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Alagille Syndrome

Synonyms: Arteriohepatic Dysplasia, Syndromic Bile Duct Paucity

, PhD, , BA, and , MD.

Author Information
, PhD
Professor of Pathology and Laboratory Medicine, Perelman School of Medicine
University of Pennsylvania
Professor of Pediatrics, Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
, BA
Clinical Research Assistant, Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
, MD
Professor of Pediatrics and Genetics, Perelman School of Medicine
University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: February 28, 2013.

Summary

Disease 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; congenital cardiac 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 are JAG1 and NOTCH2. Sequence analysis of JAG1 detects mutations in more than 89% of individuals who meet clinical diagnostic criteria; deletion/duplication analysis detects exonic and whole-gene deletions, including microdeletion of 20p12, in approximately 7% of affected individuals. Mutations in NOTCH2 are 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: Offer molecular genetic testing to first-degree relatives if the family-specific mutation is known or assess first-degree relatives for disease manifestations.

Genetic counseling. ALGS is inherited in an autosomal dominant manner. Approximately 30%-50% of individuals have an inherited mutation and about 50%-70% have a de novo mutation. For parents of a child with an apparent de novo mutation, recurrence risk to subsequent offspring of having Alagille syndrome is low but greater than in the general population because of the possibility of germline 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 disease-causing mutation in an affected family member is known. Prenatal testing cannot predict the occurrence or severity of clinical manifestations.

Diagnosis

Clinical Diagnosis

The 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 features

In 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 highly variable expressivity of the clinical manifestations [Goldman & Pranikoff 2011, Guegan et al 2012].

Individuals with an affected relative. 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 affected first-degree relative is identified, the presence of one or more features is considered sufficient to make the diagnosis on clinical grounds.

Molecular Genetic Testing

Genes

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Alagille Syndrome

Gene 1Proportion of ALGS Attributed to Mutations in This GeneTest MethodMutations Detected 2
JAG189%Sequence analysis / mutation scanning 3Sequence variants 4
See footnote 5Sequence analysis of select exonsSequence variants in select exons 4
~5%-7% 6Deletion/duplication analysis (including FISH7Deletion and duplication of exon(s) and entire gene deletion 8
Linkage analysisNASee footnote 9
NOTCH21%-2% 10Sequence analysisSequence variants 4
UnknownDeletion/duplication analysis 7Unknown, none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

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 of deletion detected may vary by method and by laboratory.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Extent of deletion detected may vary by method and by laboratory [Kamath et al 2009].

9. Linkage analysis may be performed if the family pedigree structure is sufficient and family members agree to the testing process (1) to confirm cosegregation of a potential pathogenic mutation with disease in individual families and (2) as an ancillary test to obtain preliminary data prior to the completion of sequence analysis. Linkage testing cannot be used to confirm the diagnosis of Alagille syndrome.

10. McDaniell et al [2006], Kamath et al [2012a]

Testing Strategy

To confirm/establish the diagnosis of ALGS in a proband

  • In situations in which the diagnosis is suspected but the criteria for clinical diagnosis are not met, sequence analysis of JAG1 should be performed first, as this identifies mutations in more than 89% of persons with a JAG1 mutation.
  • If no mutations are detected by sequence analysis of JAG1, deletion/duplication analysis can be performed to detect deletions or duplications of JAG1 exon(s) or of the whole gene. Given the wide availability of targeted CMA testing, this could be used to determine both the presence and extent of a chromosomal deletion/duplication involving JAG1 if there was high density of probes in the region. Other deletion/duplication methods (e.g., MLPA) also detect exonic or whole-gene deletions.
  • If a deletion involving the entire JAG1 gene is identified, a full cytogenetic study may be considered to determine if a rare chromosomal rearrangement (translocation or inversion) 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 a chromosome deletion.
  • NOTCH2 molecular genetic testing should be considered when the diagnosis is strongly suspected on clinical grounds, but no JAG1 mutation/deletion/duplication was identified.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies at risk for ALGS require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Alagille syndrome (ALGS) is a multisystem disorder. Studies of families with multiple affected members and/or JAG1 mutations 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 53 mutation-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 by Emerick et al [1999] and Subramaniam et al [2011] discuss the frequency of clinical manifestations in individuals with ALGS (Table 2).

Table 2. Clinical Manifestations of ALGS in Two Studies

Clinical FindingFrequency (% of Individuals)
Emerick et al [1999]Subramaniam et al [2011]
Bile duct paucity 69/81 (85%)77/103 (75%)
Chronic cholestasis 88/92 (96%)104/117 (89%)
Cardiac murmur 90/92 (97%)107/117 (91%)
Eye findings65/83 (78%)72/117 (61%) 1
Vertebral anomalies 37/71 (51%)44/117 (39%) 2
Characteristic facies 86/92 (96%)91/117 (77%)
Renal disease 28/69 (40%)27/117 (23%)
Pancreatic insufficiency7/17 (41%)NR
Growth retardation 27/31 (87%)NR
Intellectual disability2/92 (2%)NR
Developmental delay 15/92 (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 with JAG1 mutations have no detectable hepatic manifestations [Gurkan et al 1999, Krantz et al 1999, Kamath et al 2003], in most affected persons 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% of affected individuals, 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 identify affected individuals 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 otherwise unaffected can complicate the identification of relatives with the gene mutation.

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 (see Figure 1).

Figure 1

Figure

Figure 1. Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes, and pointed chin.

Although the facial phenotype in 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

Genotype-Phenotype Correlations

The phenotype of ALGS caused by mutations in JAG1 is indistinguishable from the phenotype caused by mutations in NOTCH2. Initially, 3/3 relatives who had NOTCH2 mutations had 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 4/9 affected individuals evaluated for renal anomalies. This observation is consistent with the renal involvement observed in those with JAG1 mutations. However, it is important to note that the number of individuals identified with ALGS caused by NOTCH2 mutations is still too small to draw any conclusions about genotype-phenotype correlations [Kamath et al 2012a].

No genotype-phenotype correlations exist between clinical manifestations of ALGS and specific JAG1 mutation types or location within the gene [Krantz et al 1998, Crosnier et al 1999, Spinner et al 2001, McElhinney et al 2002]. However, two families with JAG1 missense 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 with haploinsufficiency and an individual with two normal copies of JAG1, suggesting that the heart is more sensitive to JAG1 dosage than the liver [Eldadah et al 2001, Lu et al 2003].

Individuals with ALGS with more severe impairment may have a larger deletion of chromosome 20p12 encompassing the entire JAG1 gene as well as other genes in the region.

Penetrance

ALGS demonstrates highly variable expressivity with clinical features ranging from subclinical to severe.

JAG1 mutations. To determine the range and frequency of clinical findings in individuals with a JAG1 mutation and hence, the penetrance, Kamath et al [2003] studied 53 mutation-positive relatives of probands with ALGS. Their findings:

  • 21% met diagnostic criteria independent of family 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, penetrance is 96%; however, only 53% meet clinical diagnostic criteria for ALGS.

NOTCH2 mutations. Penetrance appears complete in the ten individuals so far identified with NOTCH2 mutations, although expressivity is variable [Kamath et al 2012a].

Anticipation

ALGS has not shown anticipation. Bias of ascertainment may occur because individuals with a JAG1 mutation who reproduce have milder disease than infants who present with the severe phenotype of neonatal cholestasis [Author, personal observation].

Prevalence

The 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 by Kamath et al [2003], the authors estimate that the incidence of ALGS is 1:30,000-1:50,000 live births, but due to the variable phenotype, it remains underdiagnosed [Kamath et al 2003]. The prevalence across populations appears to be stable.

Differential Diagnosis

See Alagille 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 or galactosemia need 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 paucity is 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 (congenital CMV, 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 with intrahepatic cholestasis include the autosomal recessive disorders progressive 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 embryotoxon is seen in Rieger syndrome, Bannayan-Riley-Ruvalcaba syndrome (one of the phenotypes of the PTEN hamartoma 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 abnormalities are seen in isolation as well as in syndromes such as Noonan syndrome, Watson syndrome (pulmonic stenosis and neurofibromatosis type 1), LEOPARD syndrome, Down syndrome, and Williams syndrome. These other syndromes can be distinguished by other associated clinical findings and/or molecular genetic testing.

Several of the cardiac defects described in ALGS, particularly ventricular septal defect and tetralogy of Fallot, are commonly seen in individuals with deletion 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 the deletion 22q11.2 syndrome; testing for this deletion using the specific FISH probe distinguishes the two disorders [Greenway et al 2009].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 consultation

Treatment of Manifestations

A 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% of affected individuals; 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 by Kaye 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 Complications

The 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 activities

Surveillance

Growth 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 presymptomatic screening for 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 Avoid

Contact 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 Risk

Given the medical problems of this condition and their variability, it is appropriate to assess first-degree relatives for manifestations of the disorder.

  • If a JAG1 or NOTCH2 mutation has been identified in a proband, at-risk relatives can be evaluated using genetic testing.
  • If no JAG1 or NOTCH2 mutation 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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic 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 Inheritance

Alagille syndrome (ALGS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent is affected, the risk to sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears 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 the JAG1 or NOTCH2 mutation or deletion present in the proband cannot be found in either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism [Giannakudis et al 2001].

Offspring of a proband. Offspring of an individual with ALGS have a 50% chance of inheriting the JAG1 or NOTCH2 mutation. 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 a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are unaffected, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or 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 offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Prenatal testing cannot predict the occurrence or severity of clinical manifestations.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews 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, click here.

  • Alagille Syndrome Alliance
    10500 Southwest Starr Drive
    Tualatin OR 97062
    Phone: 503-885-0455
    Email: alagille@alagille.org
  • National Library of Medicine Genetics Home Reference
  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
    Email: info@liverfoundation.org
  • Canadian Liver Foundation (CLF)
    2235 Sheppard Avenue East
    Suite 1500
    Toronto Ontario M2J 5B5
    Canada
    Phone: 800-563-5483 (toll-free); 416-491-3353
    Fax: 416-491-4952
    Email: clf@liver.ca
  • Childhood Liver Disease Research and Education Network (ChiLDREN)
    The Children's Hospital, Section of Pediatric Gastroenterology/Hepatology/Nutrition
    13123 East 16th Avenue
    Suite B290
    Aurora CO 80045
    Phone: 720-777-2598
    Fax: 720-777-7351
    Email: hines.joan@tchden.org
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
    Email: info@childliverdisease.org

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

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

JAG1

Gene structure. JAG1 comprises 26 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A number of benign variants (benign polymorphisms) that are not expected to result in a disease phenotype have been reported [Krantz et al 1998, Crosnier et al 1999, Spinner et al 2001].

Pathogenic allelic variants. More than 226 mutations have been identified in individuals with Alagille syndrome (ALGS) (~70% of those tested). Mutation types have included: deletion of the entire JAG1 gene (4%), protein-truncating mutations (frameshift and nonsense) (69%), splicing mutations (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 mutations are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, 24; the remainder are identified by sequencing the other exons. JAG1 mutations are distributed throughout the gene with no clustering or mutational 'hot spots’.

Normal gene product. Jagged-1 is a cell surface protein that functions as a ligand for the neurogenic locus notch 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 fly Drosophila melanogaster and in the nematode Caenorhabditis 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 that mutations in JAG1 cause ALGS indicates that Notch signaling is important in the development of the affected organs (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, mutations in NOTCH1 have been associated with isolated cardiac defects [Greenway et al 2009]. Mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Mutations in exon 34 of NOTCH2 cause Hajdu-Chenney syndrome [Simpson et al 2011] (see Genetically Related Disorders). Finally, mutations in the Notch pathway genes DLL3, HES7, LFNG, and MESP2 have been shown to cause spondylocostal dysostosis (SCD) and spondylothoracic dysostosis (STD) [Turnpenny et al 2007, Dunwoodie 2009].

Abnormal gene product. Haploinsufficiency of Jagged-1 has been shown to result in ALGS as evidenced by those individuals with ALGS who have a cytogenetically detectable deletion of chromosome 20p12 encompassing the entire JAG1 gene. Haploinsufficiency is likely the pathogenic mechanism in the majority of cases of ALGS, as most mutations 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 in Drosophila that some of these truncated products can be secreted from the cell and can interfere with the signaling in a dominant-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 of JAG1, 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 functional haploinsufficiency [Morrissette et al 2001, Iso et al 2003, Penton et al 2012].

NOTCH2

Gene structure. NOTCH2 comprises 34 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A number of benign variants (benign polymorphisms) that are not expected to result in a disease phenotype have been reported [McDaniell et al 2006, Kamath et al 2012a].

Pathogenic allelic variants. See Table 3. Ten different mutations have been identified in eleven unrelated families with clinical features of ALGS including one splice site alteration, one frameshift mutation, one nonsense mutation, and seven missense mutations (Table 3). The splice site alteration (c.5930-1G>A) results in the loss of the splice acceptor of exon 33, which causes aberrant splicing out of this exon, followed by a premature termination codon. The frameshift mutation, p.Ser856LeufsTer17 [see Table 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 in Table 3 are 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. Selected NOTCH2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.1331G>Ap.Cys444TyrNM_024408​.2
NP_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. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Neurogenic locus notch 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.

Abnormal gene product. The eleven mutations 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].

References

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Suggested Reading

  1. Antsaklis A, Anastasakis E, Mousiolis A, Papantoniou N, Mesogitis S, Daskalakis G. Alagille syndrome. J Obstet Gynaecol. 2011;31:450–1. [PubMed: 21627437]
  2. Kamath BM, Schwarz KB, Hadzić N. Alagille syndrome and liver transplantation. J Pediatr Gastroenterol Nutr. 2010;50:11–5. [PubMed: 19949348]
  3. Meunier-Rotival M, Hadchouel M. Alagille syndrome (ALGS). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2005. Accessed 11-14-13.
  4. Rahmoune FC, Bruyère M, Tecsy M, Benhamou D. Alagille syndrome and pregnancy: anesthetic management for cesarean section. Int J Obstet Anesth. 2011;20:355–8. [PubMed: 21925870]
  5. Shaffer LG, Ledbetter DH, Lupski JR. Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 65. Available online. Accessed 3-26-14.

Chapter Notes

Author History

Lynn D Bason, MS, CGC; Children's Hospital of Philadelphia (2000-2003)
Anne L Hutchinson, BS; Children's Hospital of Philadelphia (2010-2013)
Binita M Kamath, MBBChir MRCP; The Hospital for Sick Children (2003-2013)
Ian D Krantz, MD (2000-present)
Laura D Leonard, BA (2013-present)
Nancy B Spinner, PhD (2000-present)

Revision History

  • 28 February 2013 (me) Comprehensive update posted live
  • 20 July 2010 (cd) Revision: prenatal testing available for NOTCH2 mutations
  • 11 May 2010 (me) Comprehensive update posted live
  • 2 July 2007 (me) Comprehensive update posted to live Web site
  • 18 May 2006 (cd) Revision: NOTCH2 mutations identified in individuals with Alagille syndrome
  • 18 February 2005 (mr) Comprehensive update posted to live Web site
  • 2 February 2004 (ns) Author revisions
  • 16 June 2003 (cd) Revision: DNA and RNA sequence analysis available on clinical basis
  • 4 February 2003 (me) Comprehensive update posted to live Web site
  • 19 May 2000 (me) Review posted to live Web site
  • January 2000 (ns) Original submission
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Tests in GTR by Gene

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