Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms

• Published in: Clinical endocrinology (Oxford) 1998-06, Vol.48 (6), p.707-711
• Main Authors: RUMSBY, G, AVEY, C. J, CONWAY, G. S, HONOUR, J. W
• Format: Article
• Language: English
• Subjects: 17-alpha-Hydroxyprogesterone - blood; Adolescent; Adrenal Hyperplasia, Congenital - diagnosis; Adrenal Hyperplasia, Congenital - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocorticotropic Hormone; Adult; Age of Onset; Biological and medical sciences; Child; DNA - analysis; Endocrinopathies; Female; Genotype; Heterozygote; Humans; Medical sciences; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Phenotype; Steroid 21-Hydroxylase - genetics
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1046/j.1365-2265.1998.00402.x

OBJECTIVE To establish the type and frequency of mutations causing late onset 21‐hydroxylase deficiency and associated clinical and biochemical phenotypes and to compare these findings to those from heterozygotes and homozygotes for classical 21‐hydroxylase deficiency. DESIGN Analysis of the 21‐hydroxylase genes by DNA amplification and mutation detection. Measurement of serum 17‐hydroxyprogesterone following stimulation with adrenocorticotrophic hormone. PATIENTS Fifteen patients with late onset congenital adrenal hyperplasia, 18 obligate heterozygotes for classical congenital adrenal hyperplasia, 95 patients with classical 21‐hydroxylase deficiency. MEASUREMENTS 17‐hydroxyprogesterone following adrenal stimulation with adrenocorticotrophic hormone; frequency of 10 common mutations in the 21‐hydroxylase gene. RESULTS Of alleles from patients with late onset CAH 46% carried V281L and 10% P30L mutations compared to 2.6% and 1.1% respectively of alleles from patients with the classical disease where the most common mutations are a splice site mutation in intron 2 (34%), deletions (25%) and I172N (15%). Serum 17‐hydroxyprogesterone following Synacthen stimulation reliably differentiated the late onset patients from carriers for the classical disease, whereas there was overlap of the basal 17‐hydroxyprogesterone concen_tration between these two conditions. CONCLUSIONS Normal basal serum 17‐hydroxyprogesterone levels cannot exclude late onset CAH, although response to adrenocorticotrophic stimulation clearly distinguished this disorder from carriers of the classical disease. The frequency of mutations causing less severe enzyme deficiency was higher in the late onset patients than in a group of classical patients, although other genes or environmental pressures may determine the age of onset of disease.