Deficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease (WOLD; 620151) and cholesteryl ester storage disease (CESD). WOLD is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. Death occurs early in life. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood (summary by Du et al., 2001).

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).

Congenital bile acid synthesis defect-3 (CBAS3) is an autosomal recessive disorder characterized by prolonged jaundice after birth, hepatomegaly, conjugated hyperbilirubinemia, elevations in characteristic abnormal bile acids, and progressive intrahepatic cholestasis with liver fibrosis (summary by Setchell et al., 1998 and Ueki et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see 607765.

Immunodeficiency-47 (IMD47) is an X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Some patients also have neurologic abnormalities (summary by Jansen et al., 2016).

Neonatal sclerosing cholangitis (NSC) is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (summary by Girard et al., 2016; Grammatikopoulos et al., 2016).

Infantile liver failure syndrome-3 is an autosomal recessive disorder characterized by recurrent episodes of acute liver failure during intercurrent febrile illness. Patients first present in infancy or early childhood, and there usually is complete recovery between episodes with conservative treatment. Affected individuals also have skeletal anomalies of the vertebral bodies and femoral heads (summary by Cousin et al., 2019). For a discussion of genetic heterogeneity of infantile liver failure syndrome, see ILFS1 (615438).

Progressive intrahepatic cholestasis-7 with or without hearing loss (PFIC7) is an autosomal recessive liver disorder characterized by infantile-onset jaundice and itching associated with cholestasis, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and normal gamma glutamyltransferase (GGT). Liver biopsy shows hepatocellular and canalicular cholestasis with fibrotic changes. Many patients have resolution of the liver abnormalities with age, although some may have persistent liver enzyme abnormalities or splenomegaly. A subset of patients develops hearing loss in childhood between early infancy and the teenage years. Rifampicin may be effective for pruritis (summary by Maddirevula et al., 2019). For a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600).

Progressive familial intrahepatic cholestasis-8 (PFIC8) is an autosomal recessive disorder characterized by cholestasis and high gamma-glutamyltransferase presenting in the infantile period (summary by Unlusoy Aksu et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600).

Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015). The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018).

Hepatorenocardiac degenerative fibrosis (HRCDF) is a primarily fibrotic disease affecting the liver, kidney, and heart, with considerable variability in disease onset and expression. Affected individuals develop degenerative hepatic fibrosis in childhood or early adulthood, with variable later onset of fibrocystic kidney disease and hypertrophic cardiomyopathy (Devane et al., 2022).