ESPE Abstracts

Background: The rate of direct genotype–phenotype correlation in 21 hydroxylase deficiency congenital adrenal hyperplasia (CAH) is <50%. We report two cases of genotype/phenotype non-concordance, which has been explained by gene sequencing.

Family 1: in a non-consanguineous family of Irish, German, and Italian ethnicity there are five children. Two of the boys have hormonal evidence of CAH owing to 21-hydroxylase deficiency. The third boy has no symptoms of CAH. The father had no mutations while the mother was heterozygous for a deletion of the CYP21A2 gene. The genotype for the common mutations in the three boys only revealed a heterozygous mutation for the deletion transmitted by the mother yet the phenotype was that of a CAH patient. Family 2: in a non-consanguineous Ashkenazi Jewish family, the father’s DNA analysis revealed no mutation in the CYP21A2 gene. The mother was diagnosed with non-classical 21-hydroxylase deficiency and her genotype revealed an Ex7 mutation on one allele and a deletion of the CYP21A2 gene on the other allele. Their born infant had clear hormonal evidence of being a patient with classic simple virilizing CAH. Initial genotyping revealed a heterozygous genotype with a deletion of the CYP21A2 gene on one allele and no mutations on the other allele yet the infant was clearly a CAH patient and not a heterozygote.

Objective and hypotheses: Identify rare mutations in the CYP21A2 gene of families with hormonal evidence of CAH not explained by initial genotyping

Method: Sequencing of CYP21A2 gene.

Results: Family 1: upon sequencing of the CYP21A2 gene, a rare mutation (Ex8366H) was found in the father and the three boys indicating they were patients with a genotype Ex8366H/Del. Family 2: upon sequencing of the CYP21A2 gene another rare mutation was found (p.Trp19x) in the child and father. This explained the diagnosis of classic CAH in the infant.

Conclusion: These cases are emblematic of the need to search for rare mutations by sequencing in the CYP21A2 gene when there is genotype/phenotype non-concordance.