PubMed · 13974679
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J L RODRIGUEZ-MINON, F ARRIETA. [Androgenic adrenocortical hyperfunction].. https://pubmed.ncbi.nlm.nih.gov/13974679/
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More than 90% of all cases of congenital adrenal hyperplasia result from steroid 21-hydroxylase (CYP21) gene mutations. Around 95% of these are either gene deletions or any of nine sequence aberrations that have been transferred from the nearby pseudogene through apparent gene conversions. One such recurrent pseudogene-derived mutation is Cluster E6, a combination of three amino acid substitutions in exon 6: I236N, V237E, and M239K. Cluster E6 is associated with the most severe, salt-wasting form of congenital adrenal hyperplasia. We studied the functional consequences of each missense mutation individually as well as the combined effect of the three mutations comprising Cluster E6. V237E abolished enzyme function and is thus a null mutation, whereas very low but measurable activity remained for I236N. M239K, on the other hand, had no effect on enzyme activity and consequently does not contribute to the disease. Although no allele has been reported yet to contain only one or two missense mutations of Cluster E6, it is a well-known feature of CYP21 that it can harbor many different combinations of pseudogene-derived mutations. The exclusion of M239K as a disease-causing mutation is thus relevant when designing protocols for genetic diagnostics.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children's Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone than their white counterparts (p = 0.055). There was an equal sex ratio in both the I2 splice (12 female/14 male) and I172N (5 female/6 male) groups. However, in the Null group, the ratio was 4.0 (20 female/5 male; p = 0.003), suggesting that some Null male infants perish before being clinically detected to have CYP21 deficiency. Our findings strongly support the need for implementation of a neonatal screening programme for CAH in the UK which may reduce the male infant mortality.
Based on newborn screening data, the carrier frequency of congenital adrenal hyperplasia (CAH) in the general population has been estimated to be 1:55. The higher CAH frequency (particularly of milder forms of the disease) reported for certain populations including Yugoslavs (1.6%) relates to population genetic and hormonal data. However, so far, true carrier frequency for CAH due to 21-OH deficiency has not been determined by comprehensive mutation analysis of the 21-OH gene (CYP21A2) in an unselected European population. This study used CYP21A2 genotyping (sequence/Southern blot analysis) to determine CAH carrier frequency in a middle European (Austrian) population. The study included 100 migrants from the former Yugoslavia and 100 individuals of non-Yugoslavian origin. None of these individuals showed clinical hyperandrogenism or had a family history of CAH. Genotyping 400 unrelated alleles from 200 clinically unaffected individuals, this study revealed a carrier frequency of 9.5%, including so-called "classic" (5.5%) and "nonclassic" (4%) CYP21A2-gene aberrations. The observed heterozygosity for CAH in Yugoslavs was not different (P = 0.8095) from that in non-Yugoslavs. In conclusion, the observed CAH carrier frequency of 9.5% suggests a higher prevalence of CAH heterozygosity in a middle European population than hitherto estimated independently of the individuals' Yugoslav or non-Yugoslav origin.