Clinical Guidance

No genotype-phenotype correlations for JAG1 or NOTCH2 have been identified.

Source: GeneReviews — "Alagille Syndrome"

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. To determine the range and frequency of clinical findings in individuals with a JAG1 pathogenic variant and, hence, the penetrance, 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. Penetrance appears complete in the individuals so far identified with NOTCH2 pathogenic variants .

Source: GeneReviews — "Alagille Syndrome"

Diagnostic Criteria

Clinical diagnostic criteria for Alagille syndrome (ALGS) have been published .

Suggestive Findings

ALGS should be suspected in individuals with any combination of the following histologic findings, major clinical features, and/or family history. 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 only identified in 65% of biopsies done in the first three months of life. In the newborn, a normal ratio of portal tracts to bile ducts, bile duct proliferation, or histology suggestive of neonatal hepatitis may be observed. Eventually, bile duct paucity is present in about 95% of individuals .

Source: GeneReviews — "Alagille Syndrome"

Differential Diagnosis

Bile duct paucity is not seen exclusively in Alagille syndrome (ALGS). Other causes of bile duct paucity include single-gene disorders , chromosome abnormalities (Down syndrome), infectious diseases (congenital cytomegalovirus, congenital rubella, congenital syphilis, hepatitis B), and immunologic disorders (graft-vs-host disease, chronic hepatic allograft rejection, primary sclerosing cholangitis). These can be distinguished from ALGS by history, by the presence of other findings, or by genetic testing. Intrahepatic cholestasis. Selected examples of inherited disorders associated with intrahepatic cholestasis are listed in . These conditions are largely confined to the liver, but some are associated with extrahepatic manifestations. Neonatal cholestasis.

Source: GeneReviews — "Alagille Syndrome"

Management Guidelines

No clinical practice guidelines for Alagille syndrome (ALGS) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ALGS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Alagille Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Gastrointestinal

| Eval by gastroenterologist to incl:

• Total conjugated/direct bilirubin

• Liver enzymes (incl GGT)

• Clotting studies

| If determined necessary by gastroenterologist, additional studies incl:

• Serum bile acids

• Lipid panel

• Fat-soluble vitamin levels

• Hepatic ultrasound

• Tc-99m DISIDA scintigraphy

• Liver biopsy

Cardiovascular

| Complete cardiology eval | Incl echocardiogram

Eyes | Ophthalmologic eval | Look for anterior chamber anomalies.

Skeletal

| AP lateral chest radiographs to evaluate for presence of butterfly vertebrae |

Renal

| Evaluate w/renal function studies renal ultrasound |

Growth

| Measurement of growth parameters plotting on age-appropriate growth charts |

Development

| Screening developmental eval | Perform more detailed eval if significant delays are identified.

Genetic counseling

| By genetics professionals1 | To inform affected persons their families re nature, MOI, implications of ALGS to facilitate medical personal decision making

Family support

Source: GeneReviews — "Alagille Syndrome"

Clinical Guidance

Contact sports should be avoided by all individuals, especially those with chronic liver disease, splenomegaly, and vascular involvement. Individuals with liver disease should avoid alcohol consumption.

Source: GeneReviews — "Alagille Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Alagille Syndrome"

Surveillance Guidelines

To date, surveillance guidelines for ALGS have not been published. In the absence of published guidelines, recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations are based on the authors' personal experience managing individuals with this disorder . Table 7. Alagille Syndrome: Recommended Surveillance

Source: GeneReviews — "Alagille Syndrome"