Isolated congenital asplenia (ICAS) is a rare cause of primary immunodeficiency. Most affected individuals die of severe bacterial infections in early childhood. Isolated asplenia is distinct from asplenia associated with other complex visceral defects, notably heterotaxy syndromes such as Ivemark syndrome (208530) (summary by Mahlaoui et al., 2011).

X-linked spinocerebellar ataxia-6 with or without sideroblastic anemia (SCAX6) is an X-linked recessive disorder characterized by delayed motor development apparent in infancy with delayed walking (often by several years) due to ataxia and poor coordination. Additional features may include dysmetria, dysarthria, spasticity of the lower limbs, hyperreflexia, dysdiadochokinesis, strabismus, and nystagmus. The disorder is slowly progressive, and patients often lose ambulation. Brain imaging usually shows cerebellar atrophy. Most affected individuals have mild hypochromic, microcytic sideroblastic anemia, which may be asymptomatic. Laboratory studies show increased free erythrocyte protoporphyrin (FEP) and ringed sideroblasts on bone marrow biopsy. Female carriers do not have neurologic abnormalities, but may have subtle findings on peripheral blood smear (Pagon et al., 1985; D'Hooghe et al., 2012). For a discussion of genetic heterogeneity of X-linked spinocerebellar ataxia (SCAX), see SCAX1 (302500).

Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).

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).