Bile Acid Synthesis Defect, Congenital, 1

A number sign (#) is used with this entry because this disorder of bile acid synthesis, referred to here as CBAS1, can be caused by homozygous or compound heterozygous mutation in the gene encoding 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase (HSD3B7; 607764) on chromosome 16p.

Description

Congenital defects of bile acid synthesis are autosomal recessive disorders characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract resulting from a primary failure to synthesize bile acids. Affected infants show failure to thrive and secondary coagulopathy. In most forms of the disorder, there is a favorable response to oral bile acid therapy (summary by Cheng et al., 2003).

Genetic Heterogeneity of Congenital Defects in Bile Acid Synthesis

There are several disorders that result from defects in bile acid synthesis. See CBAS2 (235555), caused by mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1; 604741) on chromosome 7q33; CBAS3 (613812), caused by mutation in the 7-alpha hydroxylase gene (CYP7B1; 603711) on chromosome 8q12; CBAS4 (214950), caused by mutation in the AMACR gene (604489) on chromosome 5p13; CBAS5 (616278), caused by mutation in the ABCD3 gene (170995) on chromosome 1p21; and CBAS6 (617308), caused by mutation in the ACOX2 gene (601641) on chromosome 3p14.

See also progressive familial intrahepatic cholestasis (PFIC1; 211600), which has a similar phenotype.

Clinical Features

Clayton et al. (1987) described a sibship of 5 children in which 3 had progressive liver disease starting in the neonatal period. The Saudi Arabian parents were first cousins. The jaundice in these infants was cholestatic in nature and biopsy showed aggressive hepatitis with giant cells and bridging fibrosis with cirrhosis. Chenodeoxycholic acid and cholic acid were absent from the urine and plasma, indicating a defect in bile acid synthesis. Furthermore, 2 unusual bile acid precursors were found in the urine. Clayton et al. (1987) suggested that the infants suffered from a defect in 3-beta-hydroxy-delta-5-steroid dehydrogenase/isomerase. In the family of Clayton et al. (1987), Buchmann et al. (1990) found a serum accumulation of 7-alpha-hydroxy-cholesterol. Cultured fibroblasts from the patient were completely devoid of 3-beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase activity. Fibroblasts from his parents had reduced activity, compatible with the heterozygous genotype.

Jacquemin et al. (1994) reported 5 unrelated children with progressive intrahepatic cholestasis caused by a primary defect in bile acid synthesis due to 3-beta-hydroxy-C27-steroid dehydrogenase deficiency. Clinical features included jaundice, hepatosplenomegaly, and fatty stools beginning in infancy. Liver function tests showed normal serum gamma-GGT (see 612346), low serum cholesterol and vitamin E levels, increased serum bilirubin, and coagulopathy. Liver function returned to normal after oral ursodeoxycholic acid therapy. Jacquemin et al. (1994) noted the importance of correct diagnosis in these patients to avoid liver transplantation.

Schwarz et al. (2000) studied the fifth child, a boy, from the sibship described by Clayton et al. (1987). An older sister and brother had died of complications of progressive liver disease. He weighed 4 kg at birth and exhibited jaundice 2 days later. He had been brought to clinical attention in Great Britain as a 3-month-old infant. He had moderate jaundice, hepatomegaly, and an accumulation of 3-beta,7-alpha-dihydroxy- and 3-beta,7-alpha,12-alpha-trihydroxy-5-cholenoic acids in his urine. The family returned to Saudi Arabia and the patient was lost to follow-up until age 2 years, when he was seen at the King Faisal Specialist Hospital. He was underdeveloped (25th percentile for weight, less than 5th percentile for height) and had persistent jaundice, pruritus, rickets, and hepatomegaly. Treatment with chenodeoxycholic acid led to increased well being, a decrease in pruritus, and a normalization of urinary steroids (Ichimiya et al., 1991). At the time of the report of Schwarz et al. (2000), he was 17 years old and doing well on cholic acid therapy.

Molecular Genetics

Schwarz et al. (2000) cloned the gene encoding 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase, which had been reported to be deficient in several patients with progressive neonatal cholestasis. The authors identified a homozygous 2-bp deletion in exon 6 of the HSD3B7 gene (607764.0001) in a member of the sibship described originally by Clayton et al. (1987).

Cheng et al. (2003) performed a molecular analysis of 15 additional patients from 13 kindreds with C27 3-beta-HSD deficiency and identified 12 different mutations in the HSD3B7 gene (see, e.g., 607764.0001-607764.0005). Mutations were homozygous in 13 patients from 10 families and heterozygous in 4 patients from 3 families. Five of the families had been reported by Jacquemin et al. (1994).

History

Powell et al. (1973) reported a female infant with chronic diarrhea, failure to thrive and severe malabsorption of fat. They found a low concentration of bile acids in duodenal fluid. By exclusion they arrived at a synthetic defect as the likely cause of the bile acid deficiency. Nothing in the family suggested a genetic basis. Indeed, the patient was 1 of 16 children in a Mexican American family, and the other 15 children were healthy.