Immunodeficiency 57 with AutoinflammationD81.4

Cuchet-Lourenco D et al (2018).

Immunodeficiency 57 with autoinflammation, or IMD57, is a rare (<20 patients have been described) autoinflammatory immunodeficiency syndrome (see also Immunodeficiencies primary in immunodysregulations) associated with a homozygous mutation in the RIPK1 gene (603453) on chromosome 6p25.

In 4 patients from 3 unrelated consanguineous families with IMD57 identified by Cuchet-Lourenco et al (2018), homozygous loss-of-function (LOF) mutations were detectable in the RIPK1 gene (603453.0001-603453.0003). RIPK1 protein is absent in patient cells. Functional studies in patient cells revealed impaired mitogen-activated protein kinase activation, impaired phosphorylation of downstream signaling molecules, impaired proinflammatory signaling to TNFR1 (191190) and TLR3 (603029), and impaired secretion of certain cytokines. The results are consistent with dysregulation of T cell responses. The patients' cells were also prone to necroptosis.

A heterozygous mutation in the RIPK1 gene causes AIEFL syndrome an autoinflammation with episodic fever and lymphadenopathy (OMIM: 618852).

Cuchet-Lourenco et al (2018) reported on 4 patients from three unrelated consanguineous families of Middle Eastern descent with primary immunodeficiency. Patients presented with recurrent infections in the first year of life, including bacterial, viral, and fungal infections. Features included diarrhea, vomiting, hepatosplenomegaly, oral mucosal aphthae, perianal abscesses, chronic lung disease with bronchiectasis, and failure to thrive. Three patients developed gastritis and features of inflammatory bowel disease in infancy, while the fourth patient developed inflammatory bowel disease at age 4 years.

Biopsies of the gastrointestinal tract showed chronic active inflammation, ulceration, and crypt abscesses. All patients also developed inflammatory polyarthritis. One case presented with exanthema underlying lymphocytic vasculitis. Infections by cytomegalovirus, Mycobacterium avium intracellulare, Pseudomonas aeruginosa, respiratory syncytial virus, herpes simplex, Aspergillus, and Candida were detected. Laboratory studies showed variable T-cell lymphopenia in all patients, decreased numbers of NK cells in 3 patients, and decreased numbers of B cells with variable hypogammaglobulinemia in 2 patients. The proliferative response of T cells and neutrophil oxidative burst activity were normal.

Therapeutically, 3 patients underwent hematopoietic stem cell transplantation. 2 patients died at the ages of 12 and 13 years in the weeks after transplantation. The third patient was considered cured 5 years after transplantation. The fourth patient (P4), who did not undergo stem cell transplantation, was treated with IVIG and survived to date. In one family, three siblings had died of profuse bloody diarrhea between 6 and 12 months of age.

1. Cuchet-Lourenco D et al. (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361: 810-813.
2. Lalaoui N et al (2020) Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577(7788):103-108.