Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

We report definitive diagnosis and effective chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3β-hydroxy-Δ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum γ-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3β-hydroxy-Δ 5 bile acids were detected by gas chromatography-mass spectrometry. HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patients and their parents identified four novel mutations of the HSD3B7 gene in the patients. One had a homozygous mutation, 314delA; the other had compound heterozygous mutations: V132F, T149I, and 973_974insCCTGC. Interestingly, the second patient's mother had V132F and T149I mutations in one allele. Excessive 3β-hydroxy-Δ 5 -bile acids such as 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3β-hydroxy-5-cholenoic acid. Liver dysfunction in both patients decreased with ursodeoxycholic acid treatment, but unusual bile acids were still detected. Normalization of the patients' liver function and improvement of bile acid profiles occurred with CDCA treatment. Thus, we found mutations in the HSD3B7 gene accounting for autosomal recessive neonatal cholestasis caused by 3β-hydroxy-Δ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage.