Immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90) is a autosomal recessive complex immunologic disorder with systemic manifestations in addition to primary immunodeficiency. Affected individuals usually present in infancy or early childhood with recurrent fevers and bacterial or viral infections associated with central nervous system symptoms, including irritability, drowsiness, variable seizures, and white matter abnormalities on brain imaging. There is also liver involvement and functional hyposplenism, causing increased susceptibility to invasive pneumococcal infection, which may be fatal. Susceptibility to viral infections likely results from impaired interferon immunity, and bacterial infections likely result from splenic dysfunction. A subset of patients have congenital cardiac malformations. Most individuals demonstrate developmental delay and speech delay. Laboratory findings in affected individuals are similar to those seen in autoimmune lymphoproliferative syndrome (ALPS; 601859), including high-circulating CD4-/CD8-/TCR-alpha-beta+ (double-negative) T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6; 134638) levels, but the clinical features are somewhat different from ALPS: massive lymphadenopathy and autoimmune features are not observed in IMD90 (summary by Bolze et al., 2010, Savic et al., 2015 and Kohn et al., 2020).

Infantile-onset multisystem autoimmune disease-3 (ADMIO3) is an autosomal recessive disorder of immune dysregulation characterized by the onset of various systemic autoimmune manifestations in the first months or years of life. Features may include hypothyroidism, type 1 diabetes mellitus, systemic inflammatory manifestations (fever, hepatomegaly), and autoimmune cytopenias. Laboratory studies show normal levels of T, B, and NK cells, but CD4+ (see 186940) T cells demonstrate hyperproliferation when stimulated in vitro (Janssen et al., 2022). For a discussion of genetic heterogeneity of ADMIO, see ADMIO1 (615952).

Proteasome-associated autoinflammatory syndrome-6 (PRAAS6) is characterized by a proteasome-associated autoinflammatory syndrome with immunodeficiency (Kanazawa et al., 2021).