Alagille disease

Digital cases

 Case 117 (HPC:117) : Hepatocellular carcinoma in Alagille disease

Definition: Alagille syndrome is an autosomal dominant, multisystem disorder with variable expressivity, characterized by bile duct paucity and resultant liver disease in combination with cardiac, ocular, skeletal, and facial findings.

Synopsis

 characteristic face

• broad forehead
• triangular face
• prominent zygomatic arch
• long nose with bulbous tip

 ocular anomalies

• deep-set eyes
• posterior embryotoxon
• posterior chamber anomalies
• eccentric pupils or ectopic pupils
• chorioretinal atrophy
• retinal pigment clumping
• axenfeld anomaly
• choroidal folds
• strabismus
• myopia
• anomalous optic disc
• posterior embryotoxon

 biliary lesions

• paucity of interlobular bile ducts (hepatic ductopenia, hepatic ductular hypoplasia, intrahepatic bile duct hypoplasia)
• intrahepatic biliary atresia
• extrahepatic biliary atresia (12297837)

 cardiovascular lesions

• peripheral pulmonary artery stenosis
• tetralogy of Fallot
• atrial septal defect
• ventricular septal defect
• coarctation of aorta

 renal Alagille disease

• renal dysplasia
• renal mesangiolipidosis
• medullary cystic disease
• chronic renal failure and hypertension

 rib anomalies
 vertebral anomalies
 butterfly vertebral arch
 hemivertebrae

 hands

• short ulnae
• short distal phalanges

Associations

 hepatocellular carcinoma (Case 117)
 papillary thyroid carcinoma

Etiology

 mutation of Jagged1 (JAG1 gene) of the Notch signaling pathway

• JAG1 mutations in AGS include gene deletions and protein truncating, splicing, and missense mutations, suggesting that haploinsufficiency is the mechanism of disease causation.

The cardiac-specific phenotype associated with this mutation suggests that the developing heart is more sensitive than the developing liver to decreased dosage of JAG1. (12649809)

References

 Libbrecht L, Spinner NB, Moore EC, Cassiman D, Van Damme-Lombaerts R, Roskams T. Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation. Am J Surg Pathol. 2005 Jun;29(6):820-6. PMID: 15897750

 Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987 Feb;110(2):195-200. PMID: 3806290

 Berard E, Sarles J, Triolo V, Gagnadoux MF, Wernert F, Hadchouel M, Niaudet P. Renovascular hypertension and vascular anomalies in Alagille syndrome. Pediatr Nephrol. 1998 Feb;12(2):121-4. PMID: 9543369

 Habib R, Dommergues JP, Gubler MC, Hadchouel M, Gautier M, Odievre M, Alagille D. Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia). Pediatr Nephrol. 1987 Jul;1(3):455-64. PMID: 3153318

 Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975 Jan;86(1):63-71. PMID: 803282