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. Electronic supplementary material The online version of this article (10.1186/s12881-019-0856-1) contains supplementary material, which is available to authorized users.
Systemic lupus erythematosus (SLE) is a chronic, rare autoimmune disease. In recent years, multiple monogenic diseases with early onset autoimmunity and lymphoproliferation have been identified, such as autoimmune lymphoproliferative syndrome, rat sarcoma (RAS)-associated autoimmune leukoproliferative disease, signal transducer and activator of transcription 3 gain-of-function syndrome and interleukin-2 receptor α deficiency. Therefore, we performed whole-exome sequencing in children with SLE with lymphoproliferation to identify genes associated with these conditions. We enrolled 7 patients with SLE with lymphoproliferation from different families. Demographic data, clinical manifestations, laboratory and histopathologic findings, treatment, and outcome were documented. Whole-exome sequencing was performed in 7 patients and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by western blot. Four patients were male, and 3 were female. No consanguinity was reported within the 7 families. The average age at onset was 5.0 years (range: 1.2–10.0 years). The most common features were renal (7/7 patients) and hematologic (6/7 patients) involvement and recurrent fever (6/7 patients), while only 2 patients presented with skin involvement. Antinuclear antibodies at a titer of ≥1:320 were positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from 4 patients, at levels ranging from 8.8% to 42.8% in variant tissues that were absent from their parents. B cell lymphoma (BCL)-2-interacting mediator of cell death levels in peripheral blood mononuclear cells from 4 patients were markedly reduced, whereas those in the control were normal. Another 2 mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in the PIK3CD gene were detected in 2 patients. The SLE is a novel phenotype of somatic mutations in the NRAS gene and germline mutations in the PI3CKD gene. These genes, NRAS, TNFAIP3, and PIK3CD, should be considered candidates for children with SLE with lymphoproliferation. If patients with SLE and lymphoproliferation present with renal and hematologic involvement and recurrent fever, they need gene testing, especially male patients.
Rationale: Gain of function (GOF) mutations in PIK3CD gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD 4 + lymphopenia, reduced class-switched memory B cells, lymphadenopathy, cytomegalovirus and/or epstein-Barr virus (EBV) viremia, and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Patient concerns: We report a patient who was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD . The patient not only presented with recurrent sinopulmonary infections, CD 4 + lymphopenia, lymphadenopathy, EBV viremia, and elevated serum IgM, but also met classification criteria of SLE based on persistent proteinuria and hematuria, leukopenia and anemia, low level of serum complement, and positive autoantibody for antinuclear antibodies. Diagnoses: Activated PI3Kδ syndrome. Interventions: Oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil was given to the patient. He was currently receiving intravenous immunoglobulin per month in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil. Outcomes: At present, the level of complement restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. Lessons: SLE may be a novel phenotype of GOF mutation in PI3CKD gene (GOF PIK3CD).
The HSP70-2 (+1267A/G) and TNF-α (+308G/A) gene polymorphisms were associated with HSP in children. The G/G homozygosity of HSP70-2 and the A/A homozygosity of TNF-α may be genetic predisposing factors for HSP.
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