A number sign (#) is used with this entry because of evidence that X-linked systemic autoinflammatory disease (SAIDX) is caused by hemizygous or heterozygous mutation in the IKBKG gene (300248) on chromosome Xq28.

X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature (de Jesus et al., 2020 and Lee et al., 2022).

De Jesus et al. (2020) reported 3 unrelated boys (P1-P3) and a girl (P4) with an autoinflammatory disease characterized by panniculitis, progressive B-cell lymphopenia, and hepatosplenomegaly. More variable features included chorioretinitis, granulomatous uveitis, and granulomatous hepatitis. The girl also had anemia, myositis, lipodystrophy, and basal ganglia calcifications. The 3 boys had hypogammaglobulinemia, whereas the girl had normal IgG and IgM with elevated IgA. P1 had conical incisors. None had major infections. The patients were ascertained from a cohort of individuals with a moderately elevated type I interferon signature.

Lee et al. (2022) reported 3 unrelated boys, ranging from 3 to 9 years of age, who presented with a systemic autoinflammatory disease in the first months of life. The clinical manifestations were variable. P1 developed fever, lymphoid organ hyperplasia, hepatosplenomegaly, lymphadenopathy, and panniculitis. Laboratory studies showed leukocytosis with elevated markers of systemic inflammation, and hypogammaglobulinemia. Although these features occurred 10 days after BCG inoculation, tests for persistent mycobacterial infection were negative and no infectious agents were identified. Other features included painful inflammatory bone lesions, chorioretinitis with inflammation of the optic nerve, an intracranial hemorrhagic infarct, and conical incisors. P2 had persistent fever, nodular skin rash, neutrophilic panniculitis, hepatosplenomegaly, lipodystrophy, lymphadenopathy, immune-mediated anemia and thrombocytopenia, hypogammaglobulinemia, and persistently elevated serum inflammatory markers. Other features included subdural hemorrhage and optic nerve edema. P3 had an inflammatory nodular erythematous rash, joint swelling and stiffness, hepatosplenomegaly, elevated white blood cell count, hypogammaglobulinemia, and periodic fevers. Other features included a subdural hemorrhage at 4 months of age with diffuse superficial cortical gray matter atrophy on follow-up imaging, anterior uveitis, and lipodystrophy. He later developed lymphopenia and neutropenia.

The heterozygous mutations in the IKBKG gene that were identified in patients with SAIDX by de Jesus et al. (2020) and Lee et al. (2022) occurred de novo.

In 3 unrelated boys (P1-P3) and a girl (P4) with SAIDX, de Jesus et al. (2020) identified de novo hemizygous or heterozygous mutations in the IKBKG gene, all of which were predicted to disrupt splicing and result in the deletion of exon 5 (300248.0033-300248.0036). Functional studies of the variants were not performed. The patients were ascertained from a cohort of patients with autoinflammatory disease and a moderately elevated type I interferon signature.

In 3 unrelated boys with SAIDX, Lee et al. (2022) identified de novo hemizygous mutations in the IKBKG gene (300248.0033-300248.0035). The mutations, which were confirmed by Sanger sequencing, all led to overexpression of a NEMO protein lacking the domain encoded by exon 5 (NEMOdelEx5). In vitro studies showed that this splice isoform failed to associate with TANK binding kinase-1 (TBK1; 604834). Dermal fibroblasts from affected patients activated NFKB (see 164011) in response to TNF (191160), but showed impaired NFKB activation to TLR3 (603029) or RIGI-like receptor (RLR) stimulation with poly(I:C) positively correlated with levels of the NEMOdelEx5 splice isoform. By contrast, T cells, monocytes, and macrophages that expressed the splice site variant exhibited increased NFKB activation and IFN production. Blood cells from these patients expressed a strong IFN and NFKB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi; 605048) that was stabilized by the splice variant, promoting type I IFN induction and antiviral responses. These data showed that IKBKG mutations that lead to alternative splicing of skipping exon 5 cause an autoinflammatory disorder, which the authors termed 'NEMO deleted exon 5 autoinflammatory syndrome (NDAS),' noting that it is distinct from the immunodeficiency syndrome resulting from loss-of-function IKBKG mutations.