Oct

A20 Haploinsufficiency and 6q23 Deletion

chromosome 6q23

A20 haploinsufficiency is an auto inflammatory disease with involvement of multiple organs¹. This condition is caused by defective function of the TNFAIP3 gene, located at the long arm of chromosome 6 (6q23). Although most cases of A20 haploinsufficiency are caused by mutations of this gene, significant part of patients have deletions of the 6q23 segment, involving this gene.

The autoinflammatory features that are commonly seen in individuals with A20 haploinsufficiency may vary but commonly resemble features of Beçhet’s disease or other autoimmune symptoms similar to lupus erythematosus or correlated with allergy associated features². Autoinflammation may manifest as early as infancy. Common clinical symptoms include recurrent fever, bipolar aphthosis (genital and oral), gastrointestinal aphthosis, skin eruption, or musculoskeletal damage¹. Gastrointestinal concerns may manifest as abdominal pain, diarrhea, or blood in the stool¹.

In addition to autoinflammation, 30% of individuals with A20 haploinsufficiency also develop some autoimmune disease¹. These conditions may include Hashimoto’s thyroiditis, systemic lupus, or arthritis. Less commonly, patients may present with pneumonia or other neuroinflammatory or hematological malignancies like Hodgkin’s lymphoma¹.

6q23 deletions may also cause individuals to have an enlarged liver or spleen as well as atypical blood analyses². This includes an elevated white blood cell count, elevated platelets, anemia, and elevated inflammatory markers^1,2.

There have been some documented relationships between an individual’s clinical presentation and their ancestry. For example, individuals of East Asian descent tend to more commonly present with periodic fever syndromes of an unknown etiology but have lower incidences of autoimmune disease compared to other ethnic groups. Mediterranean and European populations, however, tend to present with a Beçhet’s disease-like symptomology¹. Other relationships have also been described between an individual’s symptoms and their genetic cause of A20 haploinsufficiency. For those with large deletions including the 6q23 region, unprovoked, recurrent fever episodes are the most common symptom². This is in contrast to other symptoms such as recurrent stomatitis².

REFERENCES

¹Xue F, An C, Lei Z, et al. (2025). Clinical features and genetic analysis of A20 haploinsufficiency. Orphanet J Rare Dis. 20(1):457.

²Zhang F, Zhang L. (2024). A20 haploinsufficiency in a neonate caused by a large deletion on chromosome 6q. Pediatr Rheumatol Online J. 22(1):12