Bile Acid Synthesis Defect, Congenital, 3

A number sign (#) is used with this entry because of evidence that congenital bile acid synthesis defect-3 (CBAS3) is caused by homozygous mutation in the CYP7B1 gene (603711) on chromosome 8q12.

For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see 607765.

Clinical Features

Setchell et al. (1998) described an inborn error of bile acid synthesis involving a deficiency in 7-alpha-hydroxylation in a male offspring of first-cousin Mexican parents. The patient developed jaundice at 6 days of age, which resolved with phototherapy. During week 6 of life he intermittently passed acholic stools; jaundice returned at 8 weeks of age. Other features included hepatosplenomegaly and increased bleeding. Serum AST, ALT, and alkaline phosphatase enzymes were markedly elevated and prothrombin time was prolonged. Percutaneous liver biopsy showed marked increase in portal connective tissue with bridging fibrosis and probable cirrhosis, as well as mild portal inflammation and moderate lobular disarray with giant cell transformation. After transient treatment with oral cholic acid, he underwent liver transplantation. The diagnosis was established by fast atom bombardment, ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxycholenoic acids, and an absence of primary bile acids. Levels of 27-hydroxycholesterol were more than 4,500 times normal. Hepatic microsomal oxysterol 7-alpha-hydroxylase activity was undetectable. It was thought that an accumulation of hepatotoxic unsaturated monohydroxy bile acids accounted for the pathology. Setchell et al. (1998) stated that more than 2,500 samples from cholestatic infants had been analyzed by mass spectrometry between 1988 and 1998 at Children's Hospital in Cincinnati, and that this was the first patient identified with deficiency in 7-alpha-hydroxylation of bile acids. They speculated that the relatively early age of the patient and the severity of the liver disease may indicate that a mutation in the oxysterol 7-alpha-hydroxylase gene causes prenatal or early neonatal lethality, and that this case represents an exception to fetal death.

Molecular Genetics

In a child with congenital bile acid synthesis defect-3, Setchell et al. (1998) identified a homozygous nonsense mutation in the CYP7B1 gene (R388X; 603711.0001).