Craniosynostosis in Alagille syndrome

Abstract

Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation. © 2002 Wiley‐Liss, Inc.

Alagille syndrome: pathogenesis, diagnosis and management

“…Other axial skeletal features include narrowing of the interpedicular distance in the lumbar spine, pointed anterior process of C1, spina bifida occulta and fusion of adjacent vertebrae, hemivertebrae, and absence of the 12th rib. 23,24 Craniosynostosis has been reported, 25 as well as radioulnar synostosis, 26 and the digits may show shortening of the distal phalanges with fingers that have a fusiform appearance (Figure 3). It is not unusual for ALGS patients to develop metabolic bone disease with osteoporosis and fractures, most likely a consequence of multi-organ involvement, and a sub-optimal nutritional state.…”

Jagged-Notch signaling ensures dorsal skeletal identity in the vertebrate face

“…Several components of Jagged-Notch signaling are expressed in facial skeletal precursors, including zebrafish jag1b (Zecchin et al, 2005), mouse and human Jag1/JAG1 (Mitsiadis et al, 1997;Kamath et al, 2002b), zebrafish and mouse jag2/Jag2 (Jiang et al, 1998;Zecchin et al, 2005), and mouse Notch2 (Higuchi et al, 1995;Mitsiadis et al, 1997). Heterozygous mutations in human JAG1 or NOTCH2 are linked to Alagille syndrome, which is characterized by defects in multiple visceral organs, an abnormal facial appearance and occasional craniosynostosis and deafness (Li et al, 1997;Oda et al, 1997;Kamath et al, 2002b;Kamath et al, 2002a;Le Caignec et al, 2002;McDaniell et al, 2006). Whereas Jag1 -/-mice are embryonic lethal (Xue et al, 1999), Jag2 -/-mice die at birth from cleft palate (Jiang et al, 1998).…”

Aortic Aneurysm in Children and Adolescents

“…Another form of Alagille syndrome is caused by mutation in the NOTCH2 gene. Basillary artery aneurysm, middle cerebral artery aneurysm, aortic coarctation and aortic aneurysms have been reported in Alagille patients [44,45,46].…”