Yao-syndrome M35.-

Yao Q et al. (2011)

Yao syndrome, formerly called NOD2-associated autoinflammatory disease, is a polygenic autoinflammatory disease characterized by periodic fever, dermatitis, arthritis and swelling of the distal extremities as well as gastrointestinal and sicca-like symptoms (Khalid A et al. 2024). See also under Autoinflammatory syndromes.

The estimated prevalence of the disease is 1-10/100,000, with women and the white adult population predominating (Khalid A et al. 2024).

The disease has recently been classified as a genetic transition disease (GTD) and is associated with NOD2 variants located at multiple NOD2 gene loci. The most frequently detected gene variant is the homozygous IVS8+158, followed by the compound heterozygous IVS8+158 and R702W. NOD2 stands for: Nucleotide-binding oligomerization domain-containing protein 2), also known as NLRC2 gene or CARD15 gene, is a protein-coding gene located on chromosome 16p12-q21. The NOD2 gene codes for the protein receptor of the same name NOD2, a cytoplasmic recognition receptor (PPR). NOD2, together with other PPRs, organizes natural and acquired immunity by recognizing bacterial components of microbial (highly conserved) polypeptide glycans, which form the basic scaffold of the bacterial cell wall. The protein encoded by the NOD2 gene belongs to the family of NOD-like receptors (NLR). These are cytoplasmic (non-membrane-bound) protein receptors that mainly recognize bacterial lipopolysaccharides and peptidoglycans. Like Toll-like receptors, NOD-like receptors belong to the large group of pathogen recognition receptors (PPR). NOD-like receptors represent an important component of innate immunity.

In people with Yao syndrome, part of the immune system, known as the innate immune response, is abnormally activated, leading to fever and inflammation-related damage to tissues and organs. Because of this process, Yao syndrome is classified as an autoinflammatory disease.

The average age at the onset of the disease is between 36 and 42 years. The average age at diagnosis of the disease is between 40 and 45 years, although the duration of the disease varies.

Clinically, Yao syndrome is characterized by unmotivated episodes of fever and abnormal inflammation affecting many parts of the body, especially the skin, joints and gastrointestinal system. The episodes of fever and inflammation associated with Yao syndrome can last for several days and occur weeks to months apart. During these episodes, most patients (>90%) develop erythematous patches or plaques. The skin changes, redness, most commonly occur on the face, chest and back, but can also affect the arms and legs.

Arthritis is common, especially in the legs, as is lymphoedema of the ankles and feet. The inflammatory symptoms also affect the gastrointestinal tract (>70%) and cause attacks of abdominal pain, bloating and cramps with diarrhea in more than half of those affected. Sicca symptoms (>50%) affect the mucous membranes of the eyes and mouth and are observed in around half of those affected. Other possible signs and symptoms of Yao syndrome are aphthous erosions of the oral mucosa, lymphadenopathies and chest pain.

Increased acute phase reactions, anemia, leukocytosis, positive ANA.

Neutrophilic dermatitis and panniculitis (Bujan Bonino C et al. 2024)

Eosinophilic cellulitis (Wells syndrome)

Blue syndrome

Familial Mediterranean fever

Arthritic symptoms in Yao patients respond favorably to sulfasalazine and glucocorticoids, while non-steroidal anti-inflammatory drugs and colchicine elicit only a minimal response. Anti-IL1 and anti-IL6 agents(canakinumab, anakinra and tocilizumab) are effective treatments.

A long-lasting, relapsing course of the disease is characteristic.

1. Bujan Bonito C eretz al. (2020) Yao syndrome: clinical observations of a non-paradogmatic autoinflammatory disease. JDDG 22: 847-949

2. Esse I et al (2023) Yao syndrome: cyclical folliculitis, fevers, and abdominal pain. JAAD Case Rep 35:71-73.

3. Khalid A et al. (2024) Yao Syndrome: An Overview of Genotypic Associations, Clinical Manifestations, Diagnosis, and Treatment. Int Arch Allergy Immunol 13:1-13.
4. Shakhashiro M et al. (2024) , Yao syndrome: a novel systemic autoinflammatory disease with cutaneous manifestations. Int J Dermatol 2024. doi: 10.1111/ijd.17350.
5. Schils J et al. (2013) Distal lower extremity swelling as a prominent phenotype of NOD2-associated autoinflammatory disease. Rheumatology 52:2095-2097.
6. Yao Q et al. (2011) A New category of autoinflammatory disease associated with NOD2 gene mutations.Arthritsi Res Ther 13: R148
7. Yao Q et al. (2014) NOD2-associated autoinflammatory disease: an exploratory study of its pathogenesis. Rheumatology 53:958-960.
8. Yao Q et al. (2016) Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. Semin Arthritis Rheum 45:633-637.