'''Alagille syndrome''' is a [[genetic disorder]] that affects primarily the [[liver]] and the [[heart]]. 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 100,000 live births. It is named after the French pediatrician [[Daniel Alagille]], who first described the condition in 1969.<ref>{{WhoNamedIt|synd|729}}</ref><ref name="pmid803282">{{cite journal | vauthors = Alagille D, Odièvre M, Gautier M, Dommergues JP | title = Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur | journal = The Journal of Pediatrics | volume = 86 | issue = 1 | pages = 63–71 | date = January 1975 | pmid = 803282 | doi = 10.1016/S0022-3476(75)80706-2 }}</ref>
'''Alagille syndrome''' is a [[genetic disorder]] that affects multiple organ systems, primarily the [[liver]], [[heart]], [[eyes]], [[skeleton]], and [[kidneys]]. It is characterized by a paucity of intrahepatic bile ducts, leading to [[cholestasis]] and other systemic manifestations.
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==Etiology==
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Alagille syndrome is primarily caused by mutations in the ''[[JAG1]]'' gene, which encodes a ligand in the [[Notch signaling pathway]]. In some cases, mutations in the ''[[NOTCH2]]'' gene are also implicated. These mutations are typically inherited in an [[autosomal dominant]] pattern, although de novo mutations can occur.
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 [[Organ transplant|transplantation]].<ref name="ghr">{{cite web |title=Alagille syndrome|url=https://ghr.nlm.nih.gov/condition/alagille-syndrome|website=Genetics Home Reference|access-date=31 October 2016}}</ref> It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%.<ref>{{cite journal |last1=Diaz-Frias |first1=Josue |last2=Kondamudi |first2=Noah P. | name-list-format = vanc |title=Alagille Syndrome |date=2019 |url=https://www.ncbi.nlm.nih.gov/books/NBK507827/|publisher=StatPearls |pmid=29939604 }}</ref> The majority of deaths from ALGS are typically due to heart complications or chronic liver failure.
The [[Notch signaling pathway]] plays a crucial role in cell differentiation and organ development. Mutations in ''JAG1'' or ''NOTCH2'' disrupt this pathway, leading to the characteristic features of Alagille syndrome. The paucity of bile ducts results in impaired bile flow, causing [[cholestasis]] and subsequent liver damage.
=== Liver ===
==Clinical Features==
Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the [[skin]] and the whites of the eyes[[jaundice|(jaundice]]), itching ([[pruritus]]), pale stools ([[acholia]]), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of [[cholesterol]] in the skin ([[xanthomas]]).<ref>{{cite web |title=Symptoms & Causes for Alagille Syndrome |url=https://www.niddk.nih.gov/health-information/liver-disease/alagille-syndrome/symptoms-causes |website=National Institute of Diabetes and Digestive and Kidney Diseases}}</ref> A [[liver biopsy]] may indicate too few [[bile duct]]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]]. [[Cirrhosis]] and eventual [[liver failure]] is fairly common among ALGS patients, and 15% of those with severe [[hepatic]] manifestations require a liver transplant.<ref name="Alagille Syndrome">{{cite journal | vauthors = Krantz ID, Piccoli DA, Spinner NB | title = Alagille syndrome | journal = Journal of Medical Genetics | volume = 34 | issue = 2 | pages = 152–7 | date = February 1997 | pmid = 9039994 | pmc = 1050871 | doi = 10.1136/jmg.34.2.152 }}</ref> [[Hepatocellular cancer]] has been reported in a small number of cases, but it is extremely rare.<ref name="Sijmons2008">{{cite journal | vauthors = Sijmons RH | title = Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome | journal = Hereditary Cancer in Clinical Practice | volume = 6 | issue = 1 | pages = 22–57 | date = February 2008 | pmid = 19706204 | pmc = 2735164 | doi = 10.1186/1897-4287-6-1-22 }}</ref>
=== Heart ===
===Hepatic Manifestations===
[[File:Tetralogy of Fallot.svg|thumb|335x335px|Tetralogy of Fallot is a common heart defect experienced in Alagille syndrome patients.]]
The most prominent feature of Alagille syndrome is [[cholestasis]], which often presents in infancy. Patients may exhibit [[jaundice]], [[pruritus]], and [[xanthomas]]. Progressive liver disease can lead to [[cirrhosis]] and [[liver failure]].
Common signs of Alagille syndrome include congenital heart problems varying from heart murmurs to significant structural abnormalities, such as [[Tetralogy of Fallot]]. [[Pulmonary Stenosis]], [[overriding aorta]], [[ventricular septal defect]], and [[right ventricular hypertrophy]] are common amongst Alagille patients. Patients may also present with [[Ventricular septal defect]], [[Atrial septal defect]], [[Patent ductus arteriosus]], and [[Coarctation of the aorta]]. The mortality rate of [[Tetralogy of Fallot]] 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 ===
===Cardiac Anomalies===
Other presentations of Alagille's syndrome include [[butterfly vertebrae]], [[ophthalmology]] defects, and distinct facial structures. The [[butterfly vertebrae]] 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.<ref name="Alagille Syndrome" /> Most of the ophthalmological defects affect the [[Anterior chamber of eyeball|anterior chamber of the eyeball]], including [[Axenfeld's anomaly]] and Rieger anomaly, but [[retina]] pigment changes are also common.<ref name="Alagille Syndrome" /> 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]].<ref>{{cite journal | vauthors = Sokol RJ, Heubi JE, Balistreri WF | title = Intrahepatic "cholestasis facies": is it specific for Alagille syndrome? | journal = The Journal of Pediatrics | volume = 103 | issue = 2 | pages = 205–8 | date = August 1983 | pmid = 6875709 | doi = 10.1016/s0022-3476(83)80345-x }}</ref> 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]]s may also be affected because the mutations in ''[[JAG1]]'' and ''[[NOTCH2]]'' often lead to [[renal dysplasia]], deformed [[proximal tubule]]s, or [[lipidosis]] caused by the hindrance of [[lipid metabolism]].<ref>{{cite journal | vauthors = Bissonnette ML, Lane JC, Chang A | title = Extreme Renal Pathology in Alagille Syndrome | journal = Kidney International Reports | volume = 2 | issue = 3 | pages = 493–497 | date = May 2017 | pmid = 29318215 | pmc = 5720621 | doi = 10.1016/j.ekir.2016.11.002 }}</ref>
Congenital heart defects are common, with [[pulmonary artery stenosis]] being the most frequent. Other possible anomalies include [[tetralogy of Fallot]] and [[ventricular septal defect]].
== Genetics ==
===Skeletal Abnormalities===
ALGS is caused by loss of function mutations in either ''[[JAG1]]'' (Jagged1) or ''[[NOTCH2]]'' (Notch homolog 2).<ref name="pmid9207787">{{cite journal | vauthors = Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC | display-authors = 6 | title = Mutations in the human Jagged1 gene are responsible for Alagille syndrome | journal = Nature Genetics | volume = 16 | issue = 3 | pages = 235–42 | date = July 1997 | pmid = 9207787 | doi = 10.1038/ng0797-235 | url = https://zenodo.org/record/1233393 }}</ref><ref name="pmid22209762">{{cite journal | vauthors = Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli DA, Spinner NB | display-authors = 6 | title = NOTCH2 mutations in Alagille syndrome | journal = Journal of Medical Genetics | volume = 49 | issue = 2 | pages = 138–44 | date = February 2012 | pmid = 22209762 | pmc = 3682659 | doi = 10.1136/jmedgenet-2011-100544 }}</ref> In the majority of people with ALGS, the gene mutation occurs in the ''[[JAG1]]'' gene. The ''[[JAG1]]'' mutation is either intragenic and found on [[chromosome]] 20p12, or it is a deletion of the entire ''[[JAG1]]'' gene.<ref name="Vajro et al 2012">{{cite journal | vauthors = Vajro P, Ferrante L, Paolella G | title = Alagille syndrome: an overview | journal = Clinics and Research in Hepatology and Gastroenterology | volume = 36 | issue = 3 | pages = 275–7 | date = June 2012 | pmid = 22521120 | doi = 10.1016/j.clinre.2012.03.019 }}</ref> Mutations in ''[[NOTCH2]]'' are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation in ''[[NOTCH2]]'' is a [[missense mutation]].<ref name="ReferenceA">{{cite book |last1=Gilbert |first1=Melissa A. |last2=Spinner |first2=Nancy B. | name-list-format = vanc |title=Alagille Syndrome |date=2018 |publisher=Springer |pages=33–48}}</ref> A [[missense mutation]] is a [[point mutation]] that changes one [[nucleotide]], which results in a [[codon]] that codes for the wrong [[amino acid]]. Alagille syndrome is inherited in an [[autosomal dominant]] pattern, which means one copy of the altered gene is sufficient to cause the disorder. The "[[autosome|autosomal]]" 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]] (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.<ref name="Vajro et al 2012" /> 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.<ref name="ReferenceA"/> Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such as [[benzene]], which is found in cigarette smoke.<ref>{{cite web |title=What is a gene mutation and how do mutations occur? |url=https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation |website=U.S. National Library of Medicine}}</ref> These cases occur in people with no familial history of the disorder.
Characteristic skeletal findings include [[butterfly vertebrae]], which are often asymptomatic but can be detected on [[X-ray]].
== Pathophysiology ==
===Ocular Features===
''[[JAG1]]'' and ''[[NOTCH2]]'' encode for proteins that are crucial to the [[Notch signaling pathway|notch gene–signaling cascade]]. Specifically, ''[[JAG1]]'' 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.<ref name="Reference">{{Cite web|url=https://ghr.nlm.nih.gov/condition/alagille-syndrome|title=Alagille syndrome | work = Genetics Home Reference|access-date=2016-12-23}}</ref> 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.<ref name="Reference"/>
Patients may have posterior embryotoxon, a thickened and anteriorly displaced [[Schwalbe's line]] visible on [[slit-lamp examination]].
The [[Notch signaling pathway|notch gene–signaling cascade]] is also important for [[cell–cell recognition]], which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life, and is specially important for:
===Renal Involvement===
Renal abnormalities can include renal tubular acidosis and other structural anomalies.
* Atrioventricular (AV) canal development
==Diagnosis==
*[[Ventricle (heart)|Ventricular development]]
Diagnosis of Alagille syndrome is based on clinical criteria and confirmed by genetic testing. A [[liver biopsy]] may show bile duct paucity, supporting the diagnosis. Genetic testing can identify mutations in ''JAG1'' or ''NOTCH2''.
*[[Ventricle (heart)]] outflow tract development
*[[Angiogenesis]]
*[[Pancreatic development]]
*[[Intestinal|Intestinal development]]
*[[Bone development]]
*[[Respiratory system|Respiratory system development]]
*[[Neuron]] cell differentiation
*[[Neurite|Neurite development]]
*[[Gliogenesis]]
* Adult brain function
== Diagnosis ==
==Management==
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.<ref name=":0">{{cite web |title=Alagille Syndrome - Diagnosis & Treatment |url=http://www.childrenshospital.org/conditions-and-treatments/conditions/a/alagille-syndrome/diagnosis-and-treatment |website=Boston Children's Hospital}}</ref> 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]], and a [[liver biopsy]] to detect liver disease or any precursors. If a patient presents with multiple symptoms such as [[jaundice]], [[heart murmur]], and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome.<ref name=":0" /> A more calculated and specific diagnosis can be done with [[genetic testing]]. [[Next-generation sequencing]] can be utilized to detect [[single nucleotide polymorphisms]] (SNPs) in the affected gene(s). [[Multiplex ligation-dependent probe amplification]] (MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA <ref>{{cite journal | vauthors = Ohashi K, Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Negishi Y, Kudo T, Ito R, Saitoh S | display-authors = 6 | title = Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome | journal = Acta Paediatrica | volume = 106 | issue = 11 | pages = 1817–1824 | date = November 2017 | pmid = 28695677 | doi = 10.1111/apa.13981 | url = https://www.semanticscholar.org/paper/706c916e59901bb44eb708c85d4b97c74b99a3b4 }}</ref>
Management of Alagille syndrome is primarily supportive and symptomatic. Treatment options include:
== Treatment ==
* [[Ursodeoxycholic acid]] to improve bile flow.
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.<ref name=":1">{{Cite web|url=https://surgery.ucsf.edu/conditions--procedures/alagille-syndrome.aspx|title=Department of Surgery - Alagille Syndrome|website=surgery.ucsf.edu|access-date=2019-10-08}}</ref> Diet can also be a crucial factor in improving quality of life when living with ALGS.
* [[Cholestyramine]] or [[rifampicin]] for pruritus.
* Nutritional support, including fat-soluble vitamin supplementation.
* [[Liver transplantation]] in cases of end-stage liver disease.
=== Medication ===
==Prognosis==
Several medications are used to improve bile flow, including [[Ursodiol]] (Actigall or Urso).<ref name=":1" /> These medications differ in their rates of success. Certain drugs may be used to reduce itching ([[pruritus]]), such as [[cholestyramine]] and [[rifampicin|rifampin]]. While these medications can reduce [[pruritus]], the itching often is reduced when bile flow is improved via [[Ursodiol]] or [[Liver transplantation|liver transplant]].<ref name=":1" />
The prognosis of Alagille syndrome varies depending on the severity of organ involvement. Liver disease is a major determinant of outcome, and some patients may require liver transplantation. Cardiac anomalies may also impact prognosis.
Many patients with Alagille syndrome have nutritional and/or [[malabsorption]] 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]] tube to maintain the high caloric intake.
==Epidemiology==
Alagille syndrome occurs in approximately 1 in 30,000 to 45,000 live births. It affects both males and females equally.
=== Surgery ===
==See Also==
Surgery is common in more severe cases on Alagille syndrome, especially for patients with liver disease or end-stage liver failure. [[Liver transplantation|Liver transplants]] can either be a complete liver transplant from a deceased organ donor, or a partial transplant from a living donor.<ref>{{Cite book|title=Contemporary Liver Transplantation : The Successful Liver Transplant Program| veditors = Doria C |isbn=9783319055435|oclc=1111825084|year = 2016 }}</ref><ref>{{Cite web|url=https://www.lahey.org/lhmc/department/transplantation/live-donor-liver-transplant/donor-requirements-evaluation/|title=Donor Requirements & Evaluation - Live Liver Transplant|website=Lahey Hospital & Medical Center, Burlington & Peabody|language=en-US|access-date=2019-10-08}}</ref> 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.
* [[Cholestasis]]
* [[Congenital heart defect]]
* [[Genetic disorder]]
Partial biliary diversion has been used to significantly reduce [[pruritus]], [[jaundice]], and [[xanthoma]] 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.
==References==
* Kamath BM, et al. "Alagille syndrome: diagnosis and management." ''Clin Liver Dis.'' 2018.
Patients with [[biliary atresia]] may require a [[Kasai procedure]] to improve bile drainage; however, later liver transplantation is still often necessary.
* McDaniell R, et al. "NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway." ''Am J Hum Genet.'' 2006.
Alagille syndrome is a genetic disorder that affects multiple organ systems, primarily the liver, heart, eyes, skeleton, and kidneys. It is characterized by a paucity of intrahepatic bile ducts, leading to cholestasis and other systemic manifestations.
Alagille syndrome is primarily caused by mutations in the JAG1 gene, which encodes a ligand in the Notch signaling pathway. In some cases, mutations in the NOTCH2 gene are also implicated. These mutations are typically inherited in an autosomal dominant pattern, although de novo mutations can occur.
The Notch signaling pathway plays a crucial role in cell differentiation and organ development. Mutations in JAG1 or NOTCH2 disrupt this pathway, leading to the characteristic features of Alagille syndrome. The paucity of bile ducts results in impaired bile flow, causing cholestasis and subsequent liver damage.
Diagnosis of Alagille syndrome is based on clinical criteria and confirmed by genetic testing. A liver biopsy may show bile duct paucity, supporting the diagnosis. Genetic testing can identify mutations in JAG1 or NOTCH2.
The prognosis of Alagille syndrome varies depending on the severity of organ involvement. Liver disease is a major determinant of outcome, and some patients may require liver transplantation. Cardiac anomalies may also impact prognosis.
