For girl in Asia, limited access to genetic testing delayed an Alagille diagnosis
Misdiagnosis in infancy led to surgery for wrong disease, per case report
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Due to limited access to genetic testing, a young girl with Alagille syndrome in Indonesia was misdiagnosed in infancy with biliary atresia — a condition that shares liver symptoms with Alagille — and received the wrong treatment for many years.
That’s according to a new case report, which noted that the girl underwent surgical treatment for biliary atresia due to that initial misdiagnosis. While the procedure resulted in favorable outcomes, the benefits were only temporary, the researchers noted.
Comprehensive genetic testing years after that surgery finally allowed a correct diagnosis of Alagille, the team reported. However, by that time, the little girl had experienced skin lesions and persistent itching, and showed signs of “severe malnutrition,” among other symptoms, per the researchers.
“Early diagnosis and management are critical for mitigating the syndrome’s impact on affected children,” the researchers wrote.
According to the team, this case highlights the challenges of diagnosing Alagille in low-resource settings and emphasizes the need for greater access to genetic testing, which the researchers noted is of “critical importance.”
The case study, “Alagille syndrome with heterozygous JAG1 c.224 T > C variant: a case report and literature review,” was published in the Egyptian Liver Journal.
A rare disease, Alagille is typically caused by mutations in the JAG1 gene, which provides instructions to produce the Jagged-1 (JAG1) protein. Because this protein is involved in embryonic development, mutations in this gene may lead to several organ and tissue abnormalities.
Among the most common Alagille symptoms are liver problems, mostly caused by a reduced number of bile ducts, the tubes that transport the digestive fluid bile, inside the liver. This slows or stalls bile flow, a condition called cholestasis. It, in turn, can ultimately damage the liver and lead to symptoms such as itching.
Such symptoms can overlap with those of biliary atresia, another rare disease in which blocked or damaged bile ducts, present from birth, lead to cholestasis.
Girl wrongly diagnosed at 4 months with biliary atresia
Here, a trio of researchers in the Asian nation described the case of a young girl with Alagille who was misdiagnosed at the age of 4 months with biliary atresia (BA).
Now, the girl sought treatment at the researchers’ department for symptoms of chronic cholestasis. She had elevated blood levels of liver damage markers, including bilirubin, suggestive of BA. A liver biopsy, in which a liver sample is collected for analysis under a microscope, showed severe inflammation of the bile ducts, known as cholangitis, and a reduced number of bile ducts.
Those findings, along with the presence of facial features and heart abnormalities consistent with Alagille, suggested the genetic disease. However, according to the researchers, there still was limited access to genetic testing to confirm the diagnosis.
In taking her history, the clinicians found the girl had undergone surgery at 5 months of age with the Kasai procedure, a first-line treatment for BA. That procedure is meant to restore bile flow.
“The Kasai procedure, which is typically not beneficial in [Alagille syndrome], was performed based on biopsy findings and clinical urgency,” the researchers wrote.
The procedure led to a normalization of blood bilirubin levels after six months.
However, over time, the girl developed elevated blood levels of the fatty molecule cholesterol, and xanthomas, or waxy, cholesterol-rich skin lesions on the arms, hands, legs, and face. These symptoms persisted despite treatment with medications to reduce cholesterol levels and a fat-restricted diet.
The girl also experienced hard-to-treat itching and had a poor nutritional status, with signs of severe malnutrition and short stature. By age 7, she had developed chronic cholestasis, with increased bilirubin levels, and mild to moderate liver scarring.
Genetic testing ID’d mutation in JAG1 gene linked to Alagille
Genetic testing through whole-exome sequencing, a technique that sequences the protein-coding regions in the entire DNA, identified a mutation, called c.224T>C (p.Phe75Ser), in one copy of the JAG1 gene. This variant is a missense mutation, meaning it results in a change in a single amino acid (protein’s building block) in the resulting JAG1 protein.
This mutation has been associated before with Alagille. It was previously classified as a variant of uncertain significance, meaning it is unclear whether it results in disease-causing protein changes.
However, further studies using computational approaches consistently indicated that the mutation is likely to have damaging effects on JAG1 protein’s structure or function, suggesting that it may be disease-causing.
In this case, the [Kasai] procedure was undertaken prior to genetic confirmation as an unavoidable consequence of early diagnostic uncertainty due to limited access to genetic testing.
Resource limitations had prevented genetic testing in the girl’s parents, but the researchers noted that they did not show any symptoms suggestive of Alagille.
The team also noted that while some medications have been approved for Alagille, they were not available at their hospital and the girl did not receive them.
“In this case, the [Kasai] procedure was undertaken prior to genetic confirmation as an unavoidable consequence of early diagnostic uncertainty due to limited access to genetic testing,” the researchers wrote. “This emphasizes the importance of early genetic testing in cases of ambiguous neonatal cholestasis.”
According to the team, this little girl’s case shows the need to improve access to genetic testing for patients.
The limitations to care that resulted from her misdiagnosis “highlight the challenges faced in low-resource settings and emphasize the critical importance of access to molecular diagnostics,” the team wrote.
