Pseudo-TORCH syndrome-2 (PTORCH2) is an autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway (summary by Meuwissen et al., 2016). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).

Primordial dwarfism-immunodeficiency-lipodystrophy syndrome (PDIL) is characterized by pre- and postnatal growth restriction, with extreme microcephaly, short stature, and absence of subcutaneous fat. There is also significant hematologic/immune dysfunction, with hypo- or agammaglobulinemia, as well as lymphopenia, anemia, and thrombocytopenia, and most affected individuals succumb to infection in early childhood (Parry et al., 2020).

X-linked multisystem autoinflammatory disease with immune dysregulation (ADMIDX) is an X-linked recessive disorder with onset of symptoms in infancy or early childhood. Affected individuals may present with variable cytopenias, including anemia, thrombocytopenia, neutropenia, lymphopenia, or hypogammaglobulinemia, and systemic or organ-specific autoinflammatory manifestations. These include skin lesions, panniculitis, inflammatory bowel disease, pulmonary disease, or arthritis associated with recurrent fever, leukocytosis, lymphoproliferation, and hepatosplenomegaly in the absence of an infectious agent. Some patients have circulating autoantibodies that underlie the cytopenias or systemic features, whereas others do not have circulating autoantibodies. In addition, some patients have recurrent infections, whereas others do not show signs of an immunodeficiency. Laboratory studies are consistent with immune dysregulation, including altered B-cell subsets and variably elevated proinflammatory cytokines. Detailed functional studies of platelets, red cells, and T lymphocytes suggest that abnormal actin cytoskeleton remodeling is a basic defect, indicating that this disorder can be classified as an immune-related actinopathy. Severe complications of the disease may result in death in childhood (Boussard et al., 2023; Block et al., 2023).