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

OBJECTIVE: To describe and discuss our experience of patients with congenital adrenal hyperplasia (CAH) conceived via assisted reproduction techniques (ART). DESIGN: Case reports. SETTING: Tertiary hospitals and a CAH molecular diagnosis reference laboratory belonging to one of these. PATIENT(S): Five patients with CAH (with 21-hydroxylase deficiency [21OHD]) conceived via homo/heterologous ART with egg or sperm donations. INTERVENTION(S): 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. MAIN OUTCOME MEASURE(S): Genotype identification and segregation analysis of alleles. Clinical evaluation of patients. RESULT(S): 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. CONCLUSION(S): As a common, infertility-related and prenatal treatment-susceptible recessive genetic disease, 21OHD genotyping should be considered in ART.

[Prevalence of frequent recessive diseases in the Spanish population through DNA analyses on samples from the neonatal screening]. / Prevalencia de enfermedades recesivas frecuentes en población española mediante análisis de ADN en muestras del cribado neonatal.

BACKGROUND AND OBJECTIVE: Cystic fibrosis (CF) and the nonclassical forms of congenital adrenal hyperplasia (NC21OHD) are frequent autosomal recessive diseases. Their frequencies in the Caucasian population are the ones applied to the management of the diseases (1:2500 and 1:1000, respectively). The aim of this study was to learn about the adequacy of these figures to the Spanish population. MATERIAL AND METHOD: Study of the recurrent mutation (about 50% of alleles) in each entity, DF508 or Val281Leu, respectively, in 300 anonymous consecutive samples (600 alleles) from the Comunidad de Madrid neonatal screening. PCR specific amplifications of the CFTR and CYP21A2 genes and direct analyses of DF508 and Val281Leu mutations were performed. RESULTS: Allele frequencies of DF508 and Val281Leu were 0.005 and 0.038 (carrier frequencies 1.1% and 7.5%, respectively). Taking into consideration the percentage of these mutations in patient alleles, 48% for CF and for 57% NC21OHD, disease frequencies of about 1:8028 (CF) and 1:230 (NC21OHD) were estimated. The standard error calculated for these data were 0.6% and 1.5%. CONCLUSIONS: We have found that CF is less frequent and NC21OHD more frequent in the Spanish population than in other Caucasian populations.