Autoinflammatory disease. Rheumatology Advisor. https://www.rheumatologyadvisor.com/ddi/autoinflammatory-disease/
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