Alagille syndrome presenting with increased intracranial pressure caused by late-onset craniosynostosis

Background

Alagille syndrome is characterized by intrahepatic cholestasis and abnormalities in the cardiovascular system, eyes, and vertebrae, along with a characteristic facial appearance. The genes responsible are JAG1 and NOTCH2. Although craniosynostosis occurs in approximately 1 % of patients with Alagille syndrome, its pathogenesis remains unclear. We report a case of Alagille syndrome, with late-onset craniosynostosis, which was associated with JAG1 gene mutation.

Case presentation

A 6 years and 5 months old boy presented with severe headache and vomiting. Magnetic resonance (MR) and computed tomography (CT) imaging revealed cerebellar tonsillar herniation and craniosynostosis of the sagittal, bilateral lambdoid, and coronal sutures. Cranial radiography showed marked digital impressions, and ophthalmological assessment revealed bilateral papilledema and reduced visual acuity, resulting in increased intracranial pressure (ICP). The patient was diagnosed with Alagille syndrome, associated with JAG1 gene mutation (heterozygosis c.1492_1495delAATG p.Asn498Glyfs*65). The same pathogenic variant was confirmed in his mother and sister. Although he had a mild hepatic disorder and pulmonary artery stenosis, he had grown uneventfully without developmental delays or growth disorders. Two weeks after the first visit, wide coronal craniotomy was performed to reduce the ICP. The headache and vomiting disappeared immediately after surgery, and the visual acuity and papilledema gradually improved.

Conclusion

The NOTCH signaling pathway involving JAG1 and NOTCH2 genes interacts with fibroblast growth factor receptors and the TWIST1 gene contributing to syndromic craniosynostosis. It is important to consider the possibility of craniosynostosis and manage increased ICP early in Alagille syndrome, even at school-going age.