Sharing of MHC haplotypes among apparently unrelated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

From the study of HLA, complement, and glyoxalase I alleles in 82 Venezuelan individuals belonging to 19 families of mixed ethnic origin having 20 affected newborns with salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency, a total of 38 disease haplotypes and 53 nondisease haplotypes were found. Of the pathological haplotypes 47% were found to share the HLA-B39 or -Bw62 specificities, 55% of them in combination with the BFS, C2C, C4A4, C4B2 (SC42) complotype. The frequencies of HLA-B39 and -Bw62 among the affected haplotypes were 29 and 18% as compared with 6 and 0% among the nondisease haplotypes of the same families. Statistical associations (P less than 0.01) with salt-wasting adrenal hyperplasia were found with the SC42 complotype and with the combination SC42, HLA-B39. These results are markedly different from those reported in the literature which show an "association" at the population level among many Caucasoid samples of HLA-Bw47 and the extended haplotype (HLA-Bw47, DR7,FC91,0) with the salt-wasting form of the disease. Furthermore, four of the unrelated patients reported here were homozygous for all the major histocompatibility complex loci tested, while three others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicated clustering of the deficiency carrier HLA haplotypes. This observation, together with the fact that there is an excess of homozygotes among the patients in Venezuela, strongly suggests that salt-wasting 21-OH deficiency congenital adrenal hyperplasia is mostly the result of a founder effect of relatively hyperplasia is mostly the result of a founder effect identity by descent of a few abnormal alleles at the 21-OHB locus in most cases. The mutation marked by HLA-Bw47 was not observed in this population.