Should 21-hydroxylase deficiency genotyping be considered in assisted reproductive technology programs?

Abstract

To describe and discuss our experience of patients with congenital adrenal hyperplasia (CAH) conceived via assisted reproduction techniques (ART). Case reports. Tertiary hospitals and a CAH molecular diagnosis reference laboratory belonging to one of these. Five patients with CAH (with 21-hydroxylase deficiency [21OHD]) conceived via homo/heterologous ART with egg or sperm donations. Molecular diagnosis following DNA analysis of patients, parents, and siblings, including direct analysis of the gene (polymerase chain reaction/allele-specific hybridization), Southern analysis (for gene deletions and duplications), semiquantitative primer extension (to confirm duplications), complementary sequencing, and microsatellite analysis to confirm allele segregation. Genotype identification and segregation analysis of alleles. Clinical evaluation of patients. Three children (two girls, one boy) with classic neonatal forms of CAH (salt wasting and severe virilization) and two with nonclassic forms (two girls, one compound heterozygous with a severe mutation who showed clinical signs at 3.5 years of age) were born to parents who used ART. All showed segregated 21OH gene mutations. The respective genotypes were: 655G/655G, Q318X/Q318X,R356W, gene deletion hybrid with break point at exons 3-4/8 bp deletion at exon 3, 655G/V281L, and V281L/V281L. The severe mutations in the donated gametes were 655G and Q318X-R356W. As a common, infertility-related and prenatal treatment-susceptible recessive genetic disease, 21OHD genotyping should be considered in ART.