Alagille syndrome

Key Points at a Glance

Alagille syndrome is an autosomal dominant disorder caused by mutations in the JAG1 or NOTCH2 gene.
It is characterized by seven major clinical features: hepatobiliary, cardiac, ocular, skeletal, renal, facial, and vascular abnormalities.
In ophthalmology, posterior embryotoxon is the most common finding, present in about 50% of patients.
Cardiac abnormalities occur in over 90% of patients, with peripheral pulmonary stenosis being the most frequent.
Up to 75% of patients may require liver transplantation, and liver disease significantly affects prognosis.
The IBAT inhibitor maralixibat has been FDA-approved, offering hope for reducing pruritus and avoiding liver transplantation.
Penetrance varies widely, and phenotypes can differ greatly even within the same family.

1. What is Alagille syndrome?

Alagille syndrome (ALGS) is an autosomal dominant genetic disorder caused by mutations in the JAG1 or NOTCH2 gene. Daniel Alagille first reported the clinical features in 1969³⁾. In 1997, JAG1 was identified as the causative gene³⁾.

The prevalence is estimated at 1 in 30,000 to 100,000 people. JAG1 mutations account for approximately 94–95% of cases, while NOTCH2 mutations account for about 2.5%⁵⁾. About 60% are de novo mutations, and 30–50% are inherited from a parent²⁾.

Clinical manifestations are diverse, with wide variability in penetrance. Discordant phenotypes have been reported even in monozygotic twins⁶⁾. Many family members of diagnosed patients have clinical features but do not meet the diagnostic criteria.

Q How rare is Alagille syndrome?

It is a rare disease estimated to affect 1 in 30,000 to 100,000 people. Many patients present with neonatal cholestasis within the first 6 months of life²⁾. The diagnostic rate is improving with the widespread use of genetic testing.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Alagille syndrome is a multi-organ disease, and eye-specific subjective symptoms are rare. The following systemic symptoms are prominent.

Jaundice: Observed from early birth due to hepatobiliary disorders.
Pruritus: Severe itching occurs due to cholestasis. In some cases, it may lead to self-harm.
Growth impairment: Caused by malabsorption of fat-soluble vitamins and nutritional deficiencies.

Regarding the eyes, most cases maintain visual function, but a few cases have been reported where macular atrophy leads to decreased visual acuity.

Clinical Findings

Alagille syndrome has seven major clinical findings.

Hepatobiliary System

Intrahepatic bile duct hypoplasia: The most fundamental pathological finding.

Cholestasis: Causes jaundice, pruritus, and xanthomas.

Portal hypertension: In advanced cases, accompanied by splenomegaly and thrombocytopenia.

Cardiovascular system

Peripheral pulmonary artery stenosis: The most common cardiac abnormality, found in over 75% of cases²⁾.

Tetralogy of Fallot: A complex congenital heart defect seen in 7–12% of cases²⁾.

Vascular abnormalities: May also affect cerebral, renal, and aortic vessels.

Ocular findings

Posterior embryotoxon: The most frequent ocular finding. Note that it is also seen in 8–15% of the general population.

Optic disc abnormalities: hypoplasia, elevation, tilting, etc.

Chorioretinal changes: extensive depigmentation and irregular RPE pigmentation.

Skeletal and facial features

Butterfly vertebra: the most common skeletal abnormality.

Characteristic facial features: prominent forehead, pointed chin, deep-set eyes, saddle nose.

Osteopenia: associated with increased fracture risk.

A literature review reported liver abnormalities in 93.8%, cardiac abnormalities in 90.2%, characteristic facial features in 87.9%, spinal abnormalities in 65.5%, posterior embryotoxon in 49.7%, and renal abnormalities in 28.9% of cases³⁾.

Details of ophthalmic findings

In the anterior segment, in addition to posterior embryotoxon, iris abnormalities may be present. However, intraocular pressure and pupillary function are usually normal.

In the posterior segment, the following have been reported.

Extensive depigmentation of the choroid and retina: Choroidal thinning (leptochoroid) can be confirmed by optical coherence tomography.
Irregular pigmentation of the retinal pigment epithelium
Recurrent intraretinal hemorrhage: This is thought to be caused by microvascular abnormalities.
Optic disc drusen

Kidneys

Renal tubular acidosis, vesicoureteral reflux, and renal dysplasia may occur²⁾⁵⁾. The reported frequency of renal abnormalities ranges from 25% to 95%⁶⁾.

Vascular abnormalities

Cerebrovascular abnormalities such as aneurysms and moyamoya syndrome are known. A neonatal case with hypoplastic internal carotid artery detected by MRA has also been reported ²⁾. Vascular events are an important cause of morbidity and mortality. In the first reported case with a vascular ring, the right aortic arch, aberrant left subclavian artery, and left ductus arteriosus formed the ring ²⁾.

Q Can vision decrease due to eye symptoms?

Visual function is preserved in many patients. However, in some cases, macular atrophy may occur and affect vision. There are also reports of vision loss due to pseudopapilledema (PTCS) ⁷⁾. Regular ophthalmologic examinations are important.

3. Causes and risk factors

Alagille syndrome is caused by mutations in genes that constitute the Notch signaling pathway.

JAG1 mutation: Accounts for approximately 94–95% of all cases. 604 pathogenic mutations have been reported, with frameshift mutations being the most common (233 cases), followed by nonsense mutations (120 cases) and missense mutations (118 cases) ³⁾. The majority of mutations (95.5%) are located in exon regions ³⁾.
NOTCH2 mutation: Accounts for approximately 2.5%.
Structural variants: Mutations such as disruption of JAG1 due to balanced translocations, which are difficult to detect by standard sequencing, have also been reported ⁴⁾.

These genes are involved in cell differentiation during the embryonic period. Mutations impair normal differentiation of multiple organs including the intrahepatic bile ducts, heart, skeleton, and eyes.

The inheritance pattern is autosomal dominant but with incomplete penetrance. Over 40% of inherited JAG1 mutations are discovered after a diagnosis of Alagille syndrome in another family member ²⁾. Somatic/germline mosaicism in parents has also been reported ²⁾.

4. Diagnosis and testing methods

Clinical diagnostic criteria

Even without definitive genetic testing, a clinical diagnosis can be made based on a combination of three or more of the seven major clinical findings. The revised criteria also include family history and the presence of a pathogenic JAG1 mutation as diagnostic requirements ²⁾.

Genetic Testing

A definitive mutation is identified in up to 95% of patients with Alagille syndrome. Testing options include the following:

Test Method	Detects	Notes
Gene panel / WES	SNVs, small indels	Most common
MLPA	Large deletion of JAG1	Complement to panel
OGM (Optical Genome Mapping)	Balanced translocation / complex structural variant	Useful in cases negative by conventional methods⁴⁾

In cases where no mutation was detected by standard panel sequencing or WGS, there is a report of a balanced translocation t(4;20)(q22.1;p12.2) identified by OGM⁴⁾. Combining multiple testing methods improves the diagnostic rate⁴⁾.

Liver biopsy

Used to confirm bile duct paucity. If the bile duct/portal tract ratio is less than 0.4 (normal: 0.9–1.8), it is judged as bile duct hypoplasia ²⁾. However, with the spread of genetic testing, the need for liver biopsy has decreased.

Differential Diagnosis

Differentiation from diseases that cause cholestasis is particularly important.

Biliary atresia: In Alagille syndrome, misdiagnosis as biliary atresia and subsequent Kasai surgery leads to poor prognosis ²⁾³⁾. Matrix metalloproteinase-7 (MMP-7) is useful for differentiation.
Alpha-1 antitrypsin deficiency / Cystic fibrosis
Progressive familial intrahepatic cholestasis (PFIC)
22q11.2 deletion syndrome: Consider as a differential for cardiac and skeletal malformations.
Differential diagnosis of posterior embryotoxon: Axenfeld-Rieger syndrome, Banayan-Riley-Ruvalcaba syndrome. It is also observed in 8–15% of the general population.

Q Why is it important to differentiate from biliary atresia?

If Alagille syndrome is misdiagnosed as biliary atresia and Kasai surgery is performed, the prognosis worsens and mortality and liver transplantation rates increase³⁾. It is important to differentiate using mucosal pemphigoid-7 measurement and genetic testing.

5. Standard Treatment

Treatment for Alagille syndrome focuses on symptomatic management of dysfunction in each organ system.

Hepatobiliary Management

Nutritional Management

The basics include a high-calorie diet and supplementation with fat-soluble vitamins (A, D, E, K). MCT-enriched formula or tube feeding may be necessary in some cases⁵⁾.

Pharmacotherapy

The main treatment goals are relief of pruritus and reduction of cholestasis.

Ursodeoxycholic acid (UDCA): 15 mg/kg/day divided into two doses. It has been used as a first-line treatment for pruritus⁵⁾.
Rifampicin: Pregnane X receptor agonist. 5 mg/kg every 12 hours⁵⁾.
Cholestyramine: Bile acid sequestrant.
Antihistamines: Such as hydroxyzine. Direct improvement of pruritus is limited, but they contribute to sleep improvement¹⁾.

IBAT Inhibitors

Ileal bile acid transporter (IBAT) inhibitors are a new class of therapeutic agents.

Maralixibat (Livmarli®): FDA-approved for patients aged 3 months and older. Initial dose 190 μg/kg/day, increased to 380 μg/kg/day after confirming tolerability⁵⁾.
Odevixibat: FDA-approved for patients aged 12 months and older.

Garcia et al. (2023) reported a 7-year follow-up of a girl who started maralixibat at age 2¹⁾. Pruritus markedly improved within 10 days of starting treatment, and an ItchRO(Obs) score of 0 (complete resolution) was achieved at week 4. The Clinician Scratch Scale improved from 4 (self-injury present) to 0. Height z-score improved from −2.17 to −1.07, weight z-score from −1.65 to −0.87, and all other antipruritic medications could be discontinued.

Quintero-Bernabeu et al. (2026) reported an infant case in which liver fibrosis regressed from Ishak stage 4–5 to F2 after maralixibat treatment⁵⁾. Decreased liver stiffness on shear wave elastography, reduction in splenomegaly (16 cm → 12 cm), and recovery of platelet count (73,000 → 165,000 × 10⁹/L) were confirmed. In a 15-year-old female case, complete resolution of pruritus, improvement in liver stiffness from 13.8 to 9.2 kPa, splenomegaly from 20 to 15 cm, and platelets from 105,000 to 152,000 were observed after 24 months of treatment.

Data are accumulating that IBAT inhibitors not only improve pruritus but also suggest improvement in fibrosis and portal hypertension⁵⁾. Improvement in event-free survival has also been reported, and some experts consider them as first-line treatment.

Surgical Treatment

Partial external biliary diversion: An option for pruritus refractory to medical therapy.
Cholecystocolostomy: Reported as an internal biliary diversion procedure. Durgin et al. (2022) reported in a case series of 3 patients that the pruritus score improved from a mean of 3.33 to 1⁸⁾. However, one patient progressed to end-stage liver disease and required liver transplantation.
Liver transplantation: Performed for refractory pruritus, portal hypertension, and end-stage liver disease. Transplantation occurs at a median age of 2.8 years, with 72% performed within 5 years of age⁵⁾. Pruritus accounts for 69% of transplant indications.

Cardiovascular management

Peripheral pulmonary artery stenosis and tetralogy of Fallot may require cardiac surgery. In cardiac surgery for Alagille syndrome patients, the risk of oxygenator failure during cardiopulmonary bypass has been noted⁹⁾. This is thought to be due to membrane coating from hyperlipidemia, and circuit changes or hypothermia management have been reported as countermeasures⁹⁾.

Q Can maralixibat help avoid liver transplantation?

Not all patients can avoid it, but early administration has been reported to improve event-free survival ⁵⁾. There are cases where pruritus completely disappeared and persisted for over 7 years ¹⁾. The need for transplantation is determined by monitoring liver function.

6. Pathophysiology and Detailed Mechanisms

Alagille syndrome is fundamentally a disorder of the Notch signaling pathway. JAG1 encodes the ligand for the Notch receptor (Jagged1 protein), and NOTCH2 encodes the receptor itself ³⁾.

Notch signaling is essential for cell fate determination during embryonic development. In the liver, it is involved in the formation of intrahepatic bile ducts; in the heart, in the development of the right heart; and in the skeleton, in the segmentation of vertebrae. Disruption of this signaling leads to malformations in various organs.

Spectrum of JAG1 Mutations

To date, 604 pathogenic mutations have been reported ³⁾. The breakdown is as follows:

Frameshift mutations: 233 cases
Nonsense mutations: 120 cases
Missense mutations: 118 cases
Splice site mutations: 80 cases
Large deletions: 50 cases

Mutations are concentrated in exon regions (577/604, 95.5%), particularly in exons 2, 4, 6, 16, 23, and 24³⁾. Loss-of-function (LOF) mutations account for 79.97%³⁾.

Special mutation mechanisms

Zhang et al. (2023) identified a balanced translocation t(4;20)(q22.1;p12.2) using OGM, which was not detected by conventional panel sequencing, MLPA, or WGS⁴⁾. This translocation fuses exons 1–2 of JAG1 with exons 7–1 of FAM13A, resulting in complete loss of JAG1 transcription⁴⁾. The breakpoints are located at chr20:10,671,494 and chr4:88,813,301. A 5-base microhomology at the breakpoints suggests a mechanism involving non-homologous end joining⁴⁾.

Genotype-phenotype correlation

A clear genotype-phenotype correlation has not been established⁶⁾. Even within families carrying the same mutation, clinical presentations vary widely. In a report by Lee et al. (2023), the diagnosis of Alagille syndrome in an infant led to the diagnosis of the mother, who had a nearly asymptomatic phenotype with only characteristic facial features and a history of neonatal jaundice²⁾.

Congenital hypothyroidism (CH) is a rare complication, but Feng et al. (2024) reported CH in a patient with a JAG1 LOF mutation p.Pro325Leufs*87³⁾. It is suggested that Notch signaling may also be involved in thyroid development³⁾.

7. Latest Research and Future Perspectives (Investigational Reports)

Effect of IBAT inhibitors on liver fibrosis improvement

The pruritus-relieving effect of maralixibat is established, but its effects on liver fibrosis and portal hypertension are still under investigation.

Quintero-Bernabeu et al. (2026) confirmed regression from cirrhosis (Ishak stage 4–5) to F2 on liver biopsy after maralixibat administration ⁵⁾. It has been hypothesized that reducing bile acid accumulation in hepatocytes suppresses cell damage, inflammation, and fibrosis. However, the number of cases is small, and sampling bias or natural history effects cannot be excluded.

Management of Pseudotumor Cerebri Syndrome

Pseudotumor cerebri syndrome in Alagille syndrome is extremely rare, with only 8 reported cases ⁷⁾.

Polemikos et al. (2021) reported the first continuous intracranial pressure monitoring in a patient with Alagille syndrome ⁷⁾. In a 4-year-old boy, papilledema completely resolved after ventriculoperitoneal shunt placement, with no recurrence during 12 years of long-term follow-up. It is speculated that involvement of the Notch signaling pathway in vascular development may cause abnormalities in cerebrospinal fluid production and absorption through microvascular abnormalities in the choroid plexus ⁷⁾.

Advances in Genetic Diagnostic Technology

Optical genome mapping (OGM) has been shown to be useful for structural variants that are difficult to detect with conventional gene panels or whole-genome sequencing ⁴⁾. OGM fluorescently labels megabase-sized linear DNA molecules at CTTAAG motifs and performs de novo genome assembly. It excels at detecting translocations, inversions, tandem repeats, and complex genomic rearrangements, but cannot detect Robertsonian translocations ⁴⁾.

Pregnancy Management

Data on pregnancy outcomes in women with Alagille syndrome are extremely limited.

Morton et al. (2021) reviewed all 11 pregnancies reported in the literature and found fetal growth restriction in 64% and preeclampsia in 18% ⁶⁾. The severity of heart disease, portal hypertension, and kidney disease greatly influence pregnancy risk.

8. References

Garcia A, Hsu E, Lin HC. Resolution of pruritus in a child with Alagille syndrome treated with maralixibat for seven years: durable response and discontinuation of other medications. JPGN Reports. 2023;4(3):e335.
Lee PS, Silva Sepulveda JA, Del Campo M, et al. A neonatal case of vascular ring with Alagille syndrome. SAGE Open Med Case Rep. 2023;11:1-4.
Feng X, Ping J, Gao S, et al. Novel JAG1 variants leading to Alagille syndrome in two Chinese cases. Sci Rep. 2024;14:1812.
Zhang YQ, Gao PF, Yang JM, et al. Balanced translocation disrupting JAG1 identified by optical genomic mapping in suspected Alagille syndrome. Hum Mutat. 2023;2023:5396281.
Quintero-Bernabeu J, Padrós-Fornieles C, Mercadal-Hally M, et al. Beyond pruritus in Alagille syndrome: potential effects of maralixibat on fibrosis and portal hypertension—insights from two case studies. Front Med. 2026;12:1707258.
Morton A, Kumar S. Alagille syndrome and pregnancy. Obstet Med. 2021;14(1):39-41.
Polemikos M, Hermann EJ, Heissler HE, et al. Pseudotumor cerebri syndrome in a child with Alagille syndrome: intracranial pressure dynamics and treatment outcome after ventriculoperitoneal shunting. Childs Nerv Syst. 2021;37:2899-2904.
Durgin JM, Crum R, Kim HB, Cuenca AG. Outcomes of internal biliary diversion using cholecystocolostomy for patients with severe Alagille syndrome. J Surg Case Rep. 2022;2022(7):rjac307.
Moore AC, Sieck KN, Lojovich SJ, et al. Alagille syndrome and repeat oxygenator failure during cardiopulmonary bypass: a word of caution. J Extra Corpor Technol. 2022;54:338-342.

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