IDEDNIK syndrome is characterized by enteropathy, poor weight gain, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations (photophobia, corneal scarring, and keratitis). Reduced serum ceruloplasmin and total copper levels are common. Some individuals have findings on brain MRI (cerebral atrophy, basal ganglia abnormalities, and thin corpus callosum). Death prior to age two years occurs in some individuals due to severe enteropathy or sepsis; in others survival into adulthood is reported.

MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by: Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.

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.

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.\n\nIn 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.\n\nThere 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.\n\nMost 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.\n\nSigns 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).\n\nProgressive 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.

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.

Any congenital bile acid synthesis defect in which the cause of the disease is a mutation in the ABCD3 gene.

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.

Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).

Familial hypercholanemia-1 (FHCA1) is an autosomal recessive disorder characterized by elevated concentrations of bile acids (usually conjugated), itching, and fat malabsorption, leading to poor overall growth and deficiencies of fat-soluble vitamins. Vitamin D deficiency results in rickets, and vitamin K deficiency results in a coagulopathy (Morton et al., 2000; Shneider et al., 1997; summary by Carlton et al., 2003). Genetic Heterogeneity of FHCA See FHCA2 (619256), caused by mutation in the SLC10A1 gene (182396) on chromosome 14q24, and FCHA3 (619232), caused by mutation in the BAAT gene (602938) on chromosome 9q31. Other disorders that may have hypercholanemia as a feature include THNS (618268), caused by mutation in the CCDC47 gene (618260) on chromosome 17q23, and NEDFHCA (621016), caused by mutation in the WDR83OS gene (618474) on chromosome 19p13.

Familial hypercholanemia-2 (FHCA2) is an autosomal recessive inborn error of metabolism characterized by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT) (summary by Deng et al., 2016 and Liu et al., 2017). For a discussion of genetic heterogeneity of FHCA, see FHCA1 (607748).

Osteootohepatoenteric syndrome (OOHE) is characterized by a variable combination of bone fragility, hearing loss, cholestasis, and congenital diarrhea. Some patients also display mild developmental delay and intellectual disability (Esteve et al., 2018).

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).

Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis (NEDMSC) is an autosomal recessive disorder characterized by severely impaired global development apparent from infancy, progressive microcephaly, and neonatal cholestasis manifest as jaundice and elevated liver enzymes. The liver disease resolves, but affected individuals show feeding difficulties, failure to thrive, hypotonia, seizures, hyperkinetic movements, irritability, and poor eye contact or vision, and achieve almost no motor or cognitive developmental milestones. Brain imaging demonstrates agenesis or hypoplasia of the corpus callosum. Death in early childhood may occur (summary by Schneeberger et al., 2021).

Progressive familial intrahepatic cholestasis-10 (PFIC10) is an autosomal recessive liver disorder characterized by the onset of symptoms in the first months or years of life. Features include jaundice, pruritis, and hepatomegaly associated with increased serum bilirubin and bile acids. Liver transaminases may be variably increased, but gamma-glutamyltransferase (GGT; see 612346) is normal. Liver biopsy shows hepatocellular and canalicular cholestasis with giant cell changes. Although rare patients may have episodes of diarrhea and even show endoscopic features of microvillus inclusion disease (MVID), this tends to be transient and cholestasis dominates the clinical picture (Gonzales et al., 2017; Cockar et al., 2020). For a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600).

Progressive familial intrahepatic cholestasis-12 (PFIC12) is characterized by neonatal-onset jaundice and conjugated hyperbilirubinemia, associated with intense pruritus. Transaminases are mildly elevated but GGT (see 612346) is normal. Hepatosplenomegaly and mildly prolonged activated partial thromboplastin time (APTT) have been observed in some patients (Qiu et al., 2019).