title: A new presentation of the chimeric CYP11B1/CYP11B2 gene with low prevalence of primary aldosteronism and atypical gene segregation pattern.
abstract: Familial hyperaldosteronism type I is caused by an unequal crossover of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, giving rise to a chimeric CYP11B1/CYP11B2 gene (CG). We describe a family carrying a CG with high levels of free 18-hydroxycortisol but low prevalence of primary aldosteronism (PA) and an atypical CG inheritance pattern in a family of 4 generations with 16 adults and 13 children, we measured the arterial blood pressure, serum aldosterone, and plasma renin activity and then calculated the serum aldosterone:plasma renin activity ratio and urinary free 18-hydroxycortisol. We identified the CG by long-extension PCR and predicted its inheritance pattern. The CG was found in 24 of 29 subjects (10 children and 14 adults). In CG+ patients, hypertension and high 18-hydroxycortisol were prevalent (83% and 100%, respectively). High serum aldosterone:plasma renin activity ratio was more frequent in pediatric than adult patients (80% versus 36%; P<0.001). An inverse association between serum aldosterone:plasma renin activity ratio and age was observed (r=-0.48; P=0.018). Sequence analysis identified the CYP11B1/CYP11B2 crossover in a 50-bp region spanning intron 3 of CYP11B1 and exon 4 of CYP11B2. The CG segregation differs from an autosomal disease, showing 100% of CG penetrance in generations II and III. Statistical analysis suggests that inheritance pattern was not attributed to random segregation (P<0.001). In conclusion, we describe a family with an atypical CYP11B1/CYP11B2 gene inheritance pattern and variable phenotypic expression, where the majority of pediatric patients have primary aldosteronism. Most adults have normal aldosterone and renin levels, which could mask them as essential hypertensives.
authors.affiliation: Department of Endocrinology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Carvajal
authors.forename: Carmen
authors.initials: C
authors.lastname: Campino
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martinez-Aguayo
authors.forename: Juan E
authors.initials: JE
authors.lastname: Tichauer
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Bancalari
authors.forename: Carolina
authors.initials: C
authors.lastname: Valdivia
authors.forename: Pamela
authors.initials: P
authors.lastname: Trejo
authors.forename: Marlene
authors.initials: M
authors.lastname: Aglony
authors.forename: René
authors.initials: R
authors.lastname: Baudrand
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mellado
authors.forename: Hernán
authors.initials: H
authors.lastname: Garcia
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Fardella
mesh_terms: D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000097:blood; D002677:Chile / Q000453:epidemiology; D056905:Chromosome Breakpoints; D020090:Chromosome Segregation / Q000235:genetics*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D050506:Mutant Chimeric Proteins / Q000235:genetics; D010375:Pedigree; D015995:Prevalence; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*
chemical_list: D050506:Mutant Chimeric Proteins; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase