Alagille syndrome 1; ALGS1

What is Alagille syndrome 1; ALGS1?

Alagille syndrome 1; ALGS1 is a rare disease. It 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.

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).

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* This information is courtesy of the L M D.

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What gene changes cause Alagille syndrome 1; ALGS1?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Dominant - 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.


Microdeletion - Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.


In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 118450 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
JAG1 - 20p12.2
NOTCH2 - 1p12

What are the main symptoms of Alagille syndrome 1; ALGS1?

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

How does someone get tested for Alagille syndrome 1; ALGS1?

The initial testing for Alagille syndrome 1; ALGS1 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. 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.

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