MedGen

Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. NICCD. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances. FTTDCD. Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2. CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD. [from GeneReviews]

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]

Congenital disorder of glycosylation type It (CDG1T) is an autosomal recessive disorder characterized by a wide range of clinical manifestations and severity. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism (summary by Tegtmeyer et al., 2014). For a discussion of the classification of CDGs, see CDG1A (212065). [from OMIM]

Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported. [from GeneReviews]

Johanson-Blizzard syndrome is an autosomal recessive disorder characterized by poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency (summary by Al-Dosari et al., 2008). [from OMIM]

Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (Berry et al., 1995; Fellers et al., 1967; Manz et al., 1987; Odievre, 1966). Use of the term glycogenosis type XI introduced by Hug (1987) is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport. [from OMIM]

The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.

Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.

In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.

There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.

Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).

Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals. [from MedlinePlus Genetics]

Congenital bile acid synthesis defect type 4 (BAS defect type 4) is an anomaly of bile acid synthesis (see this term) characterized by mild cholestatic liver disease, fat malabsorption and/or neurological disease. [from ORDO]

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. [from OMIM]

Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group K (CGK) have mutations in the PEX14 gene. For information on the history of PBD complementation groups, see 214100. [from OMIM]

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]

Congenital bile acid synthesis defect type 2 is a disorder characterized by cholestasis, a condition that impairs the production and release of a digestive fluid called bile from liver cells. Bile is used during digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D, E, and K. People with congenital bile acid synthesis defect type 2 cannot produce (synthesize) bile acids, which are a component of bile that stimulate bile flow and help it absorb fats and fat-soluble vitamins. As a result, an abnormal form of bile is produced.

The signs and symptoms of congenital bile acid synthesis defect type 2 often develop in infancy. Affected infants usually have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. Excess fat in the feces (steatorrhea) is another feature of congenital bile acid synthesis defect type 2. As the condition progresses, affected individuals can develop liver abnormalities including inflammation or chronic liver disease (cirrhosis). Some individuals with congenital bile acid synthesis defect type 2 cannot absorb certain fat-soluble vitamins, which can result in softening and weakening of the bones (rickets) or problems with blood clotting that lead to prolonged bleeding.

If left untreated, congenital bile acid synthesis defect type 2 typically leads to cirrhosis and death in childhood. [from MedlinePlus Genetics]

Congenital defects of bile acid synthesis are autosomal recessive disorders characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract resulting from a primary failure to synthesize bile acids. Affected infants show failure to thrive and secondary coagulopathy. In most forms of the disorder, there is a favorable response to oral bile acid therapy (summary by Cheng et al., 2003). Genetic Heterogeneity of Congenital Defects in Bile Acid Synthesis There are several disorders that result from defects in bile acid synthesis. See CBAS2 (235555), caused by mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1; 604741) on chromosome 7q33; CBAS3 (613812), caused by mutation in the 7-alpha hydroxylase gene (CYP7B1; 603711) on chromosome 8q12; CBAS4 (214950), caused by mutation in the AMACR gene (604489) on chromosome 5p13; CBAS5 (616278), caused by mutation in the ABCD3 gene (170995) on chromosome 1p21; and CBAS6 (617308), caused by mutation in the ACOX2 gene (601641) on chromosome 3p14. See also progressive familial intrahepatic cholestasis (PFIC1; 211600), which has a similar phenotype. [from OMIM]

Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (summary by Pasmant et al., 2012). Mutation in the ABCB4 gene accounts for about 15% of ICP cases (summary by Ziol et al., 2008). For a discussion of genetic heterogeneity of ICP, see ICP1 (147480). [from OMIM]

Lathosterolosis (LATHOS) is an autosomal recessive disorder characterized by a recognizable pattern of multiple congenital anomalies involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. It is caused by a defect of cholesterol biosynthesis due to sterol C5-desaturase deficiency (summary by Rossi et al., 2007). [from OMIM]

Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Some women with ICP may also be susceptible to oral contraceptive-induced cholestasis (OCIC) (summary by Pasmant et al., 2012). Genetic Heterogeneity of Intrahepatic Cholestasis of Pregnancy See also ICP3 (614972), caused by mutation in the ABCB4 gene (171060). [from OMIM]

Disease with characteristics of early childhood onset of severe progressive liver disease. Caused by homozygous or compound heterozygous mutation in the TJP2 gene on chromosome 9q21. [from SNOMEDCT_US]

GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by Kopajtich et al., 2016). [from OMIM]

Progressive familial intrahepatic cholestasis-9 (PFIC9) is an autosomal recessive disorder characterized by onset of cholestasis associated with increased serum gamma-glutamyltransferase (GGT) in infancy or early childhood. Affected individuals have hepatosplenomegaly and may have portal hypertension or upper gastrointestinal bleeding. Liver biopsy shows fibrosis, cirrhosis, bile duct proliferation, and abnormal bile duct morphology. The disorder is thought to result from ciliary defects in cholangiocytes, consistent with a ciliopathy that appears to be restricted to the liver. Treatment with ursodeoxycholic acid (UDCA) or liver transplant is effective (Luan et al., 2021). For a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600). [from OMIM]

Progressive familial intrahepatic cholestasis-6 (PFIC6) is an autosomal recessive disorder characterized by elevated liver transaminases, cholestasis, and congenital diarrhea (Gao et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600). [from OMIM]