Alagille Syndrome

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.

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)

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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).

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].

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

• Growth failure has been observed in up to 50%-90% of individuals with ALGS; although not well understood, it has been attributed to malnutrition/malabsorption as well as cholestasis [Emerick et al 1999, Arvay et al 2005, Kamath et al 2015].
• Delayed puberty and high-pitched voice [Turnpenny & Ellard 2012]
• Mild delays of gross motor skills, identified in 16% of affected individuals. Mild intellectual disability was identified in 2% by Emerick et al [1999].
• Splenomegaly [Emerick et al 1999, Subramaniam et al 2011].
• Vascular abnormalities:
  • Neurovascular accidents, reported at rates as high as 15% [Emerick et al 1999], accounted 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].
• Craniosynostosis (unilateral coronal) has been reported in 0.9% of individuals with ALGS, compared to 0.03% in the normal population. [Kamath et al 2002, Yilmaz et al 2013]
• High risk for bone fractures with significant bone mineral deficiency, quantified by dual-energy x-ray absorptiometry (DXA) analysis [Loomes et al 2019]

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.

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.

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