weekly_question 4/6/2023

[Admin]

You are asked to consult on a four-week old infant girl with acholic stools, jaundice and serum direct bilirubin of 5 mg/dL. Your evaluation also reveals abnormal facies with deep set eyes and a broad forehead, a cardiac murmur and a thoracic butterfly vertebral anomaly. Liver ultrasound is normal and HIDA scan shows radionuclide uptake into the liver but no excretion into the intestine at twenty-four hours. Which of the following is the most common gene mutation identified during genetic testing?

A CFTR

B JAG1

C ATP8B1

D NOTCH1

E SERPINA1

[Admin]

correct answer
B JAG1

The clinical presentation of this patient strongly suggests Alagille syndrome (AS) which is an autosomal dominant inherited disorder associated with liver, heart, eye and skeletal abnormalities, as well as characteristic facial features. Over 90% of patients with AS have a mutation in the JAG1 gene. This gene codes for a cell surface protein which functions as a ligand for the Notch transmembrane receptors which play a role in cell signaling and cell-cell interaction. Notch 1 mutations also cause AS. A liver biopsy can be helpful if it demonstrates paucity of bile ducts or perhaps ductal proliferation which might suggest biliary atresia. Similar findings can be seen in alpha-1-antitrypsin deficiency (SERPINA 1 gene), cystic fibrosis (CFTR gene), and progressive familial intrahepatic cholestasis (ATP8B1 gene).

Practically, intraoperative cholangiogram, in conjunction with a surgical liver biopsy, may be helpful in diagnosing AS since the genetic testing may not return promptly especially when biliary atresia is in the differential diagnosis. In AS the cholangiogram shows free passage of contrast through the common hepatic duct into the duodenum, small right and left extrahepatic ducts and absence of intrahepatic filling defects. A cardiac echocardiogram is warranted to assess for congenital heart defects. In AS cardiac anomalies occur in greater than 90%, with the most common being peripheral pulmonic stenosis. An ophthalmologic exam may show a posterior embryotoxon or prominent Schwalbe’s ring, that is found in 80 to 90% of syndromic AS patients.

[Ismailmohamed]

Allagile syndrome the most common JAG1

[Admin]

correct answer
B JAG1

The clinical presentation of this patient strongly suggests Alagille syndrome (AS) which is an autosomal dominant inherited disorder associated with liver, heart, eye and skeletal abnormalities, as well as characteristic facial features. Over 90% of patients with AS have a mutation in the JAG1 gene. This gene codes for a cell surface protein which functions as a ligand for the Notch transmembrane receptors which play a role in cell signaling and cell-cell interaction. Notch 1 mutations also cause AS. A liver biopsy can be helpful if it demonstrates paucity of bile ducts or perhaps ductal proliferation which might suggest biliary atresia. Similar findings can be seen in alpha-1-antitrypsin deficiency (SERPINA 1 gene), cystic fibrosis (CFTR gene), and progressive familial intrahepatic cholestasis (ATP8B1 gene).

Practically, intraoperative cholangiogram, in conjunction with a surgical liver biopsy, may be helpful in diagnosing AS since the genetic testing may not return promptly especially when biliary atresia is in the differential diagnosis. In AS the cholangiogram shows free passage of contrast through the common hepatic duct into the duodenum, small right and left extrahepatic ducts and absence of intrahepatic filling defects. A cardiac echocardiogram is warranted to assess for congenital heart defects. In AS cardiac anomalies occur in greater than 90%, with the most common being peripheral pulmonic stenosis. An ophthalmologic exam may show a posterior embryotoxon or prominent Schwalbe’s ring, that is found in 80 to 90% of syndromic AS patients.