Characterization of the molecular genetic pathology in patients with 11-hydroxylase deficiency

ObjectiveSteroid 11-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. Patients and methodsFive patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an invitro expression system. ResultsCYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. ConclusionMutations causing partial impairment of 11-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.

Yazar Mooij, Christiaan F.
Parajes, Silvia
Rose, Ian T.
Taylor, Angela E.
Bayraktaroglu, Taner
Wass, John A. H.
Connell, John M. C.
Yayın Türü Article
Tek Biçim Adres https://hdl.handle.net/20.500.12628/2214
Tek Biçim Adres 10.1111/cen.12834
Koleksiyonlar Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed | SOBİAD
PubMed İndeksli Yayınlar Koleksiyonu
WoS İndeksli Yayınlar Koleksiyonu
Dergi Adı CLINICAL ENDOCRINOLOGY
Dergi Cilt Bilgisi 83
Dergi Sayısı 5
Sayfalar 629 - 635
Yayın Yılı 2015
Eser Adı
[dc.title]
Characterization of the molecular genetic pathology in patients with 11-hydroxylase deficiency
Yazar
[dc.contributor.author]
Mooij, Christiaan F.
Yazar
[dc.contributor.author]
Parajes, Silvia
Yazar
[dc.contributor.author]
Rose, Ian T.
Yazar
[dc.contributor.author]
Taylor, Angela E.
Yazar
[dc.contributor.author]
Bayraktaroglu, Taner
Yazar
[dc.contributor.author]
Wass, John A. H.
Yazar
[dc.contributor.author]
Connell, John M. C.
Yayın Yılı
[dc.date.issued]
2015
Yayıncı
[dc.publisher]
WILEY-BLACKWELL
Yayın Türü
[dc.type]
article
Özet
[dc.description.abstract]
ObjectiveSteroid 11-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. Patients and methodsFive patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an invitro expression system. ResultsCYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. ConclusionMutations causing partial impairment of 11-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.
Açıklama
[dc.description]
WOS: 000363267400006
Açıklama
[dc.description]
PubMed: 26053152
Kayıt Giriş Tarihi
[dc.date.accessioned]
2019-12-23
Açık Erişim Tarihi
[dc.date.available]
2019-12-23
Yayın Dili
[dc.language.iso]
eng
Haklar
[dc.rights]
info:eu-repo/semantics/closedAccess
ISSN
[dc.identifier.issn]
0300-0664
ISSN
[dc.identifier.issn]
1365-2265
Sponsor YAYINCI
[dc.description.sponsorship]
ZonMW AGIKO Grant; European CommissionEuropean Commission Joint Research Centre [IEF-GA-2009-255424]; Medical Research CouncilMedical Research Council UK (MRC) [G0900567]
Sponsor YAYINCI
[dc.description.sponsorship]
This work was supported by the ZonMW AGIKO Grant (to C.F.M.), the European Commission (Marie Curie Intra-European Fellowship IEF-GA-2009-255424 to S.P.).
İlk Sayfa Sayısı
[dc.identifier.startpage]
629
Son Sayfa Sayısı
[dc.identifier.endpage]
635
Dergi Adı
[dc.relation.journal]
CLINICAL ENDOCRINOLOGY
Dergi Sayısı
[dc.identifier.issue]
5
Dergi Cilt Bilgisi
[dc.identifier.volume]
83
Tek Biçim Adres
[dc.identifier.uri]
https://dx.doi.org/10.1111/cen.12834
Tek Biçim Adres
[dc.identifier.uri]
https://hdl.handle.net/20.500.12628/2214
Görüntülenme Sayısı ( Şehir )
Görüntülenme Sayısı ( Ülke )
Görüntülenme Sayısı ( Zaman Dağılımı )
Görüntülenme
7
09.12.2022 tarihinden bu yana
İndirme
1
09.12.2022 tarihinden bu yana
Son Erişim Tarihi
15 Şubat 2024 17:42
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Tıklayınız
CYP11B1 mutations mutation nonclassic activity patients presented clinical presentation previously precocious pseudopuberty characterized pressure caused 11-hydroxylase androgen excess residual detected uncharacterized between treatment essential demonstrate activities personalized A297V) co-morbidities hypertension missense prevent ConclusionMutations complete present
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