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
View in own window
Feature | % of Persons w/Feature | Comment |
---|
Hepatic abnormality incl: bile duct paucity; conjugated hyperbilirubinemia; chronic cholestasis characterized by pruritus, xanthomas & fat-soluble vitamin deficiencies; & end-stage liver disease | ≤100% | |
Cardiac malformation | 90%-97% | Most common cardiovascular malformations incl pulmonary stenosis & tetralogy of Fallot |
Posterior embryotoxon | 78%-89% | |
Renal disease | 39% | |
Vertebral anomalies | 33%-93% | |
Characteristic facies | 77%-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 2020]. 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 ).
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
Mild delays of gross motor skills, identified in 16% of affected individuals. Mild intellectual disability was identified in 2% by
Emerick et al [1999].
Vascular abnormalities:
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.