Five children with haploinsufficiency of A20 caused by heterozygous mutations in the TNFAIP3 gene

Objectives Children with A20 haploinsufficiency, resulting from heterozygous variants in the TNFAIP3 gene, are increasingly being identified. However, their diagnosis and treatment remain challenging and are not yet fully optimized. The clinical, genetic characteristics and treatment methods of five children with HA20 from different families were collected from Henan Children’s Hospital between April 2019 and August 2023 to evaluated for accumulating experience in the management of this rare condition. Results We identified five heterozygous variants in the TNFAIP3 gene among the five children, including c.866delA: p.H289Pfs* 3, c.1243_1247delAAAAC: p. N416Tfs* 11, NC_000006.11: g.136693638_138817508del, c.133C>T: p.R45X, c.1903_1906delAAAC: p. K635fs* 61. All patients were de novo (they have all been tested to confirm their origin). Besides, patient 3 also harbored two MMACHC gene mutations: c.349G>C: p.A117P-–inherited from the parents and c.482G>A: p.R161Q -– de novo . Variants in patients 3 and 5 have not been reported. All five patients presented with childhood-onset recurrent fever and intermittent diarrhea, which are hallmark features of HA20. Additionally, two of the five patients experienced intermittent bloody stool, three had oral ulcers, and two presented with skin symptoms, further aligning with the clinical manifestations of HA20. Laboratory tests revealed elevated inflammatory markers, including increased white blood cell (WBC) counts, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Endoscopic observation, there were ulcers in different parts of the intestine. Each child was treated with the oral drug thalidomide, 4 children (80%) received glucocorticoids to reduce inflammation, and had different biological agents according to individual differences. During follow-up, we observed significant improvement in all children who received targeted treatment. Conclusions HA20 is a rare monogenic early-onset auto-inflammatory disease. It can present with a variety of clinical manifestations, including Behcet disease, inflammatory bowel disease, lupus-like syndrome and periodic fever syndrome. Whole-exome sequencing should be actively considered for children who present with early-onset symptoms or features suggestive of autoimmune diseases.