Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia

Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder of steroid biosynthesis, caused by a molecular defect in the steroidogenic acute regulatory protein (StAR). Patients with CLAH usually manifest severe salt wasting, hypovolemia, enlargement of the adrenal glands and complete female external genitalia irrespective of the gonadal sex. CLAH seems to be more common in Koreans and Japanese than in other ethnic populations, with a preponderance of the mutation of a glutamine to a stop codon at the 258th amino acid residue (Q258X) in the StAR gene. Clinical findings of five unrelated Korean patients with CLAH and their molecular defects in the StAR gene are described, and the gene frequency of the Q258X mutation in the Korean population is investigated. All patients developed hypovolemic shock due to severe salt wasting in the first three months after birth. All were hyperpigmented, and three of five phenotypic females were genetic males. The basal ACTH level was extremely high in all patients with the minimal concentrations of all adrenal and gonadal steroids. The Q258X mutation was identified in 9 out of 10 alleles, indicating that the genetic defect in the StAR gene of Korean patients with CLAH is highly homogeneous probably due to a founder effect. The carrier frequency of the Q258X mutation in the normal Korean population has been estimated as approximately 1 in 250 with the allele frequency of 1 in 500. However, the confidence limits of the gene frequency for the mutant allele are wide (0.5 to 8.0 among 1,000 alleles). This implies that the carrier frequency could be lower, down to 1/1,000, or higher, up to 16/1,000.