Alagille syndrome and deletion 20p12

Alagille Syndrome and deletion 20p12

Alagille syndrome is an autosomal dominant disorder that affects several bodily systems resulting in liver, cardiac, ocular, skeletal, vascular, and renal abnormalities. Alagille syndrome is usually (95%) caused by malfunction of the JAG1 gene located on the short arm of chromosome 20 (20p12 region). Although in most cases the patients have mutations in the JAG1 gene, there are numerous reports of patients with Alagille syndrome caused by deletions of 20p12 involving the JAG1 gene. In rare cases (~2.5%), Alagille syndrome occurs due to mutations or deletions of NOTCH2, and in some cases etiology of the syndrome remains unknown¹.

JAG1 encodes a cell surface protein that functions within the Notch signaling pathway as a ligand. This pathway is incredibly important throughout early embryonic development as it regulates cell fate, especially during somatogenesis².

Alagille syndrome has several key characteristics associated with it including bile duct paucity, chronic cholestasis, cardiac, ocular, skeletal, vascular, and renal anomalies¹. It is important to note that individuals may present with a high degree of variability². Even within families it is possible to see variation³.

Hepatic and cardiac malformations are some of the most common features seen in individuals with Alagille syndrome. Specifically, 75-89% of individuals have hepatic involvement which may include chronic cholestasis, bile duct paucity, and liver failure¹. Around 15% of individuals will require a liver transplant⁴. It should be known that liver disease is one of the most important factors contributing to morbidity and mortality¹. Cardiac malformations are just as common and occur in 75-97% of patients. Features typically include branch pulmonary artery stenosis, tetralogy of Fallot, and pulmonic stenosis¹. Generally, cardiac anomalies most commonly include peripheral and main pulmonary arteries and valves⁴.

Alagille syndrome may also present through various ocular anomalies. Posterior embryotoxon, optic disc anomalies, Axenfeld anomaly (dysgenesis of the anterior segment of the eye), microcornea, keratoconus, congenital macular dystrophy, shallow anterior chamber, exotropia, and cataracts have all been previously identified in individuals¹.

Thoracic butterfly vertebrae are also common amongst patients (33-93%)¹. This often occurs due to clefting abnormalities of the vertebral bodies⁴. Additional skeletal features may include tapered distal phalanges or additional digital flexion creases¹.

Patients, less commonly, may also present with vascular or kidney anomalies. Intracranial hemorrhages or cerebrovascular accidents occur in roughly 25% of patients while kidney anomalies such as renal tubular acidosis, vesicoureteral reflux, and urinary obstruction occur in around 39% of patients¹.

Lastly, individuals with Alagille syndrome have characteristic facial features that can be identified. Individuals tend to have a triangular face shape, prominent forehead, broad nasal bridge, and a pointed chin². It is important to note that these facial features may not be readily seen early on in life or throughout childhood. It may take time for these features to clearly present themselves¹.

REFERENCES

¹Avila-Jaque D, Díaz C, & Pardo R. (2024). Alagille syndrome associated to JAG1 gene deletion. An unusual etiology. Andes Pediatr, 95(2): 196–201.

²Robert ML, Lopez T, Crolla J, et al. (2007). Alagille syndrome with deletion 20p12.2-p12.3 and hypoplastic left heart. Clin Dysmorphol, 16(4): 241–246.

³Laufer-Cahana A, Krantz ID, Bason LD, et al. (2002). Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. Am J Med Genet, 112(2): 190–193.

⁴Krantz ID, Rand EB, Genin A, et al. (1997). Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet, 70(1), 80–86.