Alagille syndrome is a
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
that affects primarily the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
and the
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician
Daniel Alagille, who first described the condition in 1969.
Signs and symptoms
The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed, to severe heart and/or liver disease that requires
transplantation.
It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%. The majority of deaths from ALGS are typically due to heart complications or chronic liver failure.
Liver
Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different de ...
and the whites of the eyes (
jaundice), itching (
pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
), pale stools (
acholia
Acholia is pallor of the faeces, which lack their normal brown colour, as a result of impaired bile secretion into the bowel. It can also be referred to as hypocholia. Acholia is a sign pointing to reduced or lacking flow of conjugated bilirubin i ...
), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
in the skin (
xanthomas
A xanthoma (pl. xanthomas or xanthomata) (condition: xanthomatosis) is a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states. They are cutaneous manifestations of lipidosis in which lip ...
). A
liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.
Medica ...
may indicate too few
bile duct
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
s (bile duct paucity) or, in some cases, the complete absence of bile ducts (
biliary atresia). Bile duct paucity results in the reduced absorption of fat and fat-soluble vitamins (A, D, E and K), which may lead to rickets or a
failure to thrive
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
.
Cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
and eventual
liver failure is fairly common among ALGS patients, and 15% of those with severe
hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...
manifestations require a liver transplant.
Hepatocellular cancer
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
has been reported in a small number of cases, but it is extremely rare.
Heart
![Tetralogy of Fallot](https://upload.wikimedia.org/wikipedia/commons/e/e6/Tetralogy_of_Fallot.svg)
Common signs of Alagille syndrome include congenital heart problems varying from heart murmurs to significant structural abnormalities, such as
Tetralogy of Fallot
Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are:
*pulmonary stenosis, which is narrowing of the exit from the r ...
,
Pulmonary Stenosis
Pulmonic stenosis, is a dynamic or fixed obstruction of flow from the right ventricle of the heart to the pulmonary artery. It is usually first diagnosed in childhood. Signs and symptoms
Cause
Pulmonic stenosis is usually due to isolated valvula ...
,
overriding aorta
An overriding aorta is a congenital heart defect where the aorta is positioned directly over a ventricular septal defect (VSD), instead of over the left ventricle. The result is that the aorta receives some blood from the right ventricle, causing ...
,
ventricular septal defect
A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...
, and
right ventricular hypertrophy
Right ventricular hypertrophy (RVH) is a condition defined by an abnormal enlargement of the cardiac muscle surrounding the right ventricle. The right ventricle is one of the four chambers of the heart. It is located towards the lower-end of the h ...
are common amongst Alagille patients. Patients may also present with
Ventricular septal defect
A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...
,
Atrial septal defect
Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...
,
Patent ductus arteriosus
''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...
, and
Coarctation of the aorta
Coarctation of the aorta (CoA or CoAo), also called aortic narrowing, is a congenital condition whereby the aorta is narrow, usually in the area where the ductus arteriosus (ligamentum arteriosum after regression) inserts. The word ''coarctation' ...
. The mortality rate of
Tetralogy of Fallot
Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are:
*pulmonary stenosis, which is narrowing of the exit from the r ...
when untreated ranges from 70% by age 10 to 95% by age 40. However, complete surgical repair can significantly improve both longevity and quality of life in patients with Alagille syndrome.
Other
Other presentations of Alagille's syndrome include
butterfly vertebrae
Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condit ...
,
ophthalmology
Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...
defects, and distinct facial structures. The
butterfly vertebrae
Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condit ...
can be detected with an x-ray, but there typically are no symptoms from this abnormality. Other skeletal defects common in ALGS patients are spina bifida and the fusion of vertebrae.
Most of the ophthalmological defects affect the
anterior chamber of the eyeball, including
Axenfeld's anomaly and Rieger anomaly, but
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
pigment changes are also common.
These anomalies can be beneficial in diagnosing Alagille syndrome. Many people with ALGS have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. While these distinct facial features are often presented in ALGS patients, the features are presumably not due to Alagille syndrome, but they are characteristic of patients with intrahepatic
cholestatic liver disease. So while these facial characteristics are extremely common in ALGS patients, it is because many patients experience extreme liver complications or liver failure, but it is not caused by the disease itself. The
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s may also be affected because the mutations in ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' and ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Membe ...
'' often lead to
renal dysplasia, deformed
proximal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal strai ...
s, or
lipidosis caused by the hindrance of
lipid metabolism
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
.
Genetics
ALGS is caused by loss of function mutations in either ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' (Jagged1) or ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Membe ...
'' (Notch homolog 2).
In the majority of people with ALGS, the gene mutation occurs in the ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' gene. The ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' mutation is either intragenic and found on
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
20p12, or it is a deletion of the entire ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' gene.
Mutations in ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Membe ...
'' are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation in ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Membe ...
'' is a
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
.
A
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
is a
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
that changes one
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...
, which results in a
codon that codes for the wrong
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
. Alagille syndrome is inherited in an
autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. The "
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...
" aspect of the disease means that the gene mutation occurs in an
autosome, which is one of the 44 chromosomes in the human body that is not a
sex chromosome
A sex chromosome (also referred to as an allosome, heterotypical chromosome, gonosome, heterochromosome, or idiochromosome) is a chromosome that differs from an ordinary autosome in form, size, and behavior. The human sex chromosomes, a typical ...
(chromosome X or Y). Although the majority of cases are due to the
autosomal dominant gene, there have been reports of a rare, autosomal recessive version of the disease.
In the autosomal recessive case, the ALGS patient must inherit two mutated genes: one from each parent. Although about 40% of the mutations are inherited from affected parents, most cases result from new, acquired mutations. These are caused by environmental factors that mutate one copy of the gene.
Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such as
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms ...
, which is found in cigarette smoke. These cases occur in people with no familial history of the disorder.
Pathophysiology
''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' and ''
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene.
NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome.
Function
Notch 2 is a member of the notch family. Membe ...
'' encode for proteins that are crucial to the
notch gene–signaling cascade. Specifically, ''
JAG1
Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...
'' encodes for a surface-binding ligand that regulates the notch signaling pathway. It plays a crucial role in cell signaling during embryonic development. If the pathway is disrupted due to mutations, an infant will not develop properly.
Alagille syndrome causes bile duct paucity, which is characterized by narrow and malformed bile ducts. Bile duct paucity causes bile to build up in the liver, resulting in scarring of the liver which hinders the liver's normal functions, like blood filtration and drug metabolism.
The
notch gene–signaling cascade is also important for
cell–cell recognition
Cell–cell recognition is a cell's ability to distinguish one type of neighboring cell from another.Campbell, et al., Biology, ''Eighth Edition'', 2008 Pearson Education Inc. This phenomenon occurs when complementary molecules on opposing cell s ...
, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life, and is specially important for:
* Atrioventricular (AV) canal development
*
Ventricular development
*
Ventricle (heart)
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...
outflow tract development
*
Angiogenesis
*
Pancreatic development
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...
*
Intestinal development
*
Bone development
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...
*
Respiratory system development
*
Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
cell differentiation
*
Neurite development
*
Gliogenesis Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.
Overview
Gliogenesis results in the formation of non-neuronal glia populations from neuronal cells. In this capacity, glial cells provide m ...
* Adult brain function
Diagnosis
Alagille syndrome can be extremely difficult to diagnose. While people are born with ALGS, it is almost always diagnosed later during childhood. The diagnosis can be difficult because the severity of the disease varies widely among patients.
Some common clinical tests that are run in order to diagnose the disease include vertebral x-rays, heart exams to detect any defects such as a
heart murmur
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...
, and a
liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.
Medica ...
to detect liver disease or any precursors. If a patient presents with multiple symptoms such as
jaundice,
heart murmur
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...
, and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome.
A more calculated and specific diagnosis can be done with
genetic testing.
Next-generation sequencing Massive parallel sequencing or massively parallel sequencing is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation ...
can be utilized to detect
single nucleotide polymorphisms (SNPs) in the affected gene(s).
Multiplex ligation-dependent probe amplification
Multiplex ligation-dependent probe amplification (MLPA) is a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer pair. It detects copy number changes at the molecular level, ...
(MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA.
Treatment
Early treatment is possible once the disease is diagnosed. Treatments of Alagille syndrome typically involve medications, therapies, and/or surgical procedures. All treatments aim to improve
bile excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies.
Diet can also be a crucial factor in improving quality of life when living with ALGS.
Medication
Several medications are used to improve bile flow, including
ursodiol (Actigall or Urso).
These medications differ in their rates of success. Certain drugs may be used to reduce itching (
pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
), such as
cholestyramine
Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, wh ...
and
rifampin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
. While these medications can reduce
pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
, the itching often is reduced when bile flow is improved via
ursodiol or
liver transplant
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...
.
Many patients with Alagille syndrome have nutritional and/or
malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
issues which often hinders normal growth. Patients benefit from vitamin A, D, E, and K supplements because the reduced bile flow makes it difficult to absorb and utilize these vitamins. A high-calorie diet is very important, and often requires a
gastrostomy
Gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression.
Typically this would include an incision in the patient's epigastrium as part of a formal operation. It can be perfor ...
tube to maintain the high caloric intake.
Maralixibat (Livmarli) was approved for medical use in the United States in September 2021.
[Highlights of prescribing information](_blank)
/ref>
Surgery
Surgery is common in more severe cases on Alagille syndrome, especially for patients with liver disease or end-stage liver failure. Liver transplants can either be a complete liver transplant from a deceased organ donor, or a partial transplant from a living donor. Liver transplants can be difficult in ALGS patients because heart defects are common along with the liver failure, and such intense surgeries are dangerous for cardiac patients because they cannot handle the stress of surgery and general anesthesia.
Partial biliary diversion has been used to significantly reduce pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
, jaundice, and xanthoma
A xanthoma (pl. xanthomas or xanthomata) (condition: xanthomatosis) is a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states. They are cutaneous manifestations of lipidosis in which lip ...
caused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically created stoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile. Patients with biliary atresia may require a Kasai procedure
A hepatoportoenterostomy or Kasai portoenterostomy is a surgical treatment performed on infants with Type IVb choledochal cyst and biliary atresia to allow for bile drainage. In these infants, the bile is not able to drain normally from the smal ...
to improve bile drainage; however, later liver transplantation is still often necessary.
See also
* Progressive familial intrahepatic cholestasis
References
External links
GeneReviews/NCBI/UW/NIH entry on Alagille syndrome
OMIM entries on Alagille syndrome
{{Other genetic disorders by mechanism
''This article incorporates public domain text fro
The U.S. National Library of Medicine
'
Accessory digestive gland disorders
Ciliopathy
Hepatology
Rare syndromes
Syndromes affecting the hepatobiliary system
Congenital disorders of digestive system
Cardiogenetic disorders
Syndromes affecting the heart
Syndromes with tumors