Background 11ß-hydroxylase deficiency (11-OHD) is the second most common cause of congenital adrenal hyperplasia and it is caused by CYP11B1 gene mutations. It is characterized by genital ambiguity in affected girls and precocious pseudopuberty in both sexes. Hypertension can occur in about two thirds of patients. The non-classic form of 11OHD is manifested by signs of androgen excess during childhood. Objective and hypothesis To characterize the CYP11B1 gene alterations of these patients. Population and/or methods Herein we report 7 patients with classical and 4 with non-classical 11-OHD, selected for high hormonal levels of 11-deoxycortisol measured by ID-LC-MS/MS or for negative analysis of the CYP21A2 gene. The entire CYP11B1 gene was sequenced and four mutations were functionally characterized (paper submitted). Results 8 novel putative mutations were identified: 5 missense mutations (p.R143W, p.E310K, p.V316M, p.R332Q, p.Q337P), 2 splicing mutations (g.-1 IVS6 G>C, g.+148 IVS5 C>G) and one non sense mutation (p.R384X). Furthermore 5 already reported mutations were identified (p.L299P, p.A306V, p.T318R, p.Q356X, exon 7 g.ins4566-4567 GA). By in vitro studies, the p.E310K and the p.A306V resulted to be severe mutations causing classical 11-OHD; instead the p.R143W and the p.R332Q, with a higher residual activity, resulted milder mutations. In a pair of brothers with non classical 11-OHD due to the same CYP11B1 mutations, the boy showed an earlier manifestation of the symptoms, that may be due to an additional intron 2 splice site mutation in the CYP21A2 gene. Precise conclusions The detection of patients with non classic phenotypes underscore the importance to screen patients with a phenotype comparable to non classic 21OHD for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling.
Menabò S., Baldazzi L., Riepe F., Cherchi G., Russo G., Franzoni A., et al. (2013). Molecular and phenotypical characterization of 10 families with 11ß-hydroxylase deficiency. HORMONE RESEARCH IN PAEDIATRICS, 80(suppl 1), 195-195.
Molecular and phenotypical characterization of 10 families with 11ß-hydroxylase deficiency
MENABO', SOARA;GAMBINERI, ALESSANDRA;FANELLI, FLAMINIA;RINALDINI, DIEGO;BALSAMO, ANTONIO
2013
Abstract
Background 11ß-hydroxylase deficiency (11-OHD) is the second most common cause of congenital adrenal hyperplasia and it is caused by CYP11B1 gene mutations. It is characterized by genital ambiguity in affected girls and precocious pseudopuberty in both sexes. Hypertension can occur in about two thirds of patients. The non-classic form of 11OHD is manifested by signs of androgen excess during childhood. Objective and hypothesis To characterize the CYP11B1 gene alterations of these patients. Population and/or methods Herein we report 7 patients with classical and 4 with non-classical 11-OHD, selected for high hormonal levels of 11-deoxycortisol measured by ID-LC-MS/MS or for negative analysis of the CYP21A2 gene. The entire CYP11B1 gene was sequenced and four mutations were functionally characterized (paper submitted). Results 8 novel putative mutations were identified: 5 missense mutations (p.R143W, p.E310K, p.V316M, p.R332Q, p.Q337P), 2 splicing mutations (g.-1 IVS6 G>C, g.+148 IVS5 C>G) and one non sense mutation (p.R384X). Furthermore 5 already reported mutations were identified (p.L299P, p.A306V, p.T318R, p.Q356X, exon 7 g.ins4566-4567 GA). By in vitro studies, the p.E310K and the p.A306V resulted to be severe mutations causing classical 11-OHD; instead the p.R143W and the p.R332Q, with a higher residual activity, resulted milder mutations. In a pair of brothers with non classical 11-OHD due to the same CYP11B1 mutations, the boy showed an earlier manifestation of the symptoms, that may be due to an additional intron 2 splice site mutation in the CYP21A2 gene. Precise conclusions The detection of patients with non classic phenotypes underscore the importance to screen patients with a phenotype comparable to non classic 21OHD for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
