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Alagille Syndrome

[Arteriohepatic Dysplasia, Syndromic Bile Duct Paucity. Includes: JAG1-Related Alagille Syndrome, NOTCH2-Related Alagille Syndrome]

Summary

Disease characteristics.  Alagille syndrome (AGS) 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 AGS 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 AGS is primarily based on clinical findings. The two genes associated with AGS are JAG1 and NOTCH2. Sequence analysis of JAG1 detects mutations in over 88% of individuals who meet clinical diagnostic criteria; fluorescence in situ hybridization (FISH) detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 7% of affected individuals. Mutations in NOTCH2 are observed in fewer than 1% of individuals with AGS.

Management.  Treatment of manifestations: management by a multidisciplinary team (medical genetics, gastroenterology, nutrition, cardiology, ophthalmology, liver transplantation); choloretic agents (ursodeoxycholic acid), other medications (cholestyramine, rifampin, naltrexone), and, when necessary, partial external biliary diversion for pruritis and xanthomas; liver transplantation for end-stage liver disease; standard treatment for cardiac, renal, neurologic involvement. Prevention of secondary complications: optimization of nutrition to maximize growth and development; fat-soluble vitamin supplementation; for those with splenomegaly, use of a spleen guard during activities. Surveillance: routine monitoring of growth, nutrition, and heart. Agents/circumstances to avoid: contact sports if splenomegaly is present; alcohol if liver disease is present. Testing of relatives at risk: Offer molecular genetic testing to first-degree relatives if family-specific mutation is known or assess first-degree relatives for disease manifestations.

Genetic counseling.   AGS 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. The parents of a child with a de novo mutation have a low but increased risk for recurrence 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 is possible if the JAG1 disease-causing mutation or a deletion detected by FISH is identified in an affected family member. Although testing can determine whether or not the fetus has inherited the JAG1 disease-causing mutation or deletion, it cannot predict the occurrence or severity of clinical manifestations. Prenatal testing for Alagille syndrome caused by mutations in NOTCH2 may be available through laboratories offering custom prenatal testing.

Diagnosis

Clinical Diagnosis

The clinical diagnostic criteria for Alagille syndrome (AGS) 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 AGS, bile duct paucity is not present in infancy in many individuals ultimately shown to have AGS. 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.

Note: The diagnosis of Alagille syndrome may be difficult because of the highly variable expressivity of the clinical manifestations.

Individuals with an affected relative.   The diagnosis of AGS 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 to make the diagnosis on clinical grounds.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Genes

• Mutations in JAG1 are associated with the majority of cases of AGS.
• Mutations in NOTCH2 are associated with fewer than 1% of individuals with AGS [McDaniell et al 2006].

Clinical testing

• Sequence analysis

  JAG1.  Sequence analysis of JAG1 DNA and mRNA detects mutations in about 88% of individuals with AGS [Warthen et al 2006]. Two-thirds of the detectable mutations are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, 24; the remainder of detectable mutations are identified by sequencing of the other exons. JAG1 mutations are distributed throughout the gene with no clustering or mutational 'hot spots.'

  NOTCH2.  Among the 11 individuals with clinically diagnosed AGS in their series who did not have an identifiable JAG1 mutation, McDaniell et al (2006) identified mutations in NOTCH2 in two individuals (10%) following sequence analysis of all 34 exons. Of the original 247 individuals from different families with a clinical diagnosis of AGS, fewer than 1% had a NOTCH2 mutation.

• FISH.  Approximately 7% of individuals with AGS have a deletion of the entire JAG1 gene detectable by cytogenetic or molecular cytogenetic techniques (i.e., fluorescence in situ hybridization [FISH] using clones containing the JAG1 gene, such as BAC-829A12).

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Alagille Syndrome Test Method Mutations Detected Mutation Detection Frequency by Test Method and Gene Test Availability Sequence analysis JAG1 sequence variants ~88%  1 Clinical FISH Deletion of JAG1 within 20p12 ~7%  2 Sequence analysis NOTCH2 sequence variants <1%  3 Clinical

1. Warthen et al 2006 2. Warthen et al 2006 ; personal communication 3. McDaniell et al (2006) identified NOTCH2 mutations in 2/11 individuals with classic AGS who did not have an identifiable JAG1 mutation.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis of AGS in a proband

• In situations in which the diagnosis is suspected but the criteria for clinical diagnosis are not met, molecular genetic testing of JAG1 should be considered. Sequence analysis of the JAG1 gene should be carried out first as this identifies mutations in more than 88% of persons with a JAG1 mutation.

• FISH can be performed if an intragenic JAG1 mutation is not identified.

  Note: It is anticipated that newer technologies (e.g., multiplex ligation-dependent probe amplification [MLPA], BAC or SNP array analysis) will be available soon to detect deletions.

• If a deletion involving JAG1 is identified by FISH analysis, a full cytogenetic study is appropriate to determine if a chromosomal rearrangement such as a translocation or inversion is present.

• The presence of developmental delay and/or hearing loss in addition to the features commonly seen in AGS 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 has been identified.

Prenatal diagnosis/preimplantation genetic diagnosis (PGD) for pregnancies at risk for JAG1-related AGS require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

JAG1.  No other phenotypes are associated with mutations in JAG1. However, it should be noted that some individuals with JAG1 mutations may express only some of the features of AGS and may not be recognized as having this diagnosis. The most clinically significant group is individuals with apparently isolated cardiac disease who have JAG1 mutations [Krantz et al 1998 , Eldadah et al 2001].

NOTCH2.  No other phenotypes are known to be associated with mutations in NOTCH2 at present; however, research looking for NOTCH2 mutations in persons with renal disorders and without the classic features of AGS is currently underway [Spinner et al, personal communication].

Clinical Description

Natural History

Alagille syndrome (AGS) 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 AGS 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 AGS 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].

A study by Emerick et al (1999) discussed the frequency of clinical manifestations in 92 individuals meeting the clinical diagnostic criteria for AGS (Table 2).

Hepatic manifestations.  Although some individuals with JAG1 gene mutations have no detectable hepatic manifestations [Gurkan et al 1999 , Krantz et al 1999 , Kamath et al 2003], liver disease most often 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 AGS, bile duct paucity is not always present and the liver biopsy may demonstrate ductal proliferation, resulting in the possible misdiagnosis of AGS as biliary atresia.

Cardiac manifestations.   Cardiac findings ranging from benign heart murmurs to significant structural defects occur in 90%-97% of individuals with AGS [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 AGS 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 AGS [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 AGS include Axenfeld anomaly and Rieger anomaly. Ocular ultrasonographic examination in 20 children with AGS found optic disk drusen in 90% [Nischal et al 1997]. Retinal pigmentary changes are also common (32% in one study) [Hingorani et al 1999]. 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].

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 AGS ranges from 33% to 87% [Emerick et al 1999 , Sanderson et al 2002]. Butterfly vertebrae are usually asymptomatic. The incidence in the general population is unknown but suspected to be low. Other skeletal manifestations in individuals with AGS have been reported less frequently.

Facial features.   The constellation of facial features observed in children with AGS include 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 [Krantz et al 1997]. The typical facial features are almost universally present in Alagille syndrome (see Figure 1).

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

Other features

• Renal abnormalities, structural (small hyperechoic kidney, ureteropelvic obstruction, renal cysts) and functional (most commonly renal tubular acidosis), occurring in 23%-74% of individuals [Emerick et al 1999]
• Pancreatic insufficiency [Emerick et al 1999]
• Growth failure (50%-90%) [Emerick et al 1999 , Arvay et al 2005]
• Mental retardation, reported in 30% of individuals in initial studies. Subsequently, mild delays of gross motor skills were identified in 16% and mild mental retardation 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 [Berard et al 1998], middle aortic syndrome [Shefler et al 1997], and moyamoya syndrome [Woolfenden et al 1999] 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, Loomes et al 2002]
• Craniosynostosis [Kamath, Stolle et al 2002]

Genotype-Phenotype Correlations

The phenotype of AGS caused by mutations in JAG1 is indistinguishable from the phenotype caused by mutations in NOTCH2, although it is noteworthy that 3/3 relatives who had NOTCH2 mutations had significant renal disease often resulting in end-stage renal disease (ESRD) [McDaniell et al 2006]; however, the number of individuals identified with AGS caused by NOTCH2 mutations is still too small to draw conclusions about genotype-phenotype correlations.

No genotype-phenotype correlations exist between clinical manifestations of AGS 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 AGS 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

AGS 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 AGS. 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 AGS.
• 4% had no features of AGS.

Based on these data, penetrance is 96%; however, only 53% meet clinical diagnostic criteria for AGS.

NOTCH2 mutations.  Penetrance appears complete in the five individuals so far identified with NOTCH2 mutations, although expressivity is variable [McDaniell et al 2006].

Anticipation

AGS 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 AGS has been estimated to be 1:70,000 live births. This is most likely an underestimate as cases were ascertained solely on the basis of presence of neonatal liver disease.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Neonatal cholestasis.  Over 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 (AGS). 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 [see Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum], Ivemark syndrome) [Piccoli & Witzleben 1996]. These can be distinguished from AGS 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, whereas only AGS 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. AGS 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 AGS, 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 AGS. Liver disease is not part of the deletion 22q11.2 syndrome; testing for this deletion using the specific FISH probe distinguishes the two disorders.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Alagille syndrome (AGS), 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 evaluated
• Measurement of growth parameters and plotting on age-appropriate growth charts

Treatment of Manifestations

A multidisciplinary approach to the management of individuals with AGS is often beneficial because of the multisystem involvement. Evaluation by specialists in medical genetics, gastroenterology, nutrition, cardiology, ophthalmology, liver transplantation, and child development may be indicated, depending on the age and specific difficulties of the individual.

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). In certain cases partial external biliary diversion has also proved successful [Emerick & Whitington 2002 , Mattei et al 2006].

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 [Kasahara et al 2003]. The success of liver transplantation in AGS is probably most influenced by the severity of any coexisting cardiac disease; those individuals with a severe cardiac anomaly may be excluded from the option of liver transplantation. The outcome of liver transplantation in terms of patient and graft survival is comparable to the outcome in children transplanted for other diseases [Englert et al 2006].

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.

Prevention of Secondary Complications

Close monitoring of plasma concentration of fat-soluble vitamins, nutritional optimization, and vitamin replacement therapy should maximize growth potential and prevent some of the developmental delay documented in early studies.

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 AGS 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

Individuals with known chronic liver disease and splenomegaly are advised to use a spleen guard during activities. Contact sports should be avoided.

Individuals with liver disease should avoid alcohol consumption.

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

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• About 30%-50% of individuals diagnosed with AGS have an affected parent.
• Approximately 50%-70% of affected individuals have AGS as the result of a de novo mutation [Krantz et al 1998 , Crosnier et al 1999 , Spinner et al 2001].
• Recommendations for the evaluation of parents of a simplex case (i.e., an individual with AGS and no known family history of AGS) include liver function testing, cardiac evaluation, radiograph of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist.
  • If the proband has an identifiable disease-causing mutation in the JAG1 gene, molecular genetic testing of the parents is recommended.
  • If the proband shows a microdeletion of 20p12 on FISH testing, FISH testing of both parents is appropriate.

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 AGS 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 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] and the possibility that a NOTCH2 mutation is responsible.

Offspring of a proband.   Offspring of an individual with AGS 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 found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

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.

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 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

DNA banking.  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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Molecular genetic testing.  Prenatal testing is available for families in which AGS is known to be caused by a mutation in the JAG1 gene demonstrated by molecular genetic testing or sequence analysis or by deletion of JAG1 detectable by FISH studies. Prenatal testing is accomplished by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Although this testing can determine whether or not the fetus has inherited the JAG1 disease-causing mutation or deletion, it cannot predict the appearance or severity of clinical manifestations.

No laboratories offering molecular genetic testing for prenatal diagnosis for AGS caused by a NOTCH2 mutation are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see .

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 AGS, fetal echocardiogram may detect a significant structural defect of the heart; however, a normal fetal echocardiogram does not eliminate the possibility of AGS or the possibility of a structural cardiac abnormality in the fetus.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

JAG1

Normal allelic variants: JAG1 comprises 26 exons. A number of 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].

Pathologic allelic variants: Approximately 226 mutations have been identified in individuals with Alagille syndrome (AGS) (~70% of those tested). Mutation types have included: deletion of entire JAG1 gene (4%), protein truncating mutations (frameshift and nonsense) (69%), splicing mutations (16%), and missense mutations (11%) [Li et al 1997 , Oda et al 1997 , Krantz et al 1998 , Yuan 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 , Yuan et al 2001 , Ropke et al 2003].

Normal gene product: Jagged-1 is a cell surface protein that functions as a ligand for the 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 are lethal, and affected fruit flies show hypertrophy of the nervous system. The finding that mutations in JAG1 cause AGS 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 two other cases of Notch pathway genes involved in human (adult) disease. Notch1 is broken by chromosomal translocations in T lymphoblastic leukemias. Mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [Joutel et al 1996].

Abnormal gene product: Haploinsufficiency of Jagged-1 has been shown to result in AGS as evidenced by those individuals with AGS who have a cytogenetically detectable deletion of chromosome 20p12 encompassing the entire JAG1 gene. Haploinsufficiency is also most likely the pathologic mechanism in the majority of cases of AGS, as most identified mutations result in 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 interfere with the signaling in a dominant-negative manner [Sun & Artavanis-Tsakonas 1996]; 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 the JAG1 gene, 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 , Gridley 2003 , Harper et al 2003 , Iso et al 2003].

NOTCH2

Normal allelic variants: NOTCH2 comprises 34 exons. A number of polymorphisms that are not expected to result in a disease phenotype have been reported [McDaniell et al 2006].

Pathologic allelic variants: Two mutations have been identified in two different families with clinical features of AGS. One 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 other is a missense mutation, causing a loss of a cysteine residue in one of the EGF-like repeats of the extracellular domain of Notch2 (p.Cys444Tyr).

Normal gene product: Neurogenic locus notch homolog protein 2 (Notch2) 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 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 two mutations identified to date occur in different parts of the Notch2 protein. One is in the extracellular domain and causes loss of a highly conserved cysteine in one of the EGF-like repeats. The second is in the intracellular domain and causes loss of 3/7 of the ankyrin repeats. No functional data are available.

Resources

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References

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

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Suggested Readings

• Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP (1987) Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110:195-200 [Medline]
  
  
• Alagille D, Odievre M, Gautier M, Dommergues JP (1975) Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 86:63-71 [Medline]
  
  
• Meunier-Rotival M and Hadchouel M (2005) Alagille syndrome (AGS). Atlas of Genetics and Cytogenetics Oncology and Haematology. atlasgeneticsoncology.org
  
  
• Shaffer LG, Ledbetter DH, Lupski JR (revised 2002) 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 Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 65. www.ommbid.com
  
  

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