NFKB1-associated sterile familial autoinflammatoriy necrotizing Fasciitis M72.6

NFKB1-associated sterile familial autoinflammatory necrotizing fasciitis (FANF) is a rare (limited to a few cases worldwide) autoinflammatory systemic disease associated with an LOF mutation R157X in the NFKB1 gene (Bergbreiter A et al.2021). Fasciitis usually develops after banal (minor) surgical procedures. Santaniemi W et al. (2023) reported on a family with recurrent necrotizing fasciitis associated with the heterozygous NFKB1 p.R157X variant. In these cases, the fasciitis also developed after banal surgical procedures.

The NFKB1 LOF variants may be associated with different clinical and immunological manifestations. It can be assumed that the LOF variant of NFKB1 p.R157X selectively interferes with immediate events such as subunit phosphorylation, protein-protein interactions, protein-lipid interactions or properties of energy metabolism (Paclet M-H et al. 2022).

Several patients were described who suffered from localized, recurrent, sterile, necrotizing inflammation following banal tissue trauma (e.g. after a minor surgical procedure) that spread to the muscle fascia (clinical picture of necrotizing fasciitis). The patients were not previously known to have any other organ or systemic involvement or any obvious manifestations of immunodeficiency (Kaustio M et al. 2017). Analogous constellations with the development of pyoderma gangraenosum were reported by Fang R et al. (2021) and Sun Q et al. (2021).

The microbiological cultures taken during the fasciitis episodes are generally negative; the CRP values are high, with exceptionally high neutrophilic leukocytosis.

The LOF mutation R157X in the NFKB1 gene causes increased inflammasome activation in vitro. Antibiotics are ineffective. Patients benefit from systemic corticosteroids and IL-1 receptor antagonists (e.g. anakinra).

Remarkably, elevated inflammatory cytokine levels are found not only in the index patients, but also in asymptomatic NFKB1 p.R157X mutation carriers in the family.

1. Bergbreiter A et al.(2021) Recurrent necrotizing cellulitis, multi-organ autoimmune disease and humoral immunodeficiency due to a novel NFKB1 frameshift mutation. Eur J Med Genet64:104144.
2. Fang R et al. (2021) Case report: a novel mutation in associated with pyoderma gangrenosum. Front Genet 12:673453.
3. Figueras-Nart I et al. (2019) Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases. Front Immunol 10:2448.
4. Kaustio M et al. (2019) Primary immunodeficiency, a possible cause of neutrophilic necrotizing dermatosis. JAMA Dermatol. 155:863-864.
5. Kaustio M et al. (2017) Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J Allergy Clin Immunol140:782-786
6. Paclet M-H et al. (2022) Regulation of neutrophil NADPH oxidase, NOX2: a crucial effector in neutrophil phenotype and function. Front Cell Dev Biol 10:945749.
7. Santaniemi W et al. (2023) Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis. J Clin Immunol 43:1007-1018.
8. Sun Q et al. (2021) A novel NFkB1 mutation linking pyoderma gangrenosum and common variable immunodeficiency. JAAD Case Reports 18:61-63.