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Alagille Syndrome

Synonyms: Arteriohepatic Dysplasia, Syndromic Bile Duct Paucity

, PhD, , PhD, , MD, and , MD.

Author Information

Initial Posting: ; Last Update: December 12, 2019.

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, developmental delays, splenomegaly, and vascular abnormalities may also occur.

Diagnosis/testing.

The diagnosis of ALGS is established in a proband who meets clinical diagnostic criteria and/or has a heterozygous pathogenic variant in JAG1 or NOTCH2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Management by a multidisciplinary team according to clinical manifestations (clinical genetics, gastroenterology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development); choloretic agents (ursodeoxycholic acid), other medications (cholestyramine, rifampin, naltrexone); liver transplantation for end-stage liver disease; standard treatment for cardiac, renal, and neurologic involvement.

Surveillance: Regular monitoring by cardiology, gastroenterology, and nutrition specialists.

Agents/circumstances to avoid: Contact sports; alcohol consumption if liver disease is present.

Genetic counseling.

ALGS is inherited in an autosomal dominant manner. Approximately 30%-50% of individuals have an inherited pathogenic variant and about 50%-70% have a de novo pathogenic variant. Parental somatic/germline mosaicism has been reported. Each child of an affected individual is at a 50% risk of inheriting the ALGS-related genetic alteration and developing signs of ALGS. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member. Because ALGS is associated with highly variable expressivity with clinical features ranging from subclinical to severe, clinical manifestations cannot be predicted by molecular genetic prenatal testing.

Diagnosis

Suggestive Findings

Alagille syndrome (ALGS) should be suspected in individuals with the following findings [Mitchell et al 2018]:

  • 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 (most commonly, triangular-shaped face with a broad forehead and a pointed chin, bulbous tip of the nose, deeply set eyes, and hypertelorism; see Figure 1)
Figure 1. . Typical facial features of Alagille syndrome.

Figure 1.

Typical facial features of Alagille syndrome. Note broad forehead, deeply set eyes, and pointed chin.

Individuals with an affected relative. The diagnosis of ALGS should also be suspected 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.

Establishing the Diagnosis

The diagnosis of Alagille syndrome (ALGS) is established in a proband who meets the clinical diagnostic criteria, and can be further confirmed by identification of a heterozygous pathogenic variant in JAG1 or NOTCH2 on molecular genetic testing (see Table 1).

Note: A very small subset (3.2%) of individuals with a clinical diagnosis of ALGS do not have an identified pathogenic variant in either JAG1 or NOTCH2 [Gilbert et al 2019].

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ALGS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ALGS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of ALGS, molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel:

  • Serial single-gene testing. Sequence analysis of JAG1 and NOTCH2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; depending on the method used, exon or whole-gene deletions/duplications may not be detected. Sequence analysis of JAG1 is performed first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis of JAG1 is performed to detect intragenic deletions or duplications. NOTCH2 molecular genetic testing should be considered when the diagnosis is strongly suspected on clinical grounds, but no JAG1 pathogenic variant (by either sequence or deletion/duplication analysis) was identified.
    Note: (1) If a deletion involving the entire JAG1 gene is identified, a full cytogenetic study may be considered to determine if a rare chromosome rearrangement (translocation or inversion) is present. (2) 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, and a chromosomal microarray analysis (CMA) would be recommended.
  • A multigene panel that includes JAG1, NOTCH2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of ALGS is not considered because an individual does not meet the clinical diagnostic criteria, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Alagille Syndrome

Gene 1, 2Proportion of ALGS
Attributed to Pathogenic
Variants in Gene
Proportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
JAG194.3% 688% 612% 6
NOTCH22.5 6100% 6Unknown 7
Unknown 83.2% 6NA
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

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, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.

6.
7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.

Individuals with a clinical diagnosis of ALGS but without a detectable pathogenic variant in either JAG1 or NOTCH2 have been hypothesized to have a pathogenic variant in JAG1 or NOTCH2 that is not yet detectable with current molecular genetic testing [Authors, personal observation]. It is also possible that another gene related to the Notch signaling pathway, or a variant in an untranslated regulatory region, may be responsible, although this has not yet been reported.

Clinical Characteristics

Clinical Description

Alagille syndrome (ALGS) is a multisystem disorder with 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) [Guegan et al 2012]. This variability is seen even among individuals from the same family [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.

To date, more than 700 individuals with ALGS have been found to have a pathogenic variant in JAG1 or NOTCH2 [Gilbert et al 2019]. Table 2 lists the phenotypic features associated with this condition based on reports by Emerick et al [1999], Subramaniam et al [2011], and Saleh et al [2016].

Table 2.

Features of Alagille Syndrome

Feature% of Persons w/FeatureComment
Hepatic abnormality incl: bile duct paucity; conjugated hyperbilirubinemia; chronic cholestasis characterized by pruritus, xanthomas & fat-soluble vitamin deficiencies; & end-stage liver disease≤100%
Cardiac malformation90%-97%Most common cardiovascular malformations incl pulmonary stenosis & tetralogy of Fallot
Posterior embryotoxon78%-89%
Renal disease39%
Vertebral anomalies33%-93%
Characteristic facies77%-97%

Hepatic manifestations. While some individuals with JAG1 or NOTCH2 pathogenic variants have no detectable hepatic manifestations [Gurkan et al 1999, Krantz et al 1999, Kamath et al 2003], in most affected people liver disease presents within the first three months of life. The severity of liver disease ranges from asymptomatic elevations of liver enzymes to jaundice, chronic cholestasis, and end-stage liver disease.

Jaundice and conjugated hyperbilirubinemia may be present in the neonatal period. Increased serum concentrations of bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), triglycerides, and the aminotransferases are also commonly observed. Impaired bile salt secretion can lead to fat-soluble vitamin deficiencies and malnutrition.

Cholestasis manifests as pruritus, increased serum concentration of bile acids, growth failure, and xanthomas.

Various reports indicate that between 20% and 70% of affected individuals will require a liver transplant by age 18 years due to liver failure or severe pruritus [Lykavieris et al 2001; Kamath et al 2012c; Author, unpublished observation]. Currently, it is not possible to predict which individuals will progress to end-stage liver disease, although work is ongoing to identify biomarkers that will help predict clinical disease course [Thakurdas et al 2016, Tsai et al 2016, Adams et al 2019]. While it is difficult to predict whether a child with cholestasis will have improvement or progression of liver disease, a retrospective study of 144 individuals with Alagille syndrome found that serum total bilirubin greater than 3.8 mg/dL can be predictive of worsened long-term hepatic outcomes in children between the ages of 12 and 24 months [Mouzaki et al 2016].

Liver biopsy typically shows paucity of the intrahepatic bile ducts, which may be progressive. In infants younger than age six months, 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.

Cardiac manifestations. Cardiac findings, which can include significant structural defects, occur in 90%-97% of individuals with ALGS [Emerick et al 1999, McElhinney et al 2002, Tretter & McElhinney 2018]. 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 pathogenic variant found in the proband.

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]. Additional eye anomalies have also been described [Makino et al 2012].

The visual prognosis is good, although mild decreases in visual acuity may occur and, in very rare instances, associated idiopathic intracranial hypertension has also been identified in individuals with ALGS, although the pathogenesis for increased intracranial pressure has not been described [Narula et al 2006, Mouzaki et al 2010].

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 2010].

Facial features. The constellation of facial features observed in children with ALGS includes a broad forehead, deeply set eyes with moderate hypertelorism, pointed chin, and a concave or straight nasal ridge 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).

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].

Renal abnormalities, both structural (small hyperechoic kidney, ureteropelvic obstruction, renal cysts) and functional (most commonly renal tubular acidosis), are found in 39% of affected individuals (73/187) [Kamath et al 2012b, Romero 2018]. Hypertension and renal artery stenosis have also been noted in adults with ALGS [Salem et al 2012].

Other features

Life span in ALGS is reduced, with the primary cause of death occurring from cardiac disease, severe liver disease, and intracranial bleeding [Emerick et al 1999, Kamath et al 2004, Cho et al 2015]. Most studies do not include long-term follow up; thus, information about life span among those with ALGS is not available.

Phenotype Correlations by Gene

Although very few patients with NOTCH2 variants have been described to date, it has been reported that individuals with pathogenic NOTCH2 variants have a lower prevalence of cardiac, vertebral, and facial anomalies than those with pathogenic JAG1 variants [Kamath et al 2012a].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for JAG1 or NOTCH2 have been identified.

Individuals with ALGS with additional abnormalities, including developmental delay, hearing loss, and autism may have a larger deletion of chromosome 20p12 encompassing the entire JAG1 gene as well as other genes in the region [Kamath et al 2009].

Penetrance

ALGS associated with pathogenic variants in either of the known causative genes (JAG1 and NOTCH2) 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 JAG1 pathogenic variant and hence, the penetrance, Kamath et al [2003] studied 53 JAG1 variant-confirmed relatives of probands with ALGS. Their findings identified two such individuals with no features of ALGS – a 96% penetrance rate.

NOTCH2 pathogenic variants. Penetrance appears complete in the individuals so far identified with NOTCH2 pathogenic variants. [Kamath et al 2012a, Gilbert et al 2019].

Prevalence

The prevalence of ALGS is estimated at 1:30,000-1:50,000 live births [Saleh et al 2016]. Advances in molecular testing have aided in increasing the detection rate for the disease; however, due to the variable phenotype, it likely remains underdiagnosed [Kamath et al 2003]. The prevalence across populations appears to be stable.

Differential Diagnosis

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), chromosome 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 spectrum disorder, Ivemark syndrome). These can be distinguished from ALGS by history, by the presence of other findings, or by genetic testing.

Inherited disorders associated with intrahepatic cholestasis include alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis (including progressive familial intrahepatic cholestasis 1 and 2 [Byler syndrome]), inborn errors of bile acid metabolism, neonatal sclerosing cholangitis, Norwegian cholestasis (Aagenaes syndrome) and North American Indian cholestasis (NAIC). These conditions are largely confined to the liver but some are associated with extrahepatic manifestations.

Neonatal cholestasis. More than 100 specific causes of neonatal cholestasis exist. Differential diagnosis depends on clinical presentation and includes infectious, metabolic, genetic, or endocrine disorders as well as structural anomalies. Evaluation typically focuses on treatable causes including sepsis, hypothyroidism, and single-gene disorders such as classic galactosemia. Biliary atresia is the most common identifiable cause of neonatal cholestasis and should be diagnosed early since surgical intervention at a young age is associated with better outcomes.

Posterior embryotoxon can be seen in a number of genetic disorders, but is a frequent finding in Axenfeld-Rieger syndrome. 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), Noonan syndrome with multiple lentigines, Down syndrome, and Williams syndrome. These other syndromes can be distinguished by other associated clinical findings and/or molecular genetic or cytogenetic 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 syndrome. 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; genetic testing can be used to distinguish the two disorders.

Table 3.

Genes of Interest in the Differential Diagnosis of Alagille Syndrome (ALGS)

Key
Overlapping
Clinical
Feature
Gene(s)DisorderMOI
Bile duct
paucity
AMACRTrihydroxycoprostanic acid excess (OMIM 214950)AR
CFTRCystic fibrosisAR
GDF1Ivemark syndrome (OMIM 208530)AR
NEK8Renal-hepatic-pancreatic-dysplasia 2 (OMIM 615415)AR
PEX1, PEX6, PEX12 1Zellweger spectrum disorderAR
SERPINA1Alpha-1-antitrypsin deficiencyAR
Intrahepatic
cholestasis
ABCB4Progressive familial intrahepatic cholestasis 3 (OMIM 602347)AR
ABCB11, ATP8B1Progressive familial intrahepatic cholestasis 1 & 2 (see ATP8B1 Deficiency)AR
Benign recurrent intrahepatic cholestasis (OMIM PS243300)AR
Neonatal
cholestasis
GALTClassic galactosemiaAR
Posterior
embryotoxon
FOXC1, PITX2Axenfeld-Rieger syndrome (OMIM PS180500)AD
Pulmonic
vascular system
abnormalities
ELNWilliams syndromeAD
NF1Watson syndrome (pulmonic stenosis & neurofibromatosis type 1)AD
PTPN11, SOS1, RAF1, RIT1 2Noonan syndromeAD
(AR 3)
PTPN11, RAF1, BRAF, MAP2K1Noonan syndrome with multiple lentiginesAD
1.

Biallelic pathogenic variants in PEX1, PEX6, and PEX12 account for 60.5%, 14.5%, and 7.6% of Zellweger spectrum disorder (ZSD), respectively. Thirteen genes are known to be associated with ZSD (see Zellweger Spectrum Disorder).

2.

Heterozygous pathogenic variants in PTPN11, SOS1, RAF1, and RIT1 account for 50%, ~10%, 5%, and 5% of Noonan syndrome, respectively. More than 8 genes are known to be associated with Noonan syndrome (see Noonan syndrome).

3.

Biallelic pathogenic variants in LZTR1 are associated with autosomal recessive Noonan syndrome (OMIM 605275).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alagille syndrome (ALGS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Alagille Syndrome

System/ConcernEvaluationComment
GastrointestinalEvaluation by gastroenterologist to incl:
  • Liver function tests
  • Clotting studies
If determined necessary by gastroenterologist, additional studies incl:
  • Serum bile acids
  • Fat-soluble vitamin levels
  • Hepatic ultrasound
  • Technitium-99m-DISIDA scintiscan
  • Liver biopsy
CardiovascularComplete cardiology evaluationIncl echocardiogram.
EyesOphthalmologic evaluationLook for anterior chamber anomalies.
SkeletalAP & lateral chest radiographs to evaluate for presence of butterfly vertebrae
RenalEvaluate w/renal function studies & renal ultrasound
GrowthMeasurement of growth parameters & plotting on age-appropriate growth charts
DevelopmentScreening developmental evaluationMore detailed evaluation should be performed if significant delays are identified.
OtherConsultation w/clinical geneticist &/or genetic counselor

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 clinical genetics, gastroenterology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development may be indicated, depending on the age and specific difficulties of the individual [Kamath et al 2010].

Many associated health concerns are treated in a standard manner (cardiovascular abnormality, renal anomalies, vascular accidents) while other findings rarely need intervention (ocular abnormalities) or are only rarely symptomatic (vertebral anomalies).

A liver specialist familiar with Alagille syndrome is recommended in the treatment of liver manifestations in individuals with this disorder (see Table 5).

Table 5.

Treatment of Liver Manifestations in Individuals with Alagille Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
Pruritus & xanthomasCholoretic agents (ursodeoxycholic acid) & other medications (cholestyramine, rifampin, naltrexone)A combination of therapies is often required. Biliary diversion may be performed for severe pruritus refractory to medical therapy.
End-stage liver diseaseLiver transplantation
Poor growthOptimized nutrition; replacement of fat-soluble vitamins as neededNasogastric feeds or gastrostomy tube may be required to maintain caloric intake.

Surveillance

Growth should be monitored using standard growth charts so that nutritional intake can be adjusted to need.

Regular monitoring by a cardiologist, gastroenterologist, and 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

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Evaluations can include:

  • Molecular genetic testing if the causative genetic alteration (i.e., a JAG1 or NOTCH2 pathogenic variant or microdeletion of 20p12) in the family is known;
  • Measurement of liver enzymes, cardiac examination, eye examination, skeletal x-rays, and evaluation of facial features if the JAG1 or NOTCH2 pathogenic variant in the family is not known.

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

Pregnancy Management

Liver and cardiac features should be monitored to ensure that portal hypertension and cardiac dysfunction do not worsen during pregnancy [Ferrarese et al 2015].

Therapies Under Investigation

Use of maralixibat, an ileal bile duct transporter inhibitor, is under investigation as a possible treatment for pruritus. Initial results suggest that the drug is safe and may alleviate pruritus in ALGS, although a more thorough investigation of efficacy is necessary [Shneider et al 2018].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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

  • 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 genetic alteration [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 known family history of ALGS) include:
    • Genetic testing for the causative genetic alteration (i.e., a JAG1 or NOTCH2 pathogenic variant or 20p12 microdeletion) identified in the proband;
    • Liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist if the causative genetic alternation has not been identified in the proband.
  • If the genetic alteration found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or somatic/germline mosaicism in a parent [Giannakudis et al 2001, Laufer-Cahana et al 2002].
    The frequency of parental somatic/germline mosaicism was approximately 8% in a study of families with JAG1-related ALGS [Giannakudis et al 2001]. Parents with somatic mosaicism for an ALGS-causing genetic alteration may be mildly/minimally affected
  • The family history of some individuals diagnosed with ALGS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. Significant intrafamilial variability is observed in ALGS; the clinical manifestations in heterozygous sibs cannot be predicted and may range from mild or subclinical features to severe heart and/or liver disease.
  • If the proband has a known ALGS-related genetic alteration that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism [Giannakudis et al 2001, Laufer-Cahana et al 2002].
  • If the parents have not been tested for the ALGS-related genetic alteration but are clinically unaffected, sibs are still presumed to be at increased risk for ALGS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. Multiple instances of a child inheriting ALGS from an apparently unaffected, phenotypically normal parent who was mosaic for a 20p microdeletion have been reported [Giannakudis et al 2001, Laufer-Cahana et al 2002].

Offspring of a proband. Offspring of an individual with ALGS have a 50% chance of inheriting the ALGS-related genetic alteration. The clinical manifestations in heterozygous offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected/has the ALGS-related genetic alteration, 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 neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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 and Preimplantation Genetic Testing

Molecular genetic testing. Once the causative genetic alteration (i.e., a JAG1 or NOTCH2 pathogenic variant or a chromosome 20p12 structural variant) has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: Because JAG1- and NOTCH2-related ALGS demonstrate highly variable expressivity with clinical features ranging from subclinical to severe, clinical manifestations cannot be predicted by molecular genetic prenatal testing.

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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)
    Phone: 720-777-2598
    Email: joan.hines@childrenscolorado.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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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

Molecular Pathogenesis

Introduction. JAG1 and NOTCH2 encode for a ligand and a receptor protein, respectively, involved in the Notch signaling pathway. Notch signaling is highly ubiquitous, with defects resulting in a variety of human diseases. The name "Notch" derives from the characteristic notched wing found in fruit flies carrying only one functional copy of the gene. Homozygous pathogenic variants in Notch in fruit flies are lethal, and the flies show hypertrophy of the nervous system. The finding that pathogenic variants 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).

The JAG1 and NOTCH2 proteins are both single-pass, transmembrane proteins. Binding of the extracellular region of JAG1 to the extracellular region of NOTCH2 prompts cleavage of the intracellular domain of NOTCH2, which translocates to the nucleus to regulate the expression of Notch signaling target genes, including those belonging to the HES and HEY gene families.

During cholangiocyte specification, mesenchymal cells surrounding the portal vein express JAG1 while the hepatocytes express NOTCH2, and mouse studies have demonstrated a requirement of Notch signaling for liver development.

Mechanism of disease causation. The disease mechanism of ALGS is haploinsufficiency, and the majority of disease-associated JAG1 variants (~87%) are loss-of-function variants. Many missense variants in JAG1, particularly those that involve loss of a cysteine, result in proteins that are unable to signal with NOTCH2 and/or are improperly trafficked and not expressed on the cell membrane.

NOTCH2 variants are predominantly missense and the pathogenicity of these variants is less understood.

Table 6.

Alagille Syndrome: Gene-Specific Laboratory Considerations

GeneSpecial Consideration
NOTCH2NOTCH2NLR, a pseudogene containing 5 exons – the first 4 corresponding to the first 4 exons of NOTCH2 & the 5th corresponding to an intronic region of NOTCH2 – interferes w/analysis of NOTCH2.

Table 7.

Alagille Syndrome: Notable Pathogenic Variants

GeneReference
Sequences
DNA Nucleotide ChangePredicted Protein ChangeComment
JAG1NM_000214​.2
NP_000205​.1
c.551G>Ap.Arg184HisA common missense variant
c.232T>Cp.Cys78ArgAn example of a cysteine residue
critical for protein function
c.232T>Gp.Cys78Gly
c.233G>Cp.Cys78Ser
c.233G>Ap.Cys78Tyr

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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

Cancer and Benign Tumors

Somatic variants in NOTCH2 have been reported in 10%-20% of splenic marginal zone lymphomas (SMZL). NOTCH2 somatic variants were found to cluster in exon 34, which encodes the C-terminal PEST domain, which is necessary for regulation of the intracellular domain and downstream regulation of transcription [Jaramillo Oquendo et al 2019].

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Chapter Notes

Author History

Lynn D Bason, MS, CGC; Children's Hospital of Philadelphia (2000-2003)
Melissa A Gilbert, PhD (2019-present)
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; Children's Hospital of Philadelphia (2013-2019)
Kathleen M Loomes, MD (2019-present)
Nancy B Spinner, PhD (2000-present)

Revision History

  • 12 December 2019 (ha) Comprehensive update posted live
  • 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 live
  • 18 May 2006 (cd) Revision: NOTCH2 mutations identified in individuals with Alagille syndrome
  • 18 February 2005 (mr) Comprehensive update posted live
  • 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 live
  • 19 May 2000 (me) Review posted live
  • January 2000 (ns) Original submission
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