Alagille syndrome
General Information (adopted from Orphanet):
Synonyms, Signs: |
Arteriohepatic dysplasia Syndromic bile duct paucity Alagille-Watson syndrome |
Number of Symptoms | 42 |
OrphanetNr: | 52 |
OMIM Id: |
118450
610205 |
ICD-10: |
Q44.7 |
UMLs: |
C0085280 |
MeSH: |
D016738 |
MedDRA: |
10053870 |
Snomed: |
31742004 |
Prevalence, inheritance and age of onset:
Prevalence: | 0.4 of 100 000 [Orphanet] |
Inheritance: |
Autosomal dominant [Orphanet] |
Age of onset: |
All ages [Orphanet] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
Genetic biliary tract disease
-Rare genetic disease Genetic multiple congenital anomalies/dysmorphic syndrome without intellectual deficit -Rare genetic disease Multiple congenital anomalies/dysmorphic syndrome without intellectual deficit -Rare developmental defect during embryogenesis Polymalformative genetic syndrome with increased risk of developing cancer -Rare genetic disease -Rare oncologic disease Rare biliary tract disease -Rare hepatic disease Rare disease with glaucoma as a major feature -Rare eye disease -Rare genetic disease Rare syndrome with cardiac malformations -Rare developmental defect during embryogenesis -Rare genetic disease Syndromic developmental defect of the eye -Rare developmental defect during embryogenesis -Rare eye disease -Rare genetic disease Syndromic renal or urinary tract malformation -Rare developmental defect during embryogenesis -Rare genetic disease -Rare renal disease Syndromic visceral malformation -Rare abdominal surgical disease -Rare developmental defect during embryogenesis -Rare genetic disease |
Symptom Information:
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(HPO:0000100) | Nephrotic syndrome | Occasional [Orphanet] | 83 / 7739 | |||
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(HPO:0000069) | Abnormality of the ureter | Occasional [Orphanet] | 47 / 7739 | |||
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(HPO:0000035) | Abnormality of the testis | Occasional [Orphanet] | 296 / 7739 | |||
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(HPO:0008678) | Renal hypoplasia/aplasia | Occasional [Orphanet] | 127 / 7739 | |||
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(HPO:0000307) | Pointed chin | Frequent [Orphanet] | 45 / 7739 | |||
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(HPO:0000494) | Downslanted palpebral fissures | Occasional [Orphanet] | 328 / 7739 | |||
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(HPO:0000490) | Deeply set eye | Occasional [Orphanet] | 131 / 7739 | |||
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(HPO:0000311) | Round face | Frequent [Orphanet] | 104 / 7739 | |||
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(HPO:0000280) | Coarse facial features | Frequent [Orphanet] | 189 / 7739 | |||
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(HPO:0012368) | Flat face | Occasional [Orphanet] | 106 / 7739 | |||
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(HPO:0002007) | Frontal bossing | Frequent [Orphanet] | 366 / 7739 | |||
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(HPO:0000322) | Short philtrum | Occasional [Orphanet] | 130 / 7739 | |||
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(HPO:0000316) | Hypertelorism | Occasional [Orphanet] | 644 / 7739 | |||
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(HPO:0000248) | Brachycephaly | Occasional [Orphanet] | 222 / 7739 | |||
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(HPO:0005105) | Abnormal nasal morphology | Frequent [Orphanet] | 114 / 7739 | |||
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(HPO:0000277) | Abnormality of the mandible | Occasional [Orphanet] | 394 / 7739 | |||
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(HPO:0000615) | Abnormality of the pupil | Occasional [Orphanet] | 39 / 7739 | |||
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(HPO:0000486) | Strabismus | Occasional [Orphanet] | 576 / 7739 | |||
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(HPO:0100692) | Increased corneal curvature | Occasional [Orphanet] | 13 / 7739 | |||
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(HPO:0001131) | Corneal dystrophy | Very frequent [Orphanet] | 56 / 7739 | |||
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(HPO:0000411) | Protruding ear | Frequent [Orphanet] | 140 / 7739 | |||
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(HPO:0008373) | Puberty and gonadal disorders | Occasional [Orphanet] | 156 / 7739 | |||
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(HPO:0003422) | Vertebral segmentation defect | Frequent [Orphanet] | 95 / 7739 | |||
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(HPO:0002750) | Delayed skeletal maturation | Occasional [Orphanet] | 250 / 7739 | |||
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(HPO:0002997) | Abnormality of the ulna | Occasional [Orphanet] | 75 / 7739 | |||
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(HPO:0000772) | Abnormality of the ribs | Occasional [Orphanet] | 146 / 7739 | |||
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(HPO:0003312) | Abnormal form of the vertebral bodies | Frequent [Orphanet] | 172 / 7739 | |||
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(HPO:0004209) | Clinodactyly of the 5th finger | Occasional [Orphanet] | 288 / 7739 | |||
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(HPO:0009882) | Short distal phalanx of finger | Occasional [Orphanet] | 125 / 7739 | |||
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(HPO:0003298) | Spina bifida occulta | Frequent [Orphanet] | 67 / 7739 | |||
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(HPO:0001396) | Cholestasis | Very frequent [Orphanet] | 136 / 7739 | |||
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(HPO:0005248) | Intrahepatic biliary atresia | Very frequent [Orphanet] | 6 / 7739 | |||
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(HPO:0002240) | Hepatomegaly | Very frequent [Orphanet] | 467 / 7739 | |||
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(HPO:0004325) | Decreased body weight | Very frequent [Orphanet] | 492 / 7739 | |||
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(HPO:0001511) | Intrauterine growth retardation | Frequent [Orphanet] | 358 / 7739 | |||
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(HPO:0100585) | Telangiectasia of the skin | Frequent [Orphanet] | 66 / 7739 | |||
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(HPO:0000822) | Hypertension | Occasional [Orphanet] | 224 / 7739 | |||
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(HPO:0001629) | Ventricular septal defect | Very frequent [Orphanet] | 316 / 7739 | |||
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(HPO:0004414) | Abnormality of the pulmonary artery | Occasional [Orphanet] | 50 / 7739 | |||
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(HPO:0001631) | Atria septal defect | Occasional [Orphanet] | 274 / 7739 | |||
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(HPO:0012758) | Neurodevelopmental delay | Occasional [Orphanet] | 949 / 7739 | |||
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(HPO:0001428) | Somatic mutation | Occasional [Orphanet] | 100 / 7739 |
Associated genes:
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Diagnosis GeneReviews | The clinical diagnostic criteria for Alagille syndrome (ALGS) include the following:... Gene SymbolProportion of ALGS Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityJAG189% | Sequence analysis / mutation scanning 1Sequence variants 2Clinical Footnote 3Sequence analysis of select exonsSequence variants in select exons 2~5%-7% 4Deletion / duplication analysis (including FISH) 5Deletion and duplication of exon(s) and entire gene deletion 6Linkage analysisNASee footnote 7NOTCH21%-2% 8Sequence analysisSequence variants 2Clinical UnknownDeletion / duplication analysis 5Unknown, none reported1. 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.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. 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 24.4. Warthen et al [2006], personal communication. Extent of deletion detected may vary by method and by laboratory.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Extent of deletion detected may vary by method and by laboratory [Kamath et al 2009].7. 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.8. McDaniell et al [2006], Kamath et al [2012a]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis of ALGS in a proband In situations in which the diagnosis is suspected but the criteria for clinical diagnosis are not met, sequence analysis of JAG1 should be performed first, as this identifies mutations in more than 89% of persons with a JAG1 mutation. If no mutations are detected by sequence analysis of JAG1, deletion/duplication analysis can be performed to detect deletions or duplications of JAG1 exon(s) or of the whole gene. Given the wide availability of targeted CMA testing, this could be used to determine both the presence and extent of a chromosomal deletion/duplication involving JAG1 if there was high density of probes in the region. Other deletion/duplication methods (e.g., MLPA) also detect exonic or whole-gene deletions.If a deletion involving the entire JAG1 gene is identified, a full cytogenetic study may be considered to determine if a rare chromosomal rearrangement (translocation or inversion) is present.The presence of developmental delay and/or hearing loss in addition to the features commonly seen in ALGS may increase the suspicion of a chromosome deletion. NOTCH2 molecular genetic testing should be considered when the diagnosis is strongly suspected on clinical grounds, but no JAG1 mutation/deletion/duplication was identified. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies at risk for ALGS require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersJAG1. No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in JAG1. However, it should be noted that some individuals with JAG1 mutations 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 NOTCH2 mutations may express only some of the features of ALGS and may not be recognized as having this diagnosis [Kamath et al 2012a]. Germline mutationsHajdu-Cheney syndrome. Specific mutations in NOTCH2 have recently been identified to cause Hajdu-Cheney syndrome, also known as serpentine fibula polycystic kidney syndrome. Hajdu-Cheney syndrome is an autosomal dominant disorder which causes focal bone destruction, osteoporosis, craniofacial dysmorphology, renal cysts, cleft palate, and cardiac defects. The NOTCH2 mutations identified in individuals with Hadju-Cheney syndrome were all localized in the last exon (exon 34) of NOTCH2; these mutations are predicted to disrupt the intracellular PEST (proline-glutamate-serine-threonine-rich) domain and decrease clearance of the notch intracellular domain, thus increasing Notch signaling [Majewski et al 2011, Penton et al 2012, Zanotti & Canalis 2012]. Somatic mutationsSplenic marginal zone lymphoma (SMZL). Recurrent somatic gain-of-function mutations in NOTCH2 have been identified in individuals with SMZL [Kiel et al 2012].
Clinical Description GeneReviews | Alagille syndrome (ALGS) is a multisystem disorder. Studies of families with multiple affected members and/or JAG1 mutations have demonstrated a wide spectrum of clinical variability ranging from life-threatening liver or cardiac disease to only subclinical manifestations (i.e., butterfly vertebrae, posterior embryotoxon, or characteristic facial features). This variability is seen even among individuals from the same family [Kamath et al 2003]. Indeed, in a study of 53 mutation-positive relatives of affected individuals, 25 (47%) did not meet clinical diagnostic criteria [Kamath et al 2003].... Clinical FindingFrequency (% of Individuals) Emerick et al [1999]Subramaniam et al [2011]Bile duct paucity | 69/81 (85%)77/103 (75%)Chronic cholestasis 88/92 (96%)104/117 (89%)Cardiac murmur 90/92 (97%)107/117 (91%)Eye findings65/83 (78%)72/117 (61%) 1Vertebral anomalies 37/71 (51%)44/117 (39%) 2Characteristic facies 86/92 (96%)91/117 (77%)Renal disease 28/69 (40%)27/117 (23%)Pancreatic insufficiency7/17 (41%)NRGrowth retardation 27/31 (87%)NRIntellectual disability2/92 (2%)NRDevelopmental delay 15/92 (16%)NRBased on 92 individuals with ALGS [Emerick et al 1999] and 117 children with ALGS [Subramaniam et al 2011]NR = Not reviewed.1. Only posterior embryotoxon was reviewed in this study. 2. Only butterfly vertebrae was reviewed in this study.Hepatic manifestations. Although some individuals with JAG1 mutations have no detectable hepatic manifestations [Gurkan et al 1999, Krantz et al 1999, Kamath et al 2003], in most affected persons liver disease presents within the first three months of life and ranges from jaundice, mild cholestasis, and pruritis to progressive liver failure. Jaundice presents as conjugated hyperbilirubinemia in the neonatal period. Increased serum concentrations of bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), triglycerides, and the aminotransferases are also seen.Cholestasis manifests as pruritis, increased serum concentration of bile acids, growth failure, and xanthomas. In approximately 15% of affected individuals, the liver disease progresses to cirrhosis and liver failure, necessitating liver transplantation [Emerick et al 1999]. Currently, it is not possible to predict which infants will progress to end-stage liver disease. Liver biopsy typically shows paucity of the intrahepatic bile ducts, which may be progressive. In the newborn with ALGS, bile duct paucity is not always present and the liver biopsy may demonstrate ductal proliferation, resulting in the possible misdiagnosis of ALGS as biliary atresia.While it is difficult to predict whether a child with cholestasis will have improvement or progression of liver disease, a retrospective study of 33 individuals with Alagille syndrome found that in children younger than age five years, a total bilirubin >6.5 mg/dL, a conjugated bilirubin >4.5 mg/dL and a cholesterol >520 mg/dL were associated with severe liver disease later in life. These biomarkers and suggested cutoff values can be used to inform medical management and may help identify affected individuals who would benefit from more aggressive therapy [Kamath et al 2010b].Cardiac manifestations. Cardiac findings ranging from benign heart murmurs to significant structural defects occur in 90%-97% of individuals with ALGS [Emerick et al 1999, McElhinney et al 2002]. The pulmonary vasculature (pulmonary valve, pulmonary artery, and its branches) is most commonly involved. Pulmonic stenosis (peripheral and branch) is the most common cardiac finding (67%) [Emerick et al 1999]. The most common complex cardiac defect is tetralogy of Fallot, seen in 7%-16% of individuals [Emerick et al 1999]. Other cardiac malformations include (in order of decreasing frequency) ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta. Ophthalmologic manifestations. The most common ophthalmologic finding in individuals with ALGS is posterior embryotoxon. Posterior embryotoxon, a prominent Schwalbe's ring, is a defect of the anterior chamber of the eye and has been reported in 78%-89% of individuals with ALGS [Emerick et al 1999, Hingorani et al 1999]. Most accurately identified on slit-lamp examination, posterior embryotoxon does not affect visual acuity but is useful as a diagnostic aid. Posterior embryotoxon is also present in approximately 8%-15% of individuals from the general population. This finding in family members who are otherwise unaffected can complicate the identification of relatives with the gene mutation. Other defects of the anterior chamber seen in ALGS include Axenfeld anomaly and Rieger anomaly. Ocular ultrasonographic examination in 20 children with ALGS found optic disk drusen in 90%. Retinal pigmentary changes are also common (32% in one study) [Hingorani et al 1999, El-Koofy et al 2011]. Although these changes were initially thought to be the result of dietary deficiency, they have been seen in individuals with normal serum concentrations of vitamins A and E [Hingorani et al 1999]. Additionally eye anomalies have also been described [Makino et al 2012].The visual prognosis is good, although mild decreases in visual acuity may occur. In particular, visual loss has been described in association with intracranial hypertension [Narula et al 2006].Skeletal manifestations. The most common radiographic finding is butterfly vertebrae, a clefting abnormality of the vertebral bodies that occurs most commonly in the thoracic vertebrae. The frequency of butterfly vertebrae reported in individuals with ALGS ranges from 33% to 93% [Emerick et al 1999, Sanderson et al 2002, Lin et al 2012]. Butterfly vertebrae are usually asymptomatic. The incidence in the general population is unknown but suspected to be low. Other skeletal manifestations in individuals with ALGS have been reported less frequently [Zanotti & Canalis 2012]. Facial features. The constellation of facial features observed in children with ALGS includes a prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and saddle or straight nose with a bulbous tip. These features give the face the appearance of an inverted triangle. The typical facial features are almost universally present in Alagille syndrome (see Figure 1). FigureFigure 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 GeneReviews | The phenotype of ALGS caused by mutations in JAG1 is indistinguishable from the phenotype caused by mutations in NOTCH2. Initially, 3/3 relatives who had NOTCH2 mutations had significant renal disease, often resulting in end-stage renal disease [McDaniell et al 2006]. More recent studies have shown that renal involvement was noted in 4/9 affected individuals evaluated for renal anomalies. This observation is consistent with the renal involvement observed in those with JAG1 mutations. However, it is important to note that the number of individuals identified with ALGS caused by NOTCH2 mutations is still too small to draw any conclusions about genotype-phenotype correlations [Kamath et al 2012a].... |
Differential Diagnosis GeneReviews |
Table 3. Alagille Syndrome: OMIM Phenotypic Series... PhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM NumberAlagille syndrome | 118450 JAG1, AGS, AHD 601920 Alagille syndrome 2 610205 NOTCH2, AGS2, HJCYS 600275 Data from Online Mendelian Inheritance in ManNeonatal cholestasis. More than 100 specific causes of neonatal cholestasis exist: Treatable causes such as sepsis or galactosemia need to be considered first. A diisopropyl iminodiacetic acid (DISIDA) scan may identify cholestasis as a result of extrahepatic causes such as biliary atresia. Hepatic ultrasound examination can detect extrahepatic structural abnormalities such as choledochal cysts. Bile duct paucity is not seen exclusively in Alagille syndrome (ALGS). Other causes of bile duct paucity include: idiopathic, metabolic disorders (alpha-1-antitrypsin deficiency, hypopituitarism, cystic fibrosis, trihydroxycoprostanic acid excess), chromosomal abnormalities (Down syndrome), infectious diseases (congenital CMV, congenital rubella, congenital syphilis, hepatitis B), immunologic disorders (graft-versus-host disease, chronic hepatic allograft rejection, primary sclerosing cholangitis), and others (Zellweger syndrome, Ivemark syndrome). These can be distinguished from ALGS by history, by the presence of other findings, or by genetic testing. Other disorders associated with intrahepatic cholestasis include the autosomal recessive disorders progressive familial intrahepatic cholestasis 1 and 2 (Byler syndrome), Norwegian cholestasis (Aagenaes syndrome), benign recurrent intrahepatic cholestasis (BRIC), and North American Indian cholestasis (NAIC). These conditions are largely confined to the liver; only ALGS demonstrates multi-organ system involvement. Posterior embryotoxon is seen in Rieger syndrome, Bannayan-Riley-Ruvalcaba syndrome (one of the phenotypes of the PTEN hamartoma tumor syndrome), and numerous other syndromes. It is also observed in 8%-15% of the general population. ALGS can be distinguished by the presence of other findings or by genetic testing. Pulmonic vascular system abnormalities are seen in isolation as well as in syndromes such as Noonan syndrome, Watson syndrome (pulmonic stenosis and neurofibromatosis type 1), LEOPARD syndrome, Down syndrome, and Williams syndrome. These other syndromes can be distinguished by other associated clinical findings and/or molecular genetic testing. Several of the cardiac defects described in ALGS, particularly ventricular septal defect and tetralogy of Fallot, are commonly seen in individuals with deletion 22q11.2. Individuals with this diagnosis have also been reported as having butterfly vertebrae and poor growth, two common features of ALGS. Liver disease is not part of the deletion 22q11.2 syndrome; testing for this deletion using the specific FISH probe distinguishes the two disorders [Greenway et al 2009]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Management GeneReviews | To establish the extent of disease and needs in an individual diagnosed with Alagille syndrome (ALGS), the following evaluations are recommended:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDJAG120p12 | Protein jagged-1Catalogue of Somatic Mutations in Cancer (COSMIC)