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

Ahmed Khattab, Shozeb Haider, Ameet Kumar, Samarth Dhawan, Dauood Alam, Raquel Romero, James Burns, Di Li, Jessica Estatico, Simran Rahi, Saleel Fatima, Ali Alzahrani, Mona Hafez, Noha Musa, Maryam Razzghy Azar, Najoua Khaloul, Moez Gribaa, Ali Saad, Ilhem Ben Charfeddine, Berenice Bilharinho De MendonçaAlicia Belgorosky, Katja Dumic, Miroslav Dumic, Javier Aisenberg, Nurgun Kandemir, Ayfer Alikasifoglu, Alev Ozon, Nazli Gonc, Tina Cheng, Ursula Kuhnle-Krahl, Marco Cappa, Paul Martin Holterhus, Munier A. Nour, Daniele Pacaud, Assaf Holtzman, Sun Li, Mone Zaidi, Tony Yuen, Maria I. New

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E1933-E1940
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number10
DOIs
Publication statusPublished - Mar 7 2017

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Steroid 11-beta-Hydroxylase
Congenital Adrenal Hyperplasia
Mixed Function Oxygenases
Mutation
Physiological Sexual Dysfunctions
Cortodoxone
Deficiency Diseases
Consanguinity
Northern Africa
Eastern Africa
Middle East
Missense Mutation
Heme
Genes
Biomarkers
Steroids
Binding Sites
Newborn Infant
Bone and Bones

Keywords

  • Ambiguous genitalia
  • Classic CAH
  • Missense mutations
  • Steroid hormones

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 10, 07.03.2017, p. E1933-E1940.

Research output: Contribution to journalArticle

Khattab, A, Haider, S, Kumar, A, Dhawan, S, Alam, D, Romero, R, Burns, J, Li, D, Estatico, J, Rahi, S, Fatima, S, Alzahrani, A, Hafez, M, Musa, N, Azar, MR, Khaloul, N, Gribaa, M, Saad, A, Charfeddine, IB, De Mendonça, BB, Belgorosky, A, Dumic, K, Dumic, M, Aisenberg, J, Kandemir, N, Alikasifoglu, A, Ozon, A, Gonc, N, Cheng, T, Kuhnle-Krahl, U, Cappa, M, Holterhus, PM, Nour, MA, Pacaud, D, Holtzman, A, Li, S, Zaidi, M, Yuen, T & New, MI 2017, 'Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 10, pp. E1933-E1940. https://doi.org/10.1073/pnas.1621082114
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. / Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 10. pp. E1933-E1940.
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AU - Khattab, Ahmed

AU - Haider, Shozeb

AU - Kumar, Ameet

AU - Dhawan, Samarth

AU - Alam, Dauood

AU - Romero, Raquel

AU - Burns, James

AU - Li, Di

AU - Estatico, Jessica

AU - Rahi, Simran

AU - Fatima, Saleel

AU - Alzahrani, Ali

AU - Hafez, Mona

AU - Musa, Noha

AU - Azar, Maryam Razzghy

AU - Khaloul, Najoua

AU - Gribaa, Moez

AU - Saad, Ali

AU - Charfeddine, Ilhem Ben

AU - De Mendonça, Berenice Bilharinho

AU - Belgorosky, Alicia

AU - Dumic, Katja

AU - Dumic, Miroslav

AU - Aisenberg, Javier

AU - Kandemir, Nurgun

AU - Alikasifoglu, Ayfer

AU - Ozon, Alev

AU - Gonc, Nazli

AU - Cheng, Tina

AU - Kuhnle-Krahl, Ursula

AU - Cappa, Marco

AU - Holterhus, Paul Martin

AU - Nour, Munier A.

AU - Pacaud, Daniele

AU - Holtzman, Assaf

AU - Li, Sun

AU - Zaidi, Mone

AU - Yuen, Tony

AU - New, Maria I.

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