title: Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients.
abstract: 17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.
authors.affiliation: Paediatric Endocrinology Unit, Vall d'Hebron Research Institute and Hospital, CIBERER, Autonomous University, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.forename: Emilio
authors.initials: E
authors.lastname: García-García
authors.forename: Carmen
authors.initials: C
authors.lastname: González-Cejudo
authors.forename: María-Angeles
authors.initials: MA
authors.lastname: Martínez-Maestre
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Mangas-Cruz
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra-Junior
authors.forename: Maricilda
authors.initials: M
authors.lastname: Pandi de Mello
authors.forename: Ivo J P
authors.initials: IJP
authors.lastname: Arnhold
authors.forename: Mirian Y
authors.initials: MY
authors.lastname: Nishi
authors.forename: Berenice
authors.initials: B
authors.lastname: Bilharinho Mendonça
authors.forename: Elena
authors.initials: E
authors.lastname: García-Arumí
authors.forename: Laura
authors.initials: L
authors.lastname: Audí
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tizzano
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrascosa
mesh_terms: D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D001938:Brazil; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006728:Hormones / Q000097:blood; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D035781:Siblings; D013030:Spain; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D013737:Testis / Q000473:pathology
chemical_list: D006728:Hormones; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: CYP17A1; Congenital adrenal hyperplasia; Replacement therapy; Steroid pathway