A highly variable phenotype and differing disease severity has been reported in 4 family members with Allagile syndrome (ALGS). The case series was published in the International Journal of Pediatrics and Child Health.

The proband, the third-born child in the family, presented with a globular abdomen, loss of appetite, and poor growth at 18 months of age. After blood tests showed increased markers of cholestasis, an ultrasound found an enlarged liver with inhomogeneous parenchyma. An eye examination revealed posterior embryotoxon, while a cardiology exam identified pulmonary stenosis.

In addition, a column x-ray showed butterfly vertebrae at the level of D6, D8, and D11. As a liver biopsy was refused by the family, the diagnosis of ALGS was confirmed through a genetic examination. The proband is now 22 years old and is on the list for liver transplantation because of severe liver disease in progression.

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Next, both parents and the proband’s sister underwent genetic testing. The father was the only one identified as an asymptomatic carrier of the same mutation. Nonetheless, specific examinations found clinically insignificant posterior embryotoxon and pulmonary stenosis, while peculiar facies exhibited by the proband could also be observed in his father.

The third reported case was the proband’s younger brother, who was diagnosed with ALGS at birth. The boy is now 10 years old and exhibits mild disease symptoms. Peculiar facies, mild pulmonary artery stenosis, papilla with blurred edges and dystrophy of the retinal pigment epithelium, liver with finely inhomogeneous echostructure, pyelic ectasia on the left, and butterfly vertebrae have all been identified.

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The last reported case is the second-born child, who died at 1 month of age due to complications related to Tetralogy of Fallot. Although no genetic examination was performed, as the child was born before the proband, the researchers suspect a form of ALGS with exclusive heart involvement.

“Taken together, these data show that ALGS is a disorder with a wide spectrum of phenotypic manifestations, even between individuals from the same family sharing the same mutation,“ Arrabito and colleagues wrote. “For this reason, the diagnosis may be difficult and it should be usually considered in the differential diagnosis in patients (children or adults) with intrahepatic cholestasis, jaundice, and pulmonic stenosis.”

The clinical variability of ALGS can be explained by the implication of the NOTCH receptor and its ligand in many key cellular signaling pathways.


Arrabito M, D’Amico S, Gulizia C, et al. Alagille syndrome nowadays: “one, no-one and one hundred thousand”. J Paediatr Child Health. Published online December 29, 2022. doi:10.12974/2311-8687.2022.10.5