Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diso rders. CAH is most often caused by deficiency of steroid 21-hydroxylase. Th e frequency of CYP21-inactivating mutations and the genotype-phenotype rela tionship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensi tivity, 98.7%). The most frequent mutation was the intron 2 splice site mut ation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7 %) and large gene conversions (7.1%). Five point mutations were detected th at have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted func tional consequences and compared to the clinical phenotype. The positive pr edictive value for null mutations (ppv(null)) was 100%, as all patients wit h these mutations had a salt wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null muta tion), the ppv(A) to manifest with salt-wasting CAH was 90%. In group B pre dicted to result in simple virilizing CAH (I172Nin homozygous or compound h eterozygous form with a more severe mutation), ppv(B) was 74%. In group C ( P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppv(C) was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotyp e-phenotype relationship is shown in patients with either the severest or t he mildest mutations. A considerable degree of divergence is observed withi n mutation groups of intermediate severity. As yet undefined factors modify ing al-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.