title: Erroneous prenatal diagnosis of congenital adrenal hyperplasia owing to a duplication of the CYP21A2 gene.
abstract: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder where steroidogenesis in the adrenal cortex is impaired. The most common form is caused by 21-hydroxylase deficiency (21OHD). Classical 21OHD is characterized by glucocorticoid and mineralocorticoid deficiency and by overproduction of adrenal androgens. The diagnosis rests on biochemical and genetic analyses. In families with history of CAH, prenatal genetic diagnosis is offered. We herein present a case of an infant whose parents were identified to carry mutations on the CYP21A2 gene. The fetal DNA analysis demonstrated that the fetus carried a paternal exon 8 (Q318X) mutation and a maternal exon 8 (R356X) mutation. The fetus was presumed to be affected with CAH, yet his clinical presentation at birth was not consistent with the diagnosis. Repeated genetic analysis identified a paternal CYP21A2 gene duplication with Q318X mutation on one copy of CYP21A2. We conclude that a duplication of the CYP21A2 gene should be suspected when clinical and hormonal findings do not support the genetic diagnosis. Furthermore, because individuals with Q318X mutation frequently have a duplication of the CYP21A2 gene, when Q318X is detected, it is important to distinguish the severe point mutation in single gene copy alleles from the non-deficient variant in gene-duplicated alleles.
authors.affiliation: Department of Pediatric Endocrinology, Adrenal Steroid Disorders Program, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: O
authors.initials: O
authors.lastname: Lekarev
authors.forename: K
authors.initials: K
authors.lastname: Tafuri
authors.forename: A H
authors.initials: AH
authors.lastname: Lane
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.forename: J M
authors.initials: JM
authors.lastname: Nakamoto
authors.forename: A M
authors.initials: AM
authors.lastname: Buller-Burckle
authors.forename: T A
authors.initials: TA
authors.lastname: Wilson
authors.forename: M I
authors.initials: MI
authors.lastname: New
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D000328:Adult; D015193:Chorionic Villi Sampling; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D020440:Gene Duplication / Q000235:genetics*; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D060148:HapMap Project; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D015997:Neonatal Screening; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012083:Renin / Q000097:blood; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: D019326:17-alpha-Hydroxyprogesterone; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D012083:Renin