Alagille Syndrome

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32 In 1969, Alagille et al. described a syndrome characterized by chronic cholestasis resulting from paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterfly-like verte- bral arch defect, posterior embryotoxon, and peculiar facies.

The syndrome is also known as arteriohepatic dysplasia.

Alagille syndrome occurs in approximately 1 in 100,000 live births.

GENETICS/BASIC DEFECTS

1. Inheritance:

a. Sporadic in 45–50% of cases b. Autosomal dominant

i. Reduced penetrance ii. Variable expressivity

c. Alagille syndrome gene mapped to 20p12 2. Molecular defect

a. Caused by mutations or deletions of Jagged-1 gene (JAG1), encoding a ligand for the Notch transmem- brane receptor, implicated in cell differentiation b. More than 120 described intragenic mutations of the

JAG1 gene

c. No clear genotype-phenotype correlation in Alagille syndrome

CLINICAL FEATURES

1. High variability of phenotypic findings 2. Major features

a. Neonatal chronic cholestasis

i. Episodes of jaundice separated by periods of remission

ii. Pruritus iii. Hepatomegaly

iv. Splenomegaly: may be associated with portal hypertension

v. Xanthoma: progressive and observed in:

a) Extensor surface of the fingers b) Palmar creases

c) Nape of the neck d) Anal folds e) Popliteal fossa

f) Inguinal areas b. Facial features

i. Broad prominent forehead ii. Deep-set, widely spaced eyes iii. Long, straight nose

iv. Underdeveloped mandible

c. Complex congenital cardiovascular anomalies i. Pulmonary artery stenosis (67%) ii. Ventricular septal defects iii. Patent ductus arteriosus

iv. Pulmonary valve atresia v. Tetralogy of Fallot (7–16%)

vi. Tricuspid regurgitation vii. Right ventricular hypertrophy

d. Vertebral arch anomalies (butterfly-like vertebrae) e. Posterior embryotoxon (prominent Schwalbe’s ring) 3. Less frequently associated features

a. Growth retardation

b. Neurologic complications from vitamin E deficiency c. Mental retardation (2–30%)

d. Systemic vascular malformations i. Coarctation of the aorta ii. Middle aortic syndrome

iii. Arterial hypoplasia (hepatic, renal, carotid, celiac) iv. Artery stenosis (renal, subclavian)

v. Moyamoya disease vi. Carotid artery aneurysm vii. Intracranial hemorrhage viii. Hypoplastic portal vein branch e. Renal abnormalities

i. Interstitial nephritis

ii. Glomerular intramembranous and mesangial lipidosis

iii. Tubular dysfunction iv. Renal hypoplasia

v. Renal agenesis vi. Horseshoe kidney vii. Cystic disease

f. Small bowel atresia or stenosis g. Pancreas

i. Diabetes

ii. Exocrine pancreatic insufficiency h. Lung: tracheal and bronchial stenosis

i. Larynx: high-pitched voice j. Eye abnormalities

i. Retinal pigmentation ii. Iris strands

iii. Cataract iv. Myopia

v. Strabismus vi. Glaucoma vii. Optic disk drusen viii. Fundus hypopigmentation k. Skeletal abnormalities

i. Lack of normal progression of interpedicular distance in the lumbar spine

ii. Spina bifida

iii. Shortening of distal phalanges and metacarpal bones

iv. Clinodactyly 4. Prognosis

a. Characterized by recurrent episodes of cholestasis b. Often associated with common respiratory tract infec-

tions, especially during the first year of life

c. Good long survival but mortality rate may be up to 25%

Alagille Syndrome

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ALAGILLE SYNDROME 33

DIAGNOSTIC INVESTIGATIONS

1. Biochemical studies a. Hypercholesterolemia b. Hyperphospholipidemia c. Hypertriglyceridemia

d. Prominent increase in the pre- β-lipoprotein and apolipoprotein B levels

e. Very high total bile acids, gammaglutamyl trans- ferase, and alkaline phosphatase blood levels 2. Ophthalmologic assessment for posterior embryotoxon

and other ocular anomalies 3. Abdominal ultrasonography

a. Evaluation of the hepatobiliary tree and hepatic parenchyma

b. Evaluation of renal anomalies 4. Radiography for vertebral anomalies 5. Other imagings

a. Dimethyl iminodiacetic acid scanning

b. Magnetic resonance cholangiopancreatography c. Endoscopic retrograde cholangiopancreatography d. Intraoperative cholangiography

6. Echocardiography for cardiovascular malformations 7. Histology (liver biopsy)

a. Paucity of interlobular bile ducts b. Cholestasis in hepatocytes and canaliculi 8. Molecular genetic analysis

a. Sequence analysis of the JAG1 gene detects muta- tions in approximately 70% of individuals who meet clinical diagnostic criteria

b. FISH detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 5–7% of cases

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. A low but slightly increased risk due to parental germline mosaicism in clinically normal appear- ing parents

ii. A 50% risk if a parent is affected

b. Patient’s offspring: a 50% risk of having an offspring with Alagille syndrome

2. Prenatal diagnosis

a. Prenatal ultrasonography

i. Severe pulmonary artery stenosis

ii. Progressive severe intrauterine growth retardation b. Prenatal molecular diagnosis on fetal DNA obtained from amniocentesis or CVS is available if a disease- causing mutation (demonstrated by molecular genetic testing) or a deletion (detected by FISH) is identified in an affected family member

3. Management a. Medical care

i. Low-fat diets with medium-chain triglyceride supplementation

ii. Hypercaloric diets to severely malnourished patients

iii. Vitamin supplements

iv. Pruritus

a) Antihistamine agents

b) Cholestyramine or rifampin in management of bile acid-induced pruritus

b. Surgical care for patients with refractory disease i. Biliary diversion

ii. Eventual orthotopic liver transplantation with following indications:

a) Progressive hepatic dysfunction b) Severe portal hypertension c) Failure to thrive

d) Intractable pruritus and osteodystrophy iii. Cardiac surgery for complex congenital heart

defects

REFERENCES

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ALAGILLE SYNDROME 35

Fig. 1. An infant with Alagille syndrome showing neonatal jaundice, broad forehead, and underdeveloped mandible. This infant had peripheral pulmonary artery stenosis and paucity of interlobular bile ducts.