Alagille SyndromeSynonyms: Arteriohepatic Dysplasia, Syndromic Bile Duct PaucityNancy B Spinner, PhD,Laura D Leonard, BA, andIan D Krantz, MD.Author InformationInitial Posting:May 19, 2000; Last Update:February 28, 2013.Go to:SummaryClinical characteristics.Alagille syndrome (ALGS) is a complex multisystem disorder involving primarily the liver, heart, eyes, face, and skeleton. The clinical features are highly variable, even within families. The major clinical manifestations of ALGS are cholestasis, characterized by bile duct paucity on liver biopsy;congenitalcardiac defects, primarily involving the pulmonary arteries; posterior embryotoxon in the eye; typical facial features; and butterfly vertebrae. Renal and central nervous abnormalities also occur. Mortality is approximately 10%, with vascular accidents, cardiac disease, and liver disease accounting for most of the deaths.Diagnosis/testing.The diagnosis of ALGS is primarily based on clinical findings. The two genes in which mutations are known to cause ALGS areJAG1andNOTCH2. Sequence analysis ofJAG1detects mutations in more than 89% of individuals who meet clinical diagnostic criteria;deletion/duplication analysisdetects exonic and whole-genedeletions, including microdeletion of 20p12, in approximately 7% ofaffectedindividuals. Mutations inNOTCH2are observed in 1%-2% of individuals with ALGS.Management.Treatment of manifestations: Management by a multidisciplinary team (medical genetics, gastroenterology, nutrition, cardiology, ophthalmology, nephrology, liver transplantation); choloretic agents (ursodeoxycholic acid), other medications (cholestyramine, rifampin, naltrexone), and, when necessary, partial external biliary diversion or ileal exclusions for pruritis and xanthomas; liver transplantation for end-stage liver disease; standard treatment for cardiac, renal, and neurologic involvement.Prevention of secondary complications: Optimization of nutrition to maximize growth and development; fat-soluble vitamin supplementation; for those with splenomegaly or with chronic liver disease, use of a spleen guard during activities.Surveillance: Routine monitoring of growth, nutrition, and heart.Agents/circumstances to avoid: Contact sports; alcohol if liver disease is present.Evaluation of relatives at risk: Offermolecular genetic testingto first-degree relatives if thefamily-specific mutationis known or assess first-degree relatives for disease manifestations.Genetic counseling.ALGS is inherited in anautosomal dominantmanner. Approximately 30%-50% of individuals have an inheritedmutationand about 50%-70% have ade novopathogenic variant. For parents of a child with an apparentde novopathogenic variant,recurrence riskto subsequent offspring of having Alagille syndrome is low but greater than in the general population because of the possibility ofgermline mosaicism. The offspring of an individual with Alagille syndrome have a 50% chance of having Alagille syndrome. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in anaffectedfamily member is known. Prenatal testing cannot predict the occurrence or severity of clinical manifestations.Go to:DiagnosisClinical DiagnosisThe clinical diagnostic criteria for Alagille syndrome (ALGS) include the following: The histologic finding of bile duct paucity(an increased portal tract-to-bile duct ratio) on liver biopsy. Although considered to be the most important and constant feature of ALGS, bile duct paucity is not present in infancy in many individuals ultimately shown to have ALGS. In the newborn, a normal ratio of portal tracts to bile ducts, bile duct proliferation, or a picture suggestive of neonatal hepatitis may be observed. Overall, bile duct paucity is present in about 90% of individuals. Three of the following five major clinical features(in addition to bile duct paucity): Cholestasis Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs) Ophthalmologic abnormalities (most commonly posterior embryotoxon) Characteristic facial featuresIn addition, abnormalities of the kidney, neurovasculature, and pancreas are important manifestations of Alagille syndrome [Kamath et al 2012b,Turnpenny & Ellard 2012].Note: The diagnosis of Alagille syndrome may be difficult because of the highlyvariable expressivityof the clinical manifestations [Goldman & Pranikoff 2011,Guegan et al 2012].Individuals with anaffectedrelative.The diagnosis of ALGS should be considered in individuals who do not meet the full clinical criteria but do have an affected relative. If an affectedfirst-degree relativeis identified, the presence of one or more features is considered sufficient to make the diagnosis on clinical grounds.Molecular Genetic TestingGenes Pathogenic variants inJAG1are known to cause about 94%-96% of cases of ALGS. Pathogenic variants inNOTCH2are known to cause ALGS in 1%-2% of individuals [McDaniell et al 2006,Kamath et al 2012a].Clinical testingTable 1.Summary of Molecular Genetic Testing Used in Alagille SyndromeGene1Proportion of ALGS Attributed to Mutation of This GeneTest MethodMutations Detected2

JAG189%Sequence analysis3/mutation scanning4Sequence variants

See footnote 5Sequence analysis of select exons3Sequence variants in select exons

~5%-7%6Deletion/duplicationanalysis (includingFISH)7Deletion andduplicationofexon(s) and entiregenedeletion8

Linkage analysisNASee footnote 9

NOTCH21%-2%10Sequence analysis3Sequence variants

UnknownDeletion/duplicationanalysis7Unknown, none reported

1.SeeTable A. Genes and Databasesforchromosomelocusand protein name.2.SeeMolecular Geneticsfor information on allelic variants.3.Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-genedeletions/duplications are not detected. For issues to consider in interpretation ofsequence analysisresults, clickhere.4.Sequence analysis andmutation scanningof the entiregenecan have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.5.Dependent on exons sequenced and methodologies used. Two thirds of the detectable mutations are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, and 24.6.Warthen et al [2006], personal communication. Extent ofdeletiondetected may vary by method and by laboratory.7.Testing that identifies deletions/duplications not readily detectable bysequence analysisof the coding and flanking intronic regions of genomicDNA; included in the variety of methods that may be used are:quantitative PCR, long-range PCR, multiplex ligation-dependentprobeamplification (MLPA), andchromosomal microarray(CMA) that includes thisgene/chromosomesegment.8.Extent ofdeletiondetected may vary by method and by laboratory [Kamath et al 2009].9.Linkage analysis may be performed if the familypedigreestructure is sufficient and family members agree to the testing process (1) to confirmcosegregationof a potential pathogenicmutationwith disease in individual families and (2) as an ancillary test to obtain preliminary data prior to the completion ofsequence analysis. Linkage testing cannot be used to confirm the diagnosis of Alagille syndrome.10.McDaniell et al [2006],Kamath et al [2012a]Testing StrategyTest characteristics.SeeClinical Utility Gene Card[Leonard et al 2014] for information on test characteristics includingsensitivityandspecificity.To confirm/establish the diagnosis of ALGS in aproband In situations in which the diagnosis is suspected but the criteria for clinical diagnosis are not met,sequence analysisofJAG1should be performed first, as this identifies mutations in more than 89% of persons with aJAG1mutation. If no mutations are detected bysequence analysisofJAG1,deletion/duplication analysiscan be performed to detect deletions or duplications ofJAG1exon(s) or of the wholegene. Given the wide availability of targeted CMA testing, this could be used to determine both the presence and extent of a chromosomal deletion/duplication involvingJAG1if there was high density of probes in the region. Other deletion/duplication methods (e.g., MLPA) also detect exonic or whole-gene deletions. If adeletioninvolving the entireJAG1geneis identified, a full cytogenetic study may be considered to determine if a rare chromosomalrearrangement(translocationorinversion) is present. The presence of developmental delay and/or hearing loss in addition to the features commonly seen in ALGS may increase the suspicion of achromosomedeletion. NOTCH2molecular genetic testingshould be considered when the diagnosis is strongly suspected on clinical grounds, but noJAG1mutation/deletion/duplicationwas identified.Prenatal diagnosis and preimplantation genetic diagnosis (PGD)for pregnancies at risk for ALGS require prior identification of the pathogenic variant in the family.Genetically Related (Allelic) DisordersJAG1.No phenotypes other than those discussed in thisGeneRevieware known to be associated withmutationofJAG1. However, it should be noted that some individuals with pathogenic variants inJAG1may express only some of the features of ALGS and may not be recognized as having this diagnosis. The most clinically significant group is individuals with apparentlyisolatedcardiac disease who haveJAG1mutations [Krantz et al 1998,Eldadah et al 2001,Bauer et al 2010,Rauch et al 2010].NOTCH2.It should be noted that some individuals with pathogenic variants inNOTCH2may express only some of the features of ALGS and may not be recognized as having this diagnosis [Kamath et al 2012a].Germline mutations Hajdu-Cheney syndrome. Specific pathogenic variants inNOTCH2have recently been identified to cause Hajdu-Cheney syndrome, also known as serpentine fibula polycystic kidney syndrome. Hajdu-Cheney syndrome is anautosomal dominantdisorder which causes focal bone destruction, osteoporosis, craniofacialdysmorphology, renal cysts, cleft palate, and cardiac defects. TheNOTCH2pathogenic variants identified in individuals with Hadju-Cheney syndrome were all localized in the lastexon(exon 34) ofNOTCH2; these variants are predicted to disrupt the intracellular PEST (proline-glutamate-serine-threonine-rich) domain and decrease clearance of the notch intracellular domain, thus increasing Notch signaling [Majewski et al 2011,Penton et al 2012,Zanotti & Canalis 2012].Somatic mutations Splenic marginal zone lymphoma (SMZL).Recurrent somatic gain-of-function mutations inNOTCH2have been identified in individuals with SMZL [Kiel et al 2012].Go to:Clinical CharacteristicsClinical DescriptionAlagille syndrome (ALGS) is a multisystem disorder. Studies of families with multipleaffectedmembers and/orJAG1pathogenic variants have demonstrated a wide spectrum of clinical variability ranging from life-threatening liver or cardiac disease to only subclinical manifestations (i.e., butterfly vertebrae, posterior embryotoxon, or characteristic facial features). This variability is seen even among individuals from the same family [Kamath et al 2003]. Indeed, in a study of 53mutation-positive relatives of affected individuals, 25 (47%) did not meet clinical diagnostic criteria [Kamath et al 2003].Individuals with ALGS who have severe liver or cardiac involvement are most often diagnosed in infancy. In those individuals with subclinical or mild hepatic manifestations, the diagnosis may not be established until later in life.Mortality in ALGS is approximately 10%, with early mortality caused by cardiac disease or severe liver disease, and later mortality often caused by vascular accidents [Emerick et al 1999,Kamath et al 2004].Two studies byEmerick et al [1999]andSubramaniam et al [2011]discuss the frequency of clinical manifestations in individuals with ALGS (Table 2).Table 2.Clinical Manifestations of ALGS in Two StudiesClinical FindingFrequency (% of Individuals)

Emerick et al [1999]Subramaniam et al [2011]

Bile duct paucity69/81 (85%)77/103 (75%)

Chronic cholestasis88/92 (96%)104/117 (89%)

Cardiac murmur90/92 (97%)107/117 (91%)

Eye findings65/83 (78%)72/117 (61%)1

Vertebral anomalies37/71 (51%)44/117 (39%)2

Characteristic facies86/92 (96%)91/117 (77%)

Renal disease28/69 (40%)27/117 (23%)

Pancreatic insufficiency7/17 (41%)NR

Growth retardation27/31 (87%)NR

Intellectual disability2/92 (2%)NR

Developmental delay15/92 (16%)NR

Based on 92 individuals with ALGS [Emerick et al 1999] and 117 children with ALGS [Subramaniam et al 2011]NR = Not reviewed.1.Only posterior embryotoxon was reviewed in this study.2.Only butterfly vertebrae was reviewed in this study.Hepatic manifestations.Although some individuals withJAG1pathogenic variants have no detectable hepatic manifestations [Gurkan et al 1999,Krantz et al 1999,Kamath et al 2003], in mostaffectedpersons liver disease presents within the first three months of life and ranges from jaundice, mild cholestasis, and pruritis to progressive liver failure.Jaundice presents as conjugated hyperbilirubinemia in the neonatal period. Increased serum concentrations of bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), triglycerides, and the aminotransferases are also seen.Cholestasis manifests as pruritis, increased serum concentration of bile acids, growth failure, and xanthomas.In approximately 15% ofaffectedindividuals, the liver disease progresses to cirrhosis and liver failure, necessitating liver transplantation [Emerick et al 1999]. Currently, it is not possible to predict which infants will progress to end-stage liver disease.Liver biopsy typically shows paucity of the intrahepatic bile ducts, which may be progressive. In the newborn with ALGS, bile duct paucity is not always present and the liver biopsy may demonstrate ductal proliferation, resulting in the possible misdiagnosis of ALGS as biliary atresia.While it is difficult to predict whether a child with cholestasis will have improvement or progression of liver disease, a retrospective study of 33 individuals with Alagille syndrome found that in children younger than age five years, a total bilirubin >6.5 mg/dL, a conjugated bilirubin >4.5 mg/dL and a cholesterol >520 mg/dL were associated with severe liver disease later in life. These biomarkers and suggested cutoff values can be used to inform medical management and may help identifyaffectedindividuals who would benefit from more aggressive therapy [Kamath et al 2010b].Cardiac manifestations.Cardiac findings ranging from benign heart murmurs to significant structural defects occur in 90%-97% of individuals with ALGS [Emerick et al 1999,McElhinney et al 2002]. The pulmonary vasculature (pulmonary valve, pulmonary artery, and its branches) is most commonly involved. Pulmonic stenosis (peripheral and branch) is the most common cardiac finding (67%) [Emerick et al 1999]. The most common complex cardiac defect is tetralogy of Fallot, seen in 7%-16% of individuals [Emerick et al 1999]. Other cardiac malformations include (in order of decreasing frequency) ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta.Ophthalmologic manifestations.The most common ophthalmologic finding in individuals with ALGS is posterior embryotoxon. Posterior embryotoxon, a prominent Schwalbe's ring, is a defect of the anterior chamber of the eye and has been reported in 78%-89% of individuals with ALGS [Emerick et al 1999,Hingorani et al 1999]. Most accurately identified on slit-lamp examination, posterior embryotoxon does not affect visual acuity but is useful as a diagnostic aid. Posterior embryotoxon is also present in approximately 8%-15% of individuals from the general population. This finding in family members who are otherwiseunaffectedcan complicate the identification of relatives with thegenemutation.Other defects of the anterior chamber seen in ALGS include Axenfeld anomaly and Rieger anomaly. Ocular ultrasonographic examination in 20 children with ALGS found optic disk drusen in 90%. Retinal pigmentary changes are also common (32% in one study) [Hingorani et al 1999,El-Koofy et al 2011]. Although these changes were initially thought to be the result of dietary deficiency, they have been seen in individuals with normal serum concentrations of vitamins A and E [Hingorani et al 1999]. Additionally eye anomalies have also been described [Makino et al 2012].The visual prognosis is good, although mild decreases in visual acuity may occur. In particular, visual loss has been described in association with intracranial hypertension [Narula et al 2006].Skeletal manifestations.The most common radiographic finding is butterfly vertebrae, a clefting abnormality of the vertebral bodies that occurs most commonly in the thoracic vertebrae. The frequency of butterfly vertebrae reported in individuals with ALGS ranges from 33% to 93% [Emerick et al 1999,Sanderson et al 2002,Lin et al 2012]. Butterfly vertebrae are usually asymptomatic. The incidence in the general population is unknown but suspected to be low. Other skeletal manifestations in individuals with ALGS have been reported less frequently [Zanotti & Canalis 2012].Facial features.The constellation of facial features observed in children with ALGS includes a prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and saddle or straight nose with a bulbous tip. These features give the face the appearance of an inverted triangle. The typical facial features are almost universally present in Alagille syndrome (seeFigure 1).

Figure 1.Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes, and pointed chin.Although the facialphenotypein ALGS is specific to the syndrome and is often a powerful diagnostic tool, Lin et al showed that North American dysmorphologists had difficulty assessing the facial features in a cohort of Vietnamese children with Alagille syndrome, suggesting that the value of this diagnostic tool is variable across populations [Lin et al 2012].Other features Renal abnormalities, both structural (small hyperechoic kidney, ureteropelvic obstruction, renal cysts) and functional (most commonly renal tubular acidosis), found in 39% ofaffectedindividuals (73/187) [Kamath et al 2012b]. Hypertension and renal artery stenosis have also been noted in adults with ALGS [Salem et al 2012]. Pancreatic insufficiency [Emerick et al 1999] Growth failure (50%-90%) [Emerick et al 1999,Arvay et al 2005] Mild delays of gross motor skills, identified in 16% ofaffectedindividuals. Whereas initial reports suggested that intellectual disability was present in 30% of affected individuals, mild intellectual disability was subsequently identified in only 2% [Emerick et al 1999]. This decreased incidence is attributed to more aggressive nutritional management and intervention. Neurovascular accidents, reported at rates as high as 15% [Emerick et al 1999] and accounting for 34% of mortality in one large study [Kamath et al 2004]. Renovascular anomalies, middle aortic syndrome, and moyamoya syndrome [Woolfenden et al 1999,Rocha et al 2012] have been reported. Anomalies of the basilar, carotid, and middle cerebral arteries also occur [Kamath et al 2004,Emerick et al 2005]. Delayed puberty and high-pitched voice Extra digital flexion crease [Kamath et al 2002a] Craniosynostosis[Kamath et al 2002b] Fractures of the lower extremities [Bales et al 2010]Genotype-Phenotype CorrelationsThephenotypeof ALGS caused bymutationofJAG1is indistinguishable from the phenotype caused by mutation ofNOTCH2. Initially, 3/3 relatives who had pathogenic variants inNOTCH2had significant renal disease, often resulting in end-stage renal disease [McDaniell et al 2006]. More recent studies have shown that renal involvement was noted in 4/9affectedindividuals evaluated for renal anomalies. This observation is consistent with the renal involvement observed in those withJAG1mutations. However, it is important to note that the number of individuals identified with ALGS caused by mutation ofNOTCH2is still too small to draw any conclusions aboutgenotype-phenotype correlations [Kamath et al 2012a].Nogenotype-phenotypecorrelations exist between clinical manifestations of ALGS and specificJAG1mutationtypes or location within thegene[Krantz et al 1998,Crosnier et al 1999,Spinner et al 2001,McElhinney et al 2002]. However, two families withJAG1missense mutations in which cardiac disease was segregating in the absence of liver disease have been reported [Eldadah et al 2001,Le Caignec et al 2002]. Molecular analysis of one of the families demonstrated a 'leaky' mutation, in which the amount of Jagged1 protein produced appeared to fall between that seen in an individual withhaploinsufficiencyand an individual with two normal copies ofJAG1, suggesting that the heart is more sensitive toJAG1dosage than the liver [Eldadah et al 2001,Lu et al 2003].Individuals with ALGS with more severe impairment may have a largerdeletionofchromosome20p12 encompassing the entireJAG1geneas well as other genes in the region.PenetranceALGS demonstrates highlyvariable expressivitywith clinical features ranging from subclinical to severe.JAG1pathogenic variants.To determine the range and frequency of clinical findings in individuals with aJAG1pathogenic variant and hence, thepenetrance,Kamath et al [2003]studied 53mutation-positive relatives of probands with ALGS. Their findings: 21% met diagnostic criteria independent offamily history. 32% were asymptomatic, but met clinical diagnostic criteria when additional testing was performed (analysis of liver enzymes, cardiac examination, eye examination, or skeletal x-rays). 43% had one or two features of ALGS. 4% had no features of ALGS.Based on these data,penetranceis 96%; however, only 53% meet clinical diagnostic criteria for ALGS.NOTCH2pathogenic variants.Penetrance appears complete in the ten individuals so far identified withNOTCH2pathogenic variants, although expressivity is variable [Kamath et al 2012a].AnticipationALGS has not shownanticipation. Bias of ascertainment may occur because individuals with aJAG1pathogenic variant who reproduce have milder disease than infants who present with the severephenotypeof neonatal cholestasis [Author, personal observation].PrevalenceThe prevalence of ALGS was originally estimated at 1:70,000 live births; however, this is most likely an underestimate, as cases were ascertained solely on the basis of presence of neonatal liver disease [Danks et al 1977]. Based on the work byKamath et al [2003], the authors estimate that the incidence of ALGS is 1:30,000-1:50,000 live births, but due to the variablephenotype, it remains underdiagnosed [Kamath et al 2003]. The prevalence across populations appears to be stable.Go to:Differential DiagnosisSeeAlagille Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.Neonatal cholestasis.More than 100 specific causes of neonatal cholestasis exist: Treatable causes such as sepsis orgalactosemianeed to be considered first. A diisopropyl iminodiacetic acid (DISIDA) scan may identify cholestasis as a result of extrahepatic causes such as biliary atresia. Hepatic ultrasound examination can detect extrahepatic structural abnormalities such as choledochal cysts.Bile duct paucityis not seen exclusively in Alagille syndrome (ALGS). Other causes of bile duct paucity include: idiopathic, metabolic disorders (alpha-1-antitrypsin deficiency, hypopituitarism,cystic fibrosis, trihydroxycoprostanic acid excess), chromosomal abnormalities (Down syndrome), infectious diseases (congenitalCMV, congenital rubella, congenital syphilis, hepatitis B), immunologic disorders (graft-versus-host disease, chronic hepatic allograft rejection, primary sclerosing cholangitis), and others (Zellweger syndrome, Ivemark syndrome). These can be distinguished from ALGS by history, by the presence of other findings, or by genetic testing.Other disorders associated withintrahepatic cholestasisinclude theautosomal recessivedisordersprogressive familial intrahepatic cholestasis 1 and 2(Byler syndrome), Norwegian cholestasis (Aagenaes syndrome), benign recurrent intrahepatic cholestasis (BRIC), and North American Indian cholestasis (NAIC). These conditions are largely confined to the liver; only ALGS demonstrates multi-organ system involvement.Posterior embryotoxonis seen in Rieger syndrome, Bannayan-Riley-Ruvalcaba syndrome (one of the phenotypes of thePTENhamartoma tumor syndrome), and numerous other syndromes. It is also observed in 8%-15% of the general population. ALGS can be distinguished by the presence of other findings or by genetic testing.Pulmonic vascular system abnormalitiesare seen in isolation as well as in syndromes such asNoonan syndrome, Watson syndrome (pulmonic stenosis andneurofibromatosis type 1),LEOPARD syndrome, Down syndrome, andWilliams syndrome. These other syndromes can be distinguished by other associated clinical findings and/ormolecular genetic testing.Several of thecardiac defectsdescribed in ALGS, particularly ventricular septal defect and tetralogy of Fallot, are commonly seen in individuals withdeletion 22q11.2. Individuals with this diagnosis have also been reported as having butterfly vertebrae and poor growth, two common features of ALGS. Liver disease is not part of thedeletion22q11.2 syndrome; testing for this deletion using the specificFISHprobedistinguishes the two disorders [Greenway et al 2009].Note to clinicians:For a patient-specific simultaneous consult related to this disorder, go toSimulConsult, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Go to:ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Alagille syndrome (ALGS), the following evaluations are recommended: Evaluation by a gastroenterologist, including a full set of liver function tests, clotting studies and if necessary, serum bile acids, fat-soluble vitamin levels, a hepatic ultrasound, a technitium-99m-DISIDA scintiscan, and liver biopsy A full cardiac evaluation, including echocardiogram AP and lateral chest radiographs to evaluate for the presence of butterfly vertebrae An ophthalmologic examination to identify anterior chamber involvement Renal function testing and renal ultrasound examination (especially in the newborn period) Screening developmental evaluation, with more detailed evaluation if significant delays are identified Measurement of growth parameters and plotting on age-appropriate growth charts Medical genetics consultationTreatment of ManifestationsA multidisciplinary approach to the management of individuals with ALGS is often beneficial because of the multisystem involvement. Evaluation by specialists in medical genetics, gastroenterology, nephrology, nutrition, cardiology, ophthalmology, liver transplantation, and child development may be indicated, depending on the age and specific difficulties of the individual [Kamath et al 2010a]. Pruritus is considered the most severe of any pediatric liver disease. Pruritis and xanthomas have been successfully treated with choloretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). Partial internal biliary diversion (PIBD) and ileal exclusions for individuals with Alagille syndrome have also been reported; however, while these procedures have the potential to relieve the intractable symptoms of liver disease (such as pruritis) and improve quality of life for those with ALGS, they are not thought to prevent the progression of liver disease [Emerick & Whitington 2002,Mattei et al 2006,Dingemann et al 2012,Sheflin-Findling et al 2012]. Liver transplantation for end-stage liver disease has an 80.4% five-year survival rate, and results in improved liver function and some catch-up growth in 90% ofaffectedindividuals; however, the catch-up growth seen in post-transplanted individuals with Allagille syndrome is still less than that observed in individuals with other cholestatic liver diseases [Quiros-Tejeira et al 2000,Kasahara et al 2003,Pawlowska et al 2010]. In a recent study on survival following liver transplant in several disorders, Kamath et al showed that the one-year survival rate for individuals with ALGS was 87%, compared to a 96% one-year survival rate for the control group (individuals with biliary atresia). The lower success rate of liver transplantation in ALGS is probably most influenced by the severity of any coexisting cardiac disease, renal disease, or vascular involvement [Kamath et al 2012c]. Additionally, the effects of long-term immosuppressants on the evolution of the other organ systems involved, including vasculature, skeleton, and kidneys, remain largely unknown [Englert et al 2006,Kamath et al 2010b,Shneider 2012].

Note: Since ALGS frequently presents with neonatal jaundice and can mimic biliary atresia, infants with ALGS may undergo an intraoperative cholangiogram and a Kasai procedure. However, a study byKaye et al [2010]demonstrated that the Kasai procedure does not benefit children with ALGS and may worsen the outcome [Kaye et al 2010]. Cardiac involvement is treated in a standard manner. Renal anomalies are treated in a standard manner. Vascular accidents should be treated in a standard manner. Head injuries and neurologic symptoms should be evaluated aggressively. Ophthalmologic abnormalities rarely need intervention. Vertebral anomalies are rarely symptomatic.Note:Elisofon et al [2010]showed that health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) is impaired and that cardiac catheterization or surgery, mental health diagnoses, and poor sleep are associated with lower scores in children with ALGS [Elisofon et al 2010]. While surgeries and mental health diagnoses may be out of the control of physicians and care-givers, poor sleep in children with ALGS is often a result of severe pruritus, which can be improved with choloretic agents as discussed above.Prevention of Secondary ComplicationsThe following are appropriate: Optimization of nutrition to maximize growth and development Close monitoring of plasma concentration of fat-soluble vitamins, nutritional optimization, and vitamin replacement therapy to maximize growth potential and prevent some of the developmental delay documented in early studies For those with splenomegaly or with known chronic liver disease, use of a spleen guard during activitiesSurveillanceGrowth should be monitored using standard growth charts so that nutritional intake can be adjusted to need.Regular monitoring by cardiology, gastroenterology, and a nutritionist is appropriate.At this time, the efficacy of presymptomaticscreeningfor vascular anomalies in individuals with ALGS has not been formally evaluated. The possibility of a vascular accident should be considered in any symptomatic individual and MRI, magnetic resonance angiography, and/or angiography to identify aneurysms, dissections, or bleeds should be pursued aggressively as warranted.Agents/Circumstances to AvoidContact sports should be avoided by all individuals, especially those with chronic liver disease, splenomegaly, and vascular involvement.Individuals with liver disease should avoid alcohol consumption.Evaluation of Relatives at RiskGiven the medical problems of this condition and their variability, it is appropriate to assess first-degree relatives for manifestations of the disorder. If aJAG1orNOTCH2pathogenic variant has been identified in aproband, at-risk relatives can be evaluated using genetic testing. If noJAG1orNOTCH2pathogenic variant has been identified, at-risk relatives can be assessed with measurement of liver enzymes, cardiac examination, eye examination, skeletal x-rays, and evaluation of facial features.SeeGenetic Counselingfor issues related to testing of at-risk relatives forgenetic counselingpurposes.Therapies Under InvestigationSearchClinicalTrials.govfor access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.Go to:Genetic CounselingGenetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. ED.Mode of InheritanceAlagille syndrome (ALGS) is inherited in anautosomal dominantmanner.Risk to Family MembersParents of aproband Approximately 30%-50% of individuals diagnosed with ALGS have anaffectedparent. Approximately 50%-70% ofaffectedindividuals have ALGS as the result of ade novopathogenic variant [Krantz et al 1998,Crosnier et al 1999,Spinner et al 2001]. Recommendations for the evaluation of parents of asimplex case(i.e., an individual with ALGS and no knownfamily historyof ALGS) include liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist. If theprobandhas an identifiableJAG1orNOTCH2pathogenic variant,molecular genetic testingof the parents is recommended. If theprobandshows a microdeletion of 20p12 onFISHtesting, FISH testing of both parents is appropriate.Sibs of aproband The risk to the sibs of theprobanddepends on the genetic status of the proband's parents. If a parent isaffected, the risk to sibs is 50%. When the parents are clinicallyunaffected, the risk to the sibs of aprobandappears to be low; however, multiple instances of a child inheriting ALGS from an apparently unaffected, phenotypically normal parent who was mosaic for a 20p microdeletion have been reported [Laufer-Cahana et al 2002]. If theJAG1orNOTCH2pathogenic variant ordeletionpresent in theprobandcannot be found in either parent, the risk to sibs is low, but greater than that of the general population because of the possibility ofgermline mosaicism[Giannakudis et al 2001].Offspring of aproband.Offspring of an individual with ALGS have a 50% chance of inheriting theJAG1orNOTCH2pathogenic variant. The clinical manifestations in the offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease.Other family members of aproband.The risk to other family members depends on the status of the proband's parents. If a parent isaffected, his or her family members are at risk.Related Genetic Counseling IssuesSee Management,Evaluation of Relatives at Riskfor information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.Considerations in families with an apparentde novopathogenic variant.When the parents of aprobandwith anautosomal dominantcondition areunaffected, it is likely that the proband has ade novopathogenic variant. However, possible non-medical explanations includingalternate paternityor maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.Family planning The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offergenetic counseling(including discussion of potential risks to offspring and reproductive options) to young adults who areaffectedor at risk.DNA bankingis the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA ofaffectedindividuals.Prenatal TestingMolecular genetic testing.If theJAG1orNOTCH2pathogenic variant has been identified in the family,prenatal diagnosisfor pregnancies at increased risk may be available from a a clinical laboratory that offers either testing of thegeneorcustom prenatal testing. Prenatal testing cannot predict the occurrence or severity of clinical manifestations.Fetal ultrasound examination.In fetuses at 50% risk for ALGS, fetal echocardiogram may detect a significant structural defect of the heart; however, a normal fetal echocardiogram does not eliminate the possibility of ALGS or the possibility of a structural cardiac abnormality in the fetus.Preimplantation genetic diagnosis (PGD)may be an option for some families in which the pathogenic variant has been identified in anaffectedfamily member.Go to:ResourcesGeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, clickhere. Alagille Syndrome Alliance10500 Southwest Starr DriveTualatin OR 97062Phone:503-885-0455Email:alagille@alagille.orgwww.alagille.org National Library of Medicine Genetics Home ReferenceAlagille syndrome American Liver Foundation75 Maiden LaneSuite 603New York NY 10038Phone:800-465-4837 (Toll-free HelpLine); 212-668-1000Fax:212-483-8179Email:info@liverfoundation.orgwww.liverfoundation.org Canadian Liver Foundation (CLF)2235 Sheppard Avenue EastSuite 1500Toronto Ontario M2J 5B5CanadaPhone:800-563-5483 (toll-free); 416-491-3353Fax:416-491-4952Email:clf@liver.cawww.liver.ca Childhood Liver Disease Research and Education Network (ChiLDREN)The Children's Hospital, Section of Pediatric Gastroenterology/Hepatology/Nutrition13123 East 16th AvenueSuite B290Aurora CO 80045Phone:720-777-2598Fax:720-777-7351Email:hines.joan@tchden.orgchildrennetwork.org Children's Liver Disease Foundation (CLDF)36 Great Charles StreetBirmingham B3 3JYUnited KingdomPhone:+44 (0) 121 212 3839Fax:+44 (0) 121 212 4300Email:info@childliverdisease.orgwww.childliverdisease.orgGo to:Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. ED.Table A.Alagille Syndrome: Genes and DatabasesGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD

JAG120p12.2Protein jagged-1JAG1 @ ZAC-GGMCCHMC - Human Genetics Mutation Database (JAG1)JAG1

NOTCH21p12-p11Neurogenic locus notch homolog protein 2NOTCH2 @ ZAC-GGMNOTCH2 databaseNOTCH2

Data are compiled from the following standard references: gene symbol fromHGNC; chromosomal locus, locus name, critical region, complementation group fromOMIM; protein name fromUniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, clickhere.Table B.OMIM Entries for Alagille Syndrome (View All in OMIM)118450ALAGILLE SYNDROME 1; ALGS1

600275NOTCH, DROSOPHILA, HOMOLOG OF, 2; NOTCH2

601920JAGGED 1; JAG1

610205ALAGILLE SYNDROME 2; ALGS2

JAG1Gene structure.JAG1comprises 26 exons. For a detailed summary ofgeneand protein information, seeTable A,Gene Symbol.Benign allelic variants.A number of benign variants (benign polymorphisms) that are not expected to result in a diseasephenotypehave been reported [Krantz et al 1998,Crosnier et al 1999,Spinner et al 2001].Pathogenic allelic variants.More than 226 pathogenic variants have been identified in individuals with Alagille syndrome (ALGS) (~70% of those tested). Mutation types have included:deletionof the entireJAG1gene(4%), protein-truncating mutations (frameshift and nonsense) (69%),splicingmutations (16%), and missense mutations (11%) [Krantz et al 1998,Crosnier et al 1999,Krantz et al 1999,Onouchi et al 1999,Pilia et al 1999,Crosnier et al 2000,Heritage et al 2000,Colliton et al 2001,Giannakudis et al 2001,Ropke et al 2003]. Two thirds of the detectable pathogenic variants are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, 24; the remainder are identified by sequencing the other exons.JAG1pathogenic variants are distributed throughout the gene with no clustering or mutational 'hot spots.Normalgene product.Jagged-1 is a cell surface protein that functions as a ligand for the neurogeniclocusnotch homolog protein 2(Notch) transmembrane receptors, key signaling molecules found on the surface of a variety of cells. Jagged-1 and Notch are components of the highly conserved Notch signaling pathway, which has been studied primarily in the fruit flyDrosophila melanogasterand in the nematodeCaenorhabditis elegans. It functions in many cell types throughout development to regulate cell fate decisions. The name Notch derives from the characteristic notched wing found in fruit flies carrying only one functional copy of the gene. Homozygous mutations in Notch in fruit flies are lethal, and the flies show hypertrophy of the nervous system. The finding thatmutationofJAG1causes ALGS indicates that Notch signaling is important in the development of theaffectedorgans (i.e., liver, heart, kidney, facial structures, skeleton, and eye).There are multiple other Notch pathway genes involved in human disease [Louvi & Artavanis-Tsakonas 2012,Penton et al 2012]. Notch1 is inactivated by chromosomal translocations in T lymphoblastic leukemias. Additionally, pathogenic variants inNOTCH1have been associated withisolatedcardiac defects [Greenway et al 2009]. Pathogenic variants inNOTCH3cause cerebralautosomal dominantarteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Pathogenic variants inexon34 ofNOTCH2cause Hajdu-Chenney syndrome [Simpson et al 2011] (seeGenetically Related Disorders). Finally, pathogenic variants in the Notch pathway genesDLL3,HES7,LFNG, andMESP2have been shown to causespondylocostal dysostosis(SCD) andspondylothoracic dysostosis(STD) [Turnpenny et al 2007,Dunwoodie 2009].Abnormalgene product.Haploinsufficiency of Jagged-1 has been shown to result in ALGS as evidenced by those individuals with ALGS who have a cytogenetically detectabledeletionofchromosome20p12 encompassing the entireJAG1gene. Haploinsufficiency is likely the pathogenic mechanism in the majority of cases of ALGS, as most pathogenic variants result in or predict a severely truncated protein product, lacking the transmembrane region necessary for the protein product to embed in the cell membrane and participate in signaling. Evidence has been presented inDrosophilathat some of these truncated products can be secreted from the cell and can interfere with the signaling in adominant-negative manner; however, no such evidence has been identified in humans to date. The identification of a significant number of missense mutations (11%) [Krantz et al 1998,Crosnier et al 1999] may indicate important regions ofJAG1, and it is possible that the resultant gene products may be produced and targeted to the cell surface and may exert a dominant-negative effect. However, in a few cases studied, the proteins produced as a result of missense mutations are improperly trafficked through the cell, and therefore fail to appear on the cell surface, resulting in functionalhaploinsufficiency[Morrissette et al 2001,Iso et al 2003,Penton et al 2012].NOTCH2Gene structure.NOTCH2comprises 34 exons. For a detailed summary ofgeneand protein information, seeTable A,Gene Symbol.Benign allelic variants.A number of benign variants (benign polymorphisms) that are not expected to result in a diseasephenotypehave been reported [McDaniell et al 2006,Kamath et al 2012a].Pathogenic allelic variants.SeeTable 3. Ten different pathogenic variants have been identified in eleven unrelated families with clinical features of ALGS including one splice site alteration, oneframeshift mutation, onenonsense mutation, and seven missense mutations (Table 3). The splice site alteration (c.5930-1G>A) results in the loss of the splice acceptor ofexon33, which causes aberrantsplicingout of this exon, followed by a premature terminationcodon. The frameshift mutation, p.Ser856LeufsTer17 [seeTable 3], is located in exon 16 and 18. The nonsense mutation (p.Arg2003Ter) has been seen in two unrelated families. The seven missense mutations shown inTable 3are localized in both the EGF-like repeats of the extracellular domain and the ANK repeats of the intracellular domain of Notch 2 [Kamath et al 2012a,Penton et al 2012].Table 3.SelectedNOTCH2Pathogenic VariantsDNANucleotide ChangeProtein Amino Acid ChangeReference Sequences

c.1331G>Ap.Cys444TyrNM_024408.2NP_077719.2

c.1117T>Cp.Cys373Arg

c.1180C>Tp.Pro394Ser

c.1147C>Tp.Pro383Ser

c.5857C>Tp.Arg1953Cys

c.5858G>Ap.Arg1953His

c.5930-1G>A--

c.1438T>Cp.Cys480Arg

c.2566_2567delAGp.Ser856LeufsTer17

c.6007C>Tp.Arg2003Ter

Note on variant classification: Variants listed in the table have been provided by the authors.GeneReviewsstaff have not independently verified the classification of variants.Note on nomenclature:GeneReviewsfollows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). SeeQuick Referencefor an explanation of nomenclature.Normalgene product.Neurogeniclocusnotch homolog protein 2 (Notch 2) encodes a member of the Notch family of transmembrane receptors. The Notch receptors (Notch 1, 2, 3, and 4 in humans) share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. The intracellular portion includes seven ankyrin (ANK) repeats that are known to be protein-protein interaction motifs. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. The protein functions as a receptor for membrane-bound ligands and may play a role in vascular, renal, and hepatic development.Abnormalgene product.The eleven pathogenic variants identified to date occur in different parts of the Notch 2 protein. Six are in the EGF-like repeats (extracellular domain) and four are in the ankyrin (ANK) repeats. Functional data and/or computer predictions are available for the reported missense mutations [Kamath et al 2012a].Go to:ReferencesLiterature Cited1. Arvay JL, Zemel BS, Gallagher PR, Rovner AJ, Mulberg AE, Stallings VA, Haber BA. Body composition of children aged 1 to 12 years with biliary atresia or Alagille syndrome.J Pediatr Gastroenterol Nutr.2005;40:14650.[PubMed]2. Bales CB, Kamath BM, Munoz PS, Nguyen A.PIccoli DA, Spinner NB, Horn D, Shults J, Leonard MB, Grimberg A, Loomes KM2010.Pathologic lower extremity fractures in children with Alagille syndrome.J Pediatr Gastroenterol Nutr.516670. [PMC free article] [PubMed]3. Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJ, Woyciechowski S, Garvarini J, Loomes KM, Krantz ID, Urban Z, Gelb BD, Goldmuntz E, Spinner NB. Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.Hum Mutat.2010;31:594601.[PMC free article] [PubMed]4. Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients.Hum Mutat.2001;17:1512.[PubMed]5. Crosnier C, Attie-Bitach T, Encha-Razavi F, Audollent S, Soudy F, Hadchouel M, Meunier-Rotival M, Vekemans M. JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome.Hepatology.2000;32:57481.[PubMed]6. Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome.Gastroenterology.1999;116:11418.[PubMed]7. Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies of the aetiology of neonatal hepatitis and biliary atresia.Arch Dis Child.1977;52:3607.[PMC free article] [PubMed]8. Dingemann C, Baumann U, Petersen C, Lentze MJ, Ure B. Ileal exclusion for intractable pruritus in Alagille syndrome.Eur J Pediatr Surg.2012;22:2513.[PubMed]9. Dunwoodie SL. The role of Notch in patterning the human vertebral column.Curr Opin Genet Dev.2009;19:32937.[PubMed]10. Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC. Familial Tetralogy of Fallot caused by mutation in the jagged1 gene.Hum Mol Genet.2001;10:1639.[PubMed]11. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome.J Pediatr Gastroenterol Nutr.2010;51:75965.[PubMed]12. El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features.Eur J Ophthalmol.2011;21:199206.[PubMed]13. Emerick KM, Krantz ID, Kamath BM, Darling C, Burrowes DM, Spinner NB, Whitington PF, Piccoli DA. Intracranial vascular abnormalities in patients with Alagille syndrome.J Pediatr Gastroenterol Nutr.2005;41:99107.[PubMed]14. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis.Hepatology.1999;29:8229.[PubMed]15. Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome.Hepatology.2002;35:15016.[PubMed]16. Englert C, Grabhorn E, Burdelski M, Ganschow R. Liver transplantation in children with Alagille syndrome: indications and outcome.Pediatr Transplant.2006;10:1548.[PubMed]17. Giannakudis J, Ropke A, Kujat A, Krajewska-Walasek M, Hughes H, Fryns JP, Bankier A, Amor D, Schlicker M, Hansmann I. Parental mosaicism of JAG1 mutations in families with Alagille syndrome.Eur J Hum Genet.2001;9:20916.[PubMed]18. Goldman M, Pranikoff T. Biliary disease in children.Curr Gastroenterol Rep.2011;13:193201.[PubMed]19. Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA, Gorham JM, Gabriel S, Altshuler DM, Quintanilla-Dieck Mde L, Artunduaga MA, Eavey RD, Plenge RM, Shadick NA, Weinblatt ME, De Jager PL, Hafler DA, Breitbart RE, Seidman JG, Seidman CE. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.Nat Genet.2009;41:9315.[PMC free article] [PubMed]20. Guegan K, Stals K, Day M, Turnpenny P, Ellard S. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome.Clin Genet.2012;82:3340.[PubMed]21. Gurkan A, Emre S, Fishbein TM, Brady L, Millis M, Birnbaum A, Kim-Schluger L, Sheiner PA. Unsuspected bile duct paucity in donors for living-related liver transplantation: two case reports.Transplantation.1999;67:4168.[PubMed]22. Heritage ML, MacMillan JC, Colliton RP, Genin A, Spinner NB, Anderson GJ. Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population.Hum Mutat.2000;16:40816.[PubMed]23. Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA. Ocular abnormalities in Alagille syndrome.Ophthalmology.1999;106:3307.[PubMed]24. Iso T, Hamamori Y, Kedes L. Notch signaling in vascular development.Arterioscler Thromb Vasc Biol.2003;23:54353.[PubMed]25. Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations.J Med Genet.2003;40:8915.[PMC free article] [PubMed]26. Kamath BM, Baur RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard LD, Ling S, Lee Ng V.Le Hoang Phuc, Piccoli DA, Spinner NB2012a.NOTCH2 mutations in Alagille syndrome.J Med Genet4913844. [PMC free article] [PubMed]27. Kamath BM, Loomes KM, Oakey RJ, Krantz ID. Supernumerary digital flexion creases: an additional clinical manifestation of Alagille syndrome.Am J Med Genet.2002a;112:1715.[PubMed]28. Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome.J Pediatr Gastroenterol Nutr.2010a;50:5806.[PubMed]29. Kamath BM, Munoz PD, Bab N, Baker A, Chen Z, Spinner NB, Piccoli DA. A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome.J Pediatr Gastroenterol Nutr.2010b;50:52630.[PMC free article] [PubMed]30. Kamath BM, Podkameni G, Hutchinson AL, Leonard LD, Gerfen J, Krantz ID, Piccoli DA, Spinner NB, Loomes KM, Meyers K. Renal anomalies in Alagille syndrome: A disease-defining feature.Am J Med Genet Part A.2012b;158A:859.[PubMed]31. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.Circulation.2004;109:13548.[PubMed]32. Kamath BM, Stolle C, Bason L, Colliton RP, Piccoli DA, Spinner NB, Krantz ID. Craniosynostosis in Alagille syndrome.Am J Med Genet.2002b;112:17680.[PubMed]33. Kamath BM, Thiel BD, Gai X, Conlin LK, Munoz PS, Glessner J, Clark D, Warthen DM, Shaikh TH, Mihci E, Piccoli DA, Grant SF, Hakonarson H, Krantz ID, Spinner NB. SNP array mapping of chromosome 20p deletions: genotypes, phenotypes, and copy number variation.Hum Mutat.2009;30:3718.[PMC free article] [PubMed]34. Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, Bucuvalas J. Studies of Pediatric Liver Transplantation. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience.Liver Transpl.2012c;18:9408.[PubMed]35. Kasahara M, Kiuchi T, Inomata Y, Uryuhara K, Sakamoto S, Ito T, Fujimoto Y, Ogura Y, Oike F, Tanaka K. Living-related liver transplantation for Alagille syndrome.Transplantation.2003;75:214750.[PubMed]36. Kaye AJ, Rand EB, Munoz PS, Spinner NB, Flake AW, Kamath BM. Effect of Kasai procedure on hepatic outcome in Alagille syndrome.J Pediatr Gastroenterol Nutr.2010;51:31921.[PubMed]37. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG, Chiang MY, Huebner-Chan DR, Bailey NG, Yang DT, Bhagat G, Miranda RN, Bahler DW, Medeiros LJ, Lim MS, Elenitoba-Johnson KS. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.J Exp Med.2012;209:155365.[PMC free article] [PubMed]38. Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.Am J Hum Genet.1998;62:13619.[PMC free article] [PubMed]39. Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, Goldmuntz E, Spinner NB. Jagged1 mutations in patients ascertained with isolated congenital heart defects.Am J Med Genet.1999;84:5660.[PubMed]40. Laufer-Cahana A, Krantz ID, Bason LD, Lu FM, Piccoli DA, Spinner NB. Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion.Am J Med Genet.2002;112:1903.[PubMed]41. Le Caignec C, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, Moisan JP. Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.Am J Hum Genet.2002;71:1806.[PMC free article] [PubMed]42. Leonard LD, Chao G, Baker A, Loomes K, Spinner NB. Clinical utility gene card for: Alagille Syndrome (ALGS).Eur J Hum Genet.2014 Mar;22(3)[PMC free article] [PubMed]43. Lin HC, Hoang PL, Hutchinson A, Chao G, Gerfen J, Loomes KM, Krantz ID, Kamath BM, Spinner NB. Alagille syndrome in a Vietnamese cohort: Mutation analysis and assessment of facial features.Am J Med Genet Part A.2012;158A:100513.[PMC free article] [PubMed]44. Louvi A, Artavanis-Tsakonas S. Notch and disease: a growing field.Semin Cell Dev Biol.2012 Jun;23:47380.[PMC free article] [PubMed]45. Lu F, Morrissette JJ, Spinner NB. Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.Am J Hum Genet.2003;72:106570.[PMC free article] [PubMed]46. Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, Boycott KM, Ste-Marie LG, McKiernan FE, Marik I, Van Esch H., FORGE Canada Consortium. Michaud JL, Samuels ME. Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.Hum Mutat.2011;32:11147.[PubMed]47. Makino S, Ohkubo Y, Tampo H. Optical coherence tomography and fundus autofluorescence imaging study of chorioretinal atrophy involving the macula in Alagille syndrome.Clin Ophthalmol.2012;6:14458.[PMC free article] [PubMed]48. Mattei P, von Allmen D, Piccoli D, Rand E. Relief of intractable pruritis in Alagille syndrome by partial external biliary diversion.J Pediatr Surg.2006;41:1047.[PubMed]49. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway.Am J Hum Genet.2006;79:16973.[PMC free article] [PubMed]50. McElhinney DB, Krantz ID, Bason L, Piccoli DA, Emerick KM, Spinner NB, Goldmuntz E. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome.Circulation.2002;106:256774.[PubMed]51. Morrissette JD, Colliton RP, Spinner NB. Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.Hum Mol Genet.2001;10:40513.[PubMed]52. Narula P, Gifford J, Steggall MA, Lloyd C, Van Mourik ID, Mckiernan PJ, Willshaw HE, Kelly D. Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome.J Pediatr Gastroenterol Nutr.2006;43:34852.[PubMed]53. Onouchi Y, Kurahashi H, Tajiri H, Ida S, Okada S, Nakamura Y. Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome.J Hum Genet.1999;44:2359.[PubMed]54. Pawlowska J, Socha P, Jankowska I. Factors affecting catch-up growth after liver transplantation in children with cholestatic liver diseases.Ann Transplant.2010;15:726.[PubMed]55. Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease.Semin Cell Dev Biol.2012;23:4507.[PMC free article] [PubMed]56. Pilia G, Uda M, Macis D, Frau F, Crisponi L, Balli F, Barbera C, Colombo C, Frediani T, Gatti R, Iorio R, Marazzi MG, Marcellini M, Musumeci S, Nebbia G, Vajro P, Ruffa G, Zancan L, Cao A, DeVirgilis S. Jagged-1 mutation analysis in Italian Alagille syndrome patients.Hum Mutat.1999;14:394400.[PubMed]57. Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Gornbein JA, McDiarmid SV, Vargas JH. Does liver transplantation affect growth pattern in Alagille syndrome?Liver Transpl.2000;6:5827.[PubMed]58. Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A. omprehensive genotypey-phenotype analysis in 230 patients with tetralogy of Fallot.J Med Genet.2010;47:32131.[PubMed]59. Rocha R, Soro I, Leito A, Silva ML, Leo M. Moyamoya vascular pattern in Alagille syndrome.Pediatr Neurol.2012;47:1258.[PubMed]60. Ropke A, Kujat A, Graber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.Hum Mutat.2003;21:100.[PubMed]61. Salem JE, Bruguiere E, Iserin L, Guiochon-Mantel A, Plouin PF. Hypertension and aortorenal disease in Alagille syndrome.J Hypertens.2012;30:13006.[PubMed]62. Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients.Pediatr Radiol.2002;32:1149.[PubMed]63. Sheflin-Findling S, Arnon R, Lee S, Chu J, Henderling F, Kerkar N, Iyer K. Partial internal biliary diversion for Alagille syndrome: case report and review of the literature.J Pediatr Surg.2012;47:14536.[PubMed]64. Shneider BL. Liver transplantation for Alagille syndrome: the jagged edge.Liver Transpl.2012 Aug;18:87880.[PubMed]65. Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.Nat Genet.2011;43:3035.[PubMed]66. Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. Jagged1 mutations in Alagille syndrome.Hum Mutat.2001;17:1833.[PubMed]67. Subramaniam P, Knisely A, Portmann B, Qureshi SA, Aclimandos WA, Karani JB, Baker AJ. Diagnosis of Alagille syndrome-25 years of experience at King's College Hospital.J Pediatr Gastroenterol Nutr.2011;52:849.[PubMed]68. Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, Pourqui O, Kusumi K, Dunwoodie S. Abnormal vertebral segmentation and the notch signaling pathway in man.Dev Dyn.2007 Jun;236:145674.[PubMed]69. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management.Eur J Hum Genet.2012;3:2517.[PMC free article] [PubMed]70. Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez P, Piccoli DA, Krantz ID, Spinner NB. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate.Hum Mutat.2006;27:43643.[PubMed]71. Woolfenden AR, Albers GW, Steinberg GK, Hahn JS, Johnston DCC, Farrell K. Moyamoya syndrome in children with Alagille syndrome: additional evidence of a vasculopathy.Pediatrics.1999;103:5058.[PubMed]72. Zanotti S, Canalis E. Notch and the skeleton.Mol Cell Biol.2012;30:88696.[PMC free article] [PubMed]Suggested Reading1. Antsaklis A, Anastasakis E, Mousiolis A, Papantoniou N, Mesogitis S, Daskalakis G. Alagille syndrome.J Obstet Gynaecol.2011;31:4501.[PubMed]2. Kamath BM, Schwarz KB, Hadzi N. Alagille syndrome and liver transplantation.J Pediatr Gastroenterol Nutr.2010;50:115.[PubMed]3. Meunier-Rotival M, Hadchouel M. Alagille syndrome (ALGS).Atlas of Genetics and Cytogenetics in Oncology and Haematology. Availableonline. 2005. Accessed 3-20-15.4. Rahmoune FC, Bruyre M, Tecsy M, Benhamou D. Alagille syndrome and pregnancy: anesthetic management for cesarean section.Int J Obstet Anesth.2011;20:3558.[PubMed]5. Shaffer LG, Ledbetter DH, Lupski JR. Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds.The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID).Chap 65. New York, NY: McGraw-Hill. 2015.