COMBINED 17-ALPHA-HYDROXYLASE 17,20-LYASE DEFICIENCY CAUSED BY HETEROZYGOUS STOP CODONS IN THE CYTOCHROME-P450 17-ALPHA-HYDROXYLASE GENE

OBJECTIVE To determine the genetic defect underlying congenital adrenal hyperplasia due to 17alpha-hydroxylase deficiency in a genetic female. DESIGN Blood samples were used as a source of genomic DNA. A library of size selected genomic DNA sequences was prepared. In addition, portions of the 17alpha-hydroxylase gene were amplified by the polymerase chain reaction and the gene products sequenced. PATIENTS Samples were obtained from a patient with sexual infantilism, lack of secondary sexual characteristics and hypertension. Streak gonads were found on laparoscopy. RESULTS Two point mutations were found, one in exon 3 and one in exon 4 which generate premature stop codons at codons 194 and 239 in place of glutamate and arginine respectively. The mutation in exon 3 has not previously been reported in patients with 17alpha-hydroxylase deficiency. CONCLUSION The protein product of these defective genes could be expected to be severely truncated with no catalytic activity. This is in keeping with the complete lack of cortisol and sex steroid output in this patient. The polymerase chain reaction provides faster access to gene sequence information than previous procedures based on library screening prior to sequencing.