Expanding the spectrum of A20 haploinsufficiency in two Chinese families: cases report

Abstract

Background: The association between mutations in the TNFAIP3 gene and a new autoinflammatory disease (called A20 haploinsufficiency, HA20) has recently been recognized. Here, we describe four patients with HA20 from two unrelated Chinese families.

Case presentation: A total of four patients from two families were included. The average age at onset was 5.9 years. All patients had no signs of eye or skin problems, such as uveitis, rash, folliculitis and dermal abscess. Prior to the recognition of HA20, P1 was diagnosed with SLE, liver fibrosis and hypothyroidism. She also had no oral, genital or perineal ulcers. P2 was diagnosed with Crohn's disease and inflammatory bowel disease-related arthritis (IBD-RA). He had a perianal abscess but no oral or genital ulcers. P3, the father of P1 and P2, only had mild oral ulcers, arthralgia, and archosyrinx. P4 was diagnosed with polyarticular juvenile idiopathic arthritis (JIA), macrophage activation syndrome (MAS) and interstitial lung disease (ILD). Whole exome sequencing (WES) was performed in two families. WES revealed heterozygous c.559C > T in the TNFAIP3 gene in P1, P2 and P3, while the c.259C > T mutation in the TNFAIP3 gene was identified in P4. The c.259C > T mutations is novel.

Conclusion: HA20 had a different phenotype between families and even between family members with the same mutation. Liver fibrosis, hypothyroidism, ILD and MAS in the patients with HA20 were first reported in this study. Our results expanded the phenotype and genotype spectrum of A20 haploinsufficiency.

Keywords: A20 haploinsufficiency; Hypothyroidism; Interstitial lung disease; Liver fibrosis; Macrophage activation syndrome; TNFAIP3 gene.

Fig. 1

Spectrum of family 1 and family 2

Fig. 2

a Abdominal contrast-enhanced MRI revealed hepatomegaly and hepatic fibrosis in P1. b Liver biopsy showed hepatic fibrosis by HE and Masson stain (× 200) in P1. c Renal biopsy showed lupus nephritis type III under light (× 400), electron (× 11600) and Immunofluorescence (× 400) microscopy in P1. d Contrast-enhanced MRI revealed chronic synovitis of the knee joint in P2. e Contrast-enhanced MRI revealed chronic synovitis of the knee joint in P3. f Lung CT scan showed interstitial lung disease (ILD) in P3

Fig. 3

Mutation analysis in TNFAIP3 gene in family 1 and family 2. P: patient; F: father; M: mother; GF: grandfather; GM: grandfather