Hormonal Profiles In Italian Late-Onset Adrenal-Hyperplasia Correlate With Hla Class-Iii Polymorphisms

To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR-beta, DQ-beta, DQ-alpha, 21-hydroxylase A and B genes; (3)fourth complement fraction lod A and B (C4A and C4B); second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes.HLA alleles B14 and DR-beta-1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p < 0.001 and p < 0.0001, respectively). Also C4B*2,1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p < 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus.These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.