title: Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia.
abstract: Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A-->G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low in spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A-->G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A-->G mutation is sometimes associated with delayed phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestations of this disease.
authors.affiliation: Department of Pediatrics, Long Island College, Brooklyn, New York, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kohn
authors.forename: D
authors.initials: D
authors.lastname: Day
authors.forename: R
authors.initials: R
authors.lastname: Alemzadeh
authors.forename: D
authors.initials: D
authors.lastname: Enerio
authors.forename: S V
authors.initials: SV
authors.lastname: Patel
authors.forename: J V
authors.initials: JV
authors.lastname: Pelczar
authors.forename: P W
authors.initials: PW
authors.lastname: Speiser
mesh_terms: D000138:Acidosis / Q000150:complications / Q000235:genetics; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D003681:Dehydration / Q000150:complications / Q000235:genetics; D006720:Homozygote; D006801:Humans; D006947:Hyperkalemia / Q000150:complications / Q000235:genetics; D007010:Hyponatremia / Q000150:complications / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D017931:DNA Primers; D013255:Steroid 21-Hydroxylase