Alagille Syndrome

Synonyms: Arteriohepatic Dysplasia, Syndromic Bile Duct Paucity

Nancy B Spinner, PhD, Laura D Leonard, BA, and Ian D Krantz, MD.

Author Information
Initial Posting: May 19, 2000; Last Update: February 28, 2013.

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Summary
Clinical 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 wholegene 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 firstdegree 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 pathogenic variant. For parents of a child with an
apparent de novo pathogenic variant, 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 pathogenic variant in

an affected family member is known. Prenatal testing cannot predict

the occurrence or severity of clinical manifestations.
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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):
o Cholestasis
o Cardiac defect (most commonly stenosis of the peripheral
pulmonary artery and its branches)
o Skeletal abnormalities (most commonly butterfly vertebrae
identified in AP chest radiographs)
o Ophthalmologic abnormalities (most commonly posterior
embryotoxon)
o 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
Pathogenic variants in JAG1 are known to cause about 94%96% of cases of ALGS.
Pathogenic variants in NOTCH2 are known to cause ALGS in
1%-2% of individuals [McDaniell et al 2006,Kamath et al
2012a].
Clinical testing
Table 1.

Summary of Molecular Genetic Testing Used in Alagille Syndrome

Gene 1

Proportion of
ALGS
Attributed to
Test Method
Mutation of This
Gene

Mutations Detected 2

JAG1

89%

Sequence variants

Sequence analysis 3 /mutation

scanning 4

Proportion of
ALGS
Attributed to
Test Method
Mutation of This
Gene

Gene 1

See footnote 5

~5%-7% 6

NOTCH
2

Mutations Detected 2

Sequence analysis of select

exons 3

Sequence variants in select

exons

Deletion/duplication analysis
(including FISH) 7

Deletion
and duplication of exon(s) and
entire gene deletion 8

Linkage analysis NA

See footnote 9

1%-2% 10

Sequence analysis 3

Sequence variants

Unknown

Deletion/duplicationanalysis 7

Unknown, 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 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 wholegene deletions/duplications are not detected. For issues to consider in
interpretation of sequence analysis results, click here.
4.
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.
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 ligationdependent 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

Test characteristics. See Clinical Utility Gene Card [Leonard et al

2014] for information on test characteristics
including sensitivity and specificity.
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 aJAG1 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 pathogenic variant in the family.
Genetically Related (Allelic) Disorders

JAG1. No phenotypes other than those discussed in

this GeneReview are known to be associated with mutation ofJAG1.

However, it should be noted that some individuals with pathogenic

variants in JAG1 may 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 apparently isolated cardiac
disease who have JAG1 mutations [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 in NOTCH2 may 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
in NOTCH2 have recently been identified to cause HajduCheney syndrome, also known as serpentine fibula polycystic
kidney syndrome. Hajdu-Cheney syndrome is an autosomal
dominant disorder which causes focal bone destruction,
osteoporosis, craniofacialdysmorphology, renal cysts, cleft
palate, and cardiac defects. The NOTCH2 pathogenic variants
identified in individuals with Hadju-Cheney syndrome were all
localized in the last exon (exon 34) of NOTCH2; these variants
are predicted to disrupt the intracellular PEST (prolineglutamate-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 in NOTCH2 have been identified in
individuals with SMZL [Kiel et al 2012].

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Clinical Characteristics
Clinical Description

Alagille syndrome (ALGS) is a multisystem disorder. Studies of

families with multiple affected members and/or JAG1pathogenic
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 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

Frequency (% of Individuals)
Clinical Finding
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 findings

65/83 (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 insufficiency

7/17 (41%)

NR

Growth retardation

27/31 (87%)

NR

Intellectual disability

2/92 (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 pathogenic variants 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 genemutation.
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.

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
Renal abnormalities, both structural (small hyperechoic kidney,
ureteropelvic obstruction, renal cysts) and functional (most
commonly renal tubular acidosis), found in 39%
of affected individuals (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%
of affected individuals. 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 Correlations

The phenotype of ALGS caused by mutation of JAG1 is

indistinguishable from the phenotype caused by mutation ofNOTCH2.
Initially, 3/3 relatives who had pathogenic variants in NOTCH2 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
mutation of NOTCH2 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 pathogenic variants. To determine the range and frequency of
clinical findings in individuals with a JAG1pathogenic variant and
hence, the penetrance, Kamath et al [2003] studied 53 mutationpositive 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 xrays).
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 pathogenic variants. Penetrance appears complete in the
ten individuals so far identified with NOTCH2pathogenic variants,
although expressivity is variable [Kamath et al 2012a].
Anticipation

ALGS has not shown anticipation. Bias of ascertainment may occur

because individuals with a JAG1 pathogenic variant 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.
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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, BannayanRiley-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, andWilliams 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 SimulConsult, an interactive diagnostic
decision support software tool that provides differential diagnoses
based on patient findings (registration or institutional access
required).
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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 technitium99m-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 ageappropriate 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 pathogenic variant has been identified in
a proband, at-risk relatives can be evaluated using genetic
testing.
If no JAG1 or NOTCH2 pathogenic 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.
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.
Go to:
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
Approximately 30%-50% of individuals diagnosed with ALGS
have an affected parent.
Approximately 50%-70% of affected individuals have ALGS as
the result of a de novo pathogenic variant [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 ALGS and no knownfamily
history of ALGS) include liver function testing, cardiac
evaluation, radiographs of the spine, ophthalmologic
examination, and evaluation of facial features by a clinical
geneticist.
o If the proband has an
identifiable JAG1 or NOTCH2 pathogenic
variant, molecular genetic testing of the parents is
recommended.
o 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 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 pathogenic variant 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 orNOTCH2 pathogenic 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 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 pathogenic
variant. When the parents of a proband with anautosomal
dominant condition are unaffected, it is likely that the proband has

a de novo pathogenic variant. 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, allelic variants, and
diseases will improve in the future, consideration should be given to
banking DNA of affected individuals.
Prenatal Testing

Molecular genetic testing. If the JAG1 or NOTCH2 pathogenic

variant has been identified in the family, prenatal diagnosis for
pregnancies at increased risk may be available from a a clinical
laboratory that offers either testing of thegene or custom 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
an affected family member.
Go to:
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
www.alagille.org
National Library of Medicine Genetics Home Reference
Alagille syndrome
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
www.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
www.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
childrennetwork.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
www.childliverdisease.org
Go to:
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

Gene
Symbol

Chromosomal
Locus

Protein Name

Locus Specific

JAG1

20p12.2

Protein jagged-1

JAG1 @ ZAC-GGM
CCHMC - Human
Genetics Mutation
Database (JAG1)

NOTCH2

1p12-p11

Neurogenic locus
NOTCH2 @ ZAC-GGM
notch homolog protein NOTCH2 database
2

HGMD

JAG1

NOTCH
2

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)

118450

ALAGILLE SYNDROME 1; ALGS1

600275

NOTCH, DROSOPHILA, HOMOLOG OF, 2; NOTCH2

601920

JAGGED 1; JAG1

610205

ALAGILLE 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 pathogenic variants 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 pathogenic

variants are identified by sequencing exons 1-6, 9, 12, 17, 20, 23, 24;
the remainder are identified by sequencing the other
exons. JAG1 pathogenic variants 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 mutation of JAG1 causes 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, pathogenic variants
in NOTCH1 have been associated with isolated cardiac defects
[Greenway et al 2009]. Pathogenic variants in NOTCH3 cause
cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL). Pathogenic variants
in exon 34 of NOTCH2 cause Hajdu-Chenney syndrome [Simpson et
al 2011] (seeGenetically Related Disorders). Finally, pathogenic

variants in the Notch pathway genes DLL3, HES7, LFNG,

andMESP2 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
entireJAG1 gene. 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 inDrosophila that 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 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 pathogenic
variants 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 Change

Protein Amino Acid Change

Reference Sequences

c.1331G>A

p.Cys444Tyr

NM_024408.2
NP_077719.2

c.1117T>C

p.Cys373Arg

c.1180C>T

p.Pro394Ser

c.1147C>T

p.Pro383Ser

c.5857C>T

p.Arg1953Cys

DNA Nucleotide Change

Protein Amino Acid Change

c.5858G>A

p.Arg1953His

c.5930-1G>A

--

c.1438T>C

p.Cys480Arg

c.2566_2567delAG

p.Ser856LeufsTer17

c.6007C>T

p.Arg2003Ter

Reference Sequences

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 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:
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