Background and Aims

Autoinflammatory diseases are a heterogeneous group of disorders caused by dysregulation in the innate immune system. The protein A20, encoded by TNFAIP3, is involved in the negative regulation of nuclear factor-κB signaling. In 2016, heterozygous mutations in the TNFAIP3 gene have been found to cause A20 haploinsufficiency, presented as an early-onset systemic inflammation that resembles Behçet’s disease.

Methods

We presented an 8-year-old boy referred to our hospital at the age of 4 with history of recurrent pain in lower limbs. He developed recurrent oral and genital aphthae, conjunctivitis and headache. He also suffered self-limited fever, abdominal pain, diarrhea and arthralgia. The patient responded poorly to colchicine requiring methotrexate. Laboratory analysis revealed high serum level of IgE (800 UI/mL) and normal IgG, IgA and IgM levels. Tests for autoantibodies and HLA-B51 were negative. The family history showed 3 patients with recurrent oral ulcer and similar symptoms, members over 3 generations in the same family (his sister, mother and grandmother).

Results

Mutation analysis of TNFAIP3 revealed the novel monoallelic (p.W356R) variant and in silico studies predicted a deleterious effect on protein function. No mutations were found in MEFV, MVK and TNFRSF1A genes. The variant is segregated in the family members with the autoinflammatory disease. After genetic diagnosis he began treatment with adalimumab with considerable clinical improvement.

Conclusions

Discovery of new monogenetic autoinflamatory diseases such as A20 haploinsufficiency helps to advance our understanding of disease pathogenesis and to develop targeted therapies for them.

Background and Aims

Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by low counts of neutrophils in peripheral blood. Several genes are responsible for SCN and genotype-phenotype correlation has been established in most of them.

Methods

We reported a 2-year-old boy with chronic neutropenia who presented at the age of two weeks with anal abscesses. Immunological analysis showed normal lymphocyte subpopulations and immunoglobulins levels. Tests for autoantibodies and the neutrophil oxidative burst were normal.

Custom Next-Generation Sequencing (NGS) panel of 10 gens associated with SCN was performed.

Results

NGS revealed two monoallelic variants of uncertain clinical significance in two different candidate genes: p.Val57Met and p.Phe338Leu in JAGN1 and SLC37A4, respectively. Both variants have low allele frequency (<0.001) and in silico tools predicted a deleterious effect on protein function.

Conclusions

Due to advances in genetic testing through NGS, the knowledge about the relationship between genes and diseases and the evidence for digenic inheritance has increased in recent years. However, the genetic basis of neutropenia remains unknown in a substantial proportion of children. Here, we described a patient with chronic neutropenia and carrier of two potentially pathogenic monoallelic variants in two candidate genes. SCN is considered a monogenic disease however, a recent study suggests that an additional variant in a second causal gene could produce an impact on clinical phenotype. These data prompt us to hypothesize that the combination of these variants could produce a synergistic effect causing chronic neutropenia. Future studies are needed to explore the synergic effect of monoallelic variants in different SCN related genes.