We report definitive diagnosis and effective
chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3[beta]-hydroxy-[DELTA]5-C27-
steroid dehydrogenase/
isomerase deficiency. Findings of
cholestasis with normal serum [
gamma]-glutamyltransferase activity and total
bile acid concentration indicated the need for definitive
bile acid analysis. Large amounts of 3[beta]-hydroxy-[DELTA]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 3[beta]-hydroxy-[DELTA]5-
bile acids such as 3[beta],7[alpha]-dihydroxy- and 3[beta],7[alpha],12[alpha]-trihydroxy-5-cholenoic
acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3[beta]-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 3[beta]-hydroxy-[DELTA]5-C27-
steroid dehydrogenase/
isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage.