Phenotype/Genotype correlations in 21-hydroxylase deficiency

Study Objective: To correlate phenotype with genotype based on molecular diagnosis in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Design: Polymerase chain reaction amplification, restriction fragment length polymorphism, and allele specific oligonucleotide hybridization were utilized to ascertain eight previously recognized deleterious mutations in affected individuals and their family members. Participants/Setting: DNA samples were obtained from 20 individuals with 21-hydroxylase deficiency followed through the Endocrine Clinic of the Children's Hospital of Pittsburgh. Fifteen individuals had salt-losing 21-hydroxylase deficiency and two families had two affected individuals. Four individuals presented prior to 5 years of age without salt loss. One individual presented in adolescence with hirsutism and oligomenorrhea. Main Outcome Measure: Molecular diagnosis of 21-hydroxylase deficiency. Results: Five patients have homozygous deletions of the promoter region. Two patients are homozygous for the splicing mutation in the second intron. Individual patients were homozygous for the following three mutations: Arg³⁵⁶ → TrP, Ile¹⁷² → Asn, and Val²⁸¹ → Leu. Ten patients were compound heterozygotes. Conclusions: In general, the magnitude of enzyme activity correlates with the phenotypic findings. For example, mutations that completely impair enzyme activity, such as homozygous deletions of the promoter region, are associated with salt-losing congenital adrenal hyperplasia. However, the splicing mutation at nucleotide 655 in the second intron is characterized by greater phenotypic heterogeneity than the other mutations in this series.