Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Authors
Khattab, Ahmed; Haider, Shozeb; Kumar, Ameet; Dhawan, Samarth; Alam, Dauood; Romero, Raquel; Burns, James; Li, Di; Estatico, Jessica; Rahi, Simran; Fatima, Saleel; Alzahrani, Ali; Hafez, Mona; Musa, Noha; Azar, Maryam Razzghy; Khaloul, Najoua; Gribaa, Moez; Saad, Ali; Charfeddine, Ilhem Ben; De Mendonça, Berenice Bilharinho; Belgorosky, Alicia; Dumic, Katja; Dumic, Miroslav; Aisenberg, Javier; Kandemir, Nurgun; Alikasifoglu, Ayfer; Ozon, Alev; Gonc, Nazli; Cheng, Tina; Kuhnle Krahl, Ursula; Cappa, Marco; Holterhus, Paul-Martin; Nour, Munier A.; Pacaud, Daniele; Holtzman, Assaf; Li, Sun; Zaidi, Mone; Yuen, Tony; New, Maria I.
Publication Year
2017
Language
English
Format
article
Status
Published version
Description
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
Fil: Khattab, Ahmed. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Haider, Shozeb. University College London; Estados Unidos
Fil: Kumar, Ameet. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Dhawan, Samarth. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Alam, Dauood. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Romero, Raquel. University College London; Estados Unidos
Fil: Burns, James. University College London; Estados Unidos
Fil: Li, Di. University College London; Estados Unidos
Fil: Estatico, Jessica. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Rahi, Simran. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Fatima, Saleel. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Alzahrani, Ali. King Faisal Specialist Hospital And Research Centre; Arabia Saudita
Fil: Hafez, Mona. Cairo University; Egipto
Fil: Musa, Noha. Cairo University; Egipto
Fil: Azar, Maryam Razzghy. Iran University Of Medical Sciences; Irán
Fil: Khaloul, Najoua. Hopital Farhat Hached Sousse; Túnez
Fil: Gribaa, Moez. Hopital Farhat Hached Sousse; Túnez
Fil: Saad, Ali. Hopital Farhat Hached Sousse; Túnez
Fil: Charfeddine, Ilhem Ben. Hopital Farhat Hached Sousse; Túnez
Fil: De Mendonça, Berenice Bilharinho. Universidade de Sao Paulo; Brasil
Fil: Belgorosky, Alicia. Hospital de Pediatria Samic Prof. Dr. Juan P. Garrahan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Dumic, Katja. University Of Zagreb. School Of Medicine; Croacia
Fil: Dumic, Miroslav. University Of Zagreb. School Of Medicine; Croacia
Fil: Aisenberg, Javier. Hackensack University Medical Center; Estados Unidos
Fil: Kandemir, Nurgun. Hacettepe Universitesi; Turquía
Fil: Alikasifoglu, Ayfer. Hacettepe Universitesi; Turquía
Fil: Ozon, Alev. Hacettepe Universitesi; Turquía
Fil: Gonc, Nazli. Hacettepe Universitesi; Turquía
Fil: Cheng, Tina. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Kuhnle Krahl, Ursula. University of Munich; Alemania
Fil: Cappa, Marco. Ospedale Pediatrico Bambino Gesu; Italia
Fil: Holterhus, Paul-Martin. Universitatsklinikum Schleswig-Holstein; Alemania
Fil: Nour, Munier A.. University of Saskatchewan; Canadá
Fil: Pacaud, Daniele. University of Calgary; Canadá
Fil: Holtzman, Assaf. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Li, Sun. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Zaidi, Mone. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: Yuen, Tony. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Fil: New, Maria I.. Icahn School Of Medicine At Mount Sinai; Estados Unidos
Subject
AMBIGUOUS GENITALIA
CLASSIC CAH
MISSENSE MUTATIONS
STEROID HORMONES
Medicina Critica y de Emergencia
Medicina Clínica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/53249