title: Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.
abstract: Congenital adrenal hyperplasia (CAH), resulting from mutations inCYP11B1, 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 ofCYP11B1revealed 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 ofCYP11B1gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khattab
authors.affiliation: School of Pharmacy, University College London, London WC1N 4AX, United Kingdom.
authors.forename: Shozeb
authors.identifier: 0000-0003-2650-2925
authors.initials: S
authors.lastname: Haider
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ameet
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Samarth
authors.initials: S
authors.lastname: Dhawan
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dauood
authors.initials: D
authors.lastname: Alam
authors.affiliation: School of Pharmacy, University College London, London WC1N 4AX, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Romero
authors.affiliation: School of Pharmacy, University College London, London WC1N 4AX, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Burns
authors.affiliation: School of Pharmacy, University College London, London WC1N 4AX, United Kingdom.
authors.forename: Di
authors.initials: D
authors.lastname: Li
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jessica
authors.initials: J
authors.lastname: Estatico
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Simran
authors.initials: S
authors.lastname: Rahi
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Saleel
authors.initials: S
authors.lastname: Fatima
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Alzahrani
authors.affiliation: Diabetes, Endocrine, and Metabolism Pediatrics Unit, Department of Pediatrics, Cairo University, 11617 Cairo, Egypt.
authors.forename: Mona
authors.initials: M
authors.lastname: Hafez
authors.affiliation: Diabetes, Endocrine, and Metabolism Pediatrics Unit, Department of Pediatrics, Cairo University, 11617 Cairo, Egypt.
authors.forename: Noha
authors.initials: N
authors.lastname: Musa
authors.affiliation: Ali Asghar Children's Hospital, Iran University of Medical Sciences, 10000 Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Razzghy Azar
authors.affiliation: Laboratory of Human Cytogenetic Molecular Genetics and Biology of Reproduction, Farhat Hached University Hospital, Sousse, Tunisia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Khaloul
authors.affiliation: Laboratory of Human Cytogenetic Molecular Genetics and Biology of Reproduction, Farhat Hached University Hospital, Sousse, Tunisia.
authors.forename: Moez
authors.initials: M
authors.lastname: Gribaa
authors.affiliation: Laboratory of Human Cytogenetic Molecular Genetics and Biology of Reproduction, Farhat Hached University Hospital, Sousse, Tunisia.
authors.forename: Ali
authors.initials: A
authors.lastname: Saad
authors.affiliation: Laboratory of Human Cytogenetic Molecular Genetics and Biology of Reproduction, Farhat Hached University Hospital, Sousse, Tunisia.
authors.forename: Ilhem Ben
authors.initials: IB
authors.lastname: Charfeddine
authors.affiliation: Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory, University of São Paulo, Sao Paulo 05508, Brazil.
authors.forename: Berenice
authors.initials: B
authors.lastname: Bilharinho de Mendonça
authors.affiliation: Garrahan Pediatric Hospital, 1881 Buenos Aires, Argentina.
authors.forename: Alicia
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authors.lastname: Belgorosky
authors.affiliation: University Hospital Centre Zagreb, 10000 Zagreb, Croatia.
authors.forename: Katja
authors.initials: K
authors.lastname: Dumic
authors.affiliation: University Hospital Centre Zagreb, 10000 Zagreb, Croatia.
authors.forename: Miroslav
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authors.affiliation: Pediatric Endocrinology and Diabetes Medicine, Hackensack University Medical Center, Hackensack, NJ 07601.
authors.forename: Javier
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authors.affiliation: Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.
authors.forename: Nurgun
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authors.affiliation: Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.
authors.forename: Ayfer
authors.initials: A
authors.lastname: Alikasifoglu
authors.affiliation: Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.
authors.forename: Alev
authors.initials: A
authors.lastname: Ozon
authors.affiliation: Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.
authors.forename: Nazli
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authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Tina
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Childrens Hospital, University of Munich, 80539 Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kuhnle-Krahl
authors.affiliation: Bambino Gesù Hospital, 00146 Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cappa
authors.affiliation: Department of Pediatrics, University Hospital of Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.affiliation: Department of Pediatrics, University of Saskatchewan College of Medicine, Saskatoon, SK, Canada S7N 0W8.
authors.forename: Munier A
authors.initials: MA
authors.lastname: Nour
authors.affiliation: Department of Pediatrics, University of Calgary, Calgary, AB, Canada T3B 6A8.
authors.forename: Daniele
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authors.lastname: Pacaud
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Assaf
authors.initials: A
authors.lastname: Holtzman
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Sun
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.affiliation: Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000473:pathology; D000352:Africa, Northern; D003241:Consanguinity; D005260:Female; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D008877:Middle East; D020125:Mutation, Missense; D010375:Pedigree; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry / Q000235:genetics*
chemical_list: D012739:Gonadal Steroid Hormones; D013252:Steroid 11-beta-Hydroxylase
keywords: ambiguous genitalia; classic CAH; missense mutations; steroid hormones