Alagille syndrome

What is Alagille syndrome?

Alagille syndrome is a genetic condition which affects mainly the liver. Individuals with the syndrome have less than the normal number of bile ducts in their liver.

This rare disease also affects the heart, and other parts of the body too. Symptoms are usually first noticed in infancy.

The syndrome occurs in approximately 1 in every 30,000 live births.

This syndrome is also known as:
AGS AHD Alagille syndrome; Algs Alagille-watson Syndrome; Aws Arteriohepatic Dysplasia; Ahd Cholestasis With Peripheral Pulmonary Stenosis Hepatic Ductular Hypoplasia, Syndromatic

What gene change causes Alagille syndrome?

88% of cases of the syndrome are caused by mutations to the JAG1 gene, with just 1% caused by mutations to the NOTCH2 gene.

The condition is inherited in an autosomal dominant pattern. In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

what are the main symptoms of Alagille syndrome?

The majority of the most severe symptoms are the result of lack of bile ducts in the liver causing liver damage and related problems. They might first be noticed by the presence of yellow tinged skin in an affected individual.

In infancy the most common symptoms are jaundice, loose and pale stools as well as poor growth and a failure to thrive. These symptoms generally stabilize between the ages of 4 and 10 years old.

From childhood symptoms include continued, recurrent jaundice, itching, fatty deposits in the skin and delayed growth and development.

Unique facial features of the syndrome include a prominent and broad forehead, deep set eyes, a straight nose, and a small pointed chin. Individuals with the condition also usually have an extra circular line on the surface of their eye.

Other less serious symptoms include a possible heart murmur, although this is rarely indicative of something serious, and spinal bones in the shape of a butterfly that rarely present any medical problems.

Possible clinical traits/features:
Depressed nasal bridge, Broad forehead, Hypercholesterolemia, Hypoplasia of the ulna, Hemivertebrae, Hepatocellular carcinoma, Hypertelorism, Short distal phalanx of finger, Hypertriglyceridemia, Stroke, Chorioretinal atrophy, Cirrhosis, Axenfeld anomaly, Atrial septal defect, Band keratopathy, Butterfly vertebral arch, Cataract, Abnormality of the ribs, Areflexia, Renal hypoplasia, Papillary thyroid carcinoma, Pigmentary retinal deposits, Autosomal dominant inheritance, Renal dysplasia, Vesicoureteral reflux, Ventricular septal defect, Tetralogy of Fallot, Triangular face, Strabismus, Renal tubular acidosis, Peripheral pulmonary artery stenosis, Reduced number of intrahepatic bile ducts, Incomplete penetrance, Infantile onset, Upslanted palpebral fissure, Specific learning disability, Macrotia, Multiple small medullary renal cysts, Long nose, Intellectual disability, mild, Prolonged neonatal jaundice, Myopia, Coarctation of aorta, Microcornea, Posterior embryotoxon, Elevated hepatic transaminase

How does someone get tested for Alagille syndrome?

The initial testing for Alagille syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Alagille syndrome

The main features are intrahepatic cholestasis, congenital heart disease, and skeletal and ocular anomalies. The following percentage figures are from Alagille et al., (1987). In most cases there is a paucity of intrahepatic bile ducts (occasionally extrahepatic as well) resulting in prolonged neonatal jaundice (91%), although a quarter develop jaundice later in infancy (Mueller et al., 1984). The cardiac lesions (85%) are predominantly peripheral pulmonary stenosis but might include pulmonary valve stenosis, partial anomalous venous drainage or atrial and ventricular septal defects. Various degrees of anterior chamber defect (particularly posterior embryotoxon) might occur as well as a pigmentary retinopathy (88%). Nischal et al., (1997) found that 80% of cases had optic disc drusen bilaterally and 95% of cases had drusen unilaterally. Ho et al., (2000) reported a case with oligodontia and oral xanthomas. Cutaneous xanthomas occur in about 28% of cases (Garcia et al., 2005).
The skeletal changes consist of hemi or butterfly vertebrae (87%) and there may be shortening of the distal phalanges, radius or ulna. Ryan et al., (2003) reported a case with bilateral radio-ulnar synostosis. Kamath et al., (2002) suggest that extra flexion creases of the fingers are a feature. Rodriguez et al., (1991) reported a possible case with features of caudal regression. The forehead is prominent, the eyes deepset and the nose long with a flattened tip. In adulthood the mandible becomes significantly prominent. Kamath et al., (2002) reported two patients with mutations in the Jagged1 gene (see below) who had unilateral coronal craniosynostosis. Craniosynostosis was also reported by Yilmaz et al., (2013). No pictues or genetic studies were published. Short stature is common (50%) and there is occasional mental retardation (16%).It has been suggested that the facial features are secondary to the prolonged effects of bile duct obstruction. However Kamath et al., (2002) provide data to suggest that the facies in Alagille syndrome are specific to the condition. In general the liver abnormalities resolve with age although occasional cases can have more severe hepatic problems leading to early death. Twenty-five percent of cases need liver transplantation. Cambiaghi et al., (1998) described a child with steatocystoma multiplex and leuconychia. Krantz et al., (1997) provide a good review.
Devriendt et al., (1996) reported a possible case who was found to have an absent kidney on one side, and developed diabetes mellitus secondary to an atrophic pancreas. He had the typical liver features, but no heart defects or skeletal abnormalities apart from clinodactyly.
Dhorne-Pollet et al., (1994) carried out segregation analysis on 33 families ascertained through 43 probands. They estimated that penetrance of the gene was 94%, and that 15% of cases were sporadic. The latter figure seems rather low as in only about 15% of probands was there an affected parent. Elmslie et al., (1995) studied fourteen cases and found that six appeared to have an affected parent.
Some cases have been shown to have a deletion of the short arm of chromosome 20 (reviewed by Teebi et al., 1992 and Krantz et al., 1997 - see also Oda et al., 2000), however Desmaze et al., (1992) failed to detect microdeletions either by high resolution chromosome banding or by using in situ hybridisation. Rand et al., (1995) found a single submicroscopic deletion of chromosome 20 markers in a detailed study of 24 cytogenetically normal Alagille patients. Moog et al., (1996) reported a family where a father and two children had a duplication of 20p11.21-20p11.23 and features consistent with Alagille syndrome.
Oda et al., (1997) and Li et al., (1997) demonstrated mutations in the Jagged 1 gene causing presumed haploinsufficiency. The Jagged1 gene encodes a ligand for the Notch receptor (Artavanis-Tsakonas 1997). Yuan et al., (1998) studied 8 families and found seven mutations (4 frameshift, one nonsense, one splice-site, and one 1.3Mb deletion). Further mutations were reported by Krantz et al., (1998). Loomes et al., (1999) studied the expression pattern of Jagged1 in the heart of both murine and human embryos.
Yuan et al., (2001) identified JAG1 mutations in 15 out of 25 Japanese families. They also identified one large deletion. Genotype/phenotype correlations suggested that absence of the Delta/Serrate/Lag-2 (DSL) domain of the protein resulted in severe liver disorder.
Krantz et al., (1999) studied a patient with tetralogy of Fallot and a butterfly vertebra, but no other features of Alagille syndrome. She was found to have a deletion of 20p12 encompassing the Jagged1 gene. Another patient with pulmonary stenosis, and a family history of this condition, was also found to have a mutation of the Jagged1 gene although there were no other feautres of Alagille syndrome. Giannakudis et al., (2001) studied 61 individuals where JAG1 mutations were detected and identified 5 cases where mosaicism was present. They stressed that this 8.2% incidence of mosaicism can complicate genetic counselling, as these individuals can be very mildly affected. Laufer-Cahana et al., (2002) reported an affected girl with a microdeletion of 20p who's mother had mosaicism for this deletion and was phenotypically normal. Genetic counselling is also complicated by the finding of mutations in relatives, 47% of whom did not meet the criteria for Alagille syndrome (Kamath et al., 2003). The facial features were the highest penetrant features as opposed to cardiac and liver manifestations.
Gridley (2003) gives a good review of Notch signaling and inherited disease syndromes. Witt et al., (2004) have achieved a DNA-based prenatal diagnosis.
A second locus at 1p12 has been identified (McDaniell et al., 2006) and mutations in 2 families were found in NOTCH2. Renal anomalies were common.
The condition is beautifully reviewed by Turnpenny and Ellard (2012) . Note the case reported by Vozzi et al., (2013) where the mutation in Jag1
Mutations in ATPB81 which cause "Progressive familial intrahepatic cholestasis type 1" can cause an Alagille phenotype (Grochowski et al., 2015).

* This information is courtesy of the L M D.

If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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