Researchers presented the case of a patient who developed progressive hepatic failure as a result of a unique pathogenic heterozygous variation of the NOTCH2 gene, resulting in a diagnosis of type 2 Alagille syndrome, according to a study published in the American Journal of Case Reports.

When infants present with cholestasis, there are more than 100 differential diagnoses that can be associated with the condition. Diagnosis becomes easier if a genetic cause is detected. Regardless, cholestasis can cause permanent liver damage, requiring the patient to undergo liver transplantation.

Alagille syndrome is usually characterized by a variety of symptoms, such as neonatal cholestasis, ocular abnormalities, vertebral deformities, and heart malformations. However, Alagille syndrome is a highly heterogeneous disease; some patients have no symptoms at all, while others have a life-threatening form of the disease. 

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“New diagnostic criteria have been developed in light of [Alagille syndrome]’s genetic foundation and the availability of molecular testing,” the authors of the study wrote. “Jagged canonical Notch ligand 1 (JAG1) and neurogenic locus Notch homolog protein 2 (NOTCH2) are 2 of the most common genes involved in the Notch signaling pathway (NSP) in the majority of patients with [Alagille syndrome].” 

Read more about Alagille syndrome etiology 

Uddin and colleagues presented the case study of a neonate who was born at 31 weeks. Upon examination, the neonate was found to have bilateral hazy eyes, ectropion, dry ichthyic skin, and bilateral undescended testes. He had no family history of neonatal jaundice. 

By the patient’s third week of hospitalization, he started to develop cholestatic jaundice. The patient died from multiorgan failure as a result of gram-negative sepsis.

“The diagnostic puzzle was solved a week after his death, after we received his whole exome sequencing results,” the authors of the study wrote. “An autosomal dominant [type 2 Alagille syndrome] was caused by a pathogenic heterozygous variant c.1076c>T (Ser359Phe) chr1: 120512166 in the NOTCH2 gene.” 

The fact that this patient was diagnosed with Alagille syndrome only after death highlights the difficulty of diagnosing newborn cholestasis since presentations can be remarkably similar.


Uddin MS, Al Fulayyih S, Al Denaini FF, Al Hatlani MM. Pathogenic novel heterozygous variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 gene, type 2 Alagille syndrome causing neonatal cholestasis: a case report. Am J Case Rep. Published online September 2, 2022. doi:10.12659/AJCR.935840