Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

Nils Krone; Nicole Reisch; Jan Idkowiak; Vivek Dhir; Hannah E. Ivison; Beverly A. Hughes; Ian T. Rose; Donna M. O'Neil; Raymon Vijzelaar; Matthew J. Smith; Fiona MacDonald; Trevor R. Cole; Nicolai Adolphs; John S. Barton; Edward M. Blair; Stephen R. Braddock; Felicity Collins; Deborah L. Cragun; Mehul T. Dattani; Ruth Day; Shelley Dougan; Miriam Feist; Michael E. Gottschalk; John W. Gregory; Michaela Haim; Rachel Harrison; Ann Haskins Olney; Berthold P. Hauffa; Peter C. Hindmarsh; Robert J. Hopkin; Petr E. Jira; Marlies Kempers; Michiel N. Kerstens; Mohamed M. Khalifa; Birgit Koehler; Dominique Maiter; Shelly Nielsen; Stephen M. O'Riordan; Christian L. Roth; Kate P. Shane; Martin Silink; Nike M. M. L. Stikkelbroeck; Elizabeth Sweeney; Maria Szarras-Czapnik; John R. Waterson; Lori Williamson; Michaela F. Hartmann; Norman F. Taylor; Stefan A. Wudy; Ewa M. Malunowicz; Cedric H. L. Shackleton; Wiebke Arlt; M.J. Smith

doi:10.1210/jc.2011-0640

Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

Nils Krone, Nicole Reisch, Jan Idkowiak, Vivek Dhir, Hannah E. Ivison, Beverly A. Hughes, Ian T. Rose, Donna M. O'Neil, Raymon Vijzelaar, Matthew J. Smith, Fiona MacDonald, Trevor R. Cole, Nicolai Adolphs, John S. Barton, Edward M. Blair, Stephen R. Braddock, Felicity Collins, Deborah L. Cragun, Mehul T. Dattani, Ruth DayShelley Dougan, Miriam Feist, Michael E. Gottschalk, John W. Gregory, Michaela Haim, Rachel Harrison, Ann Haskins Olney, Berthold P. Hauffa, Peter C. Hindmarsh, Robert J. Hopkin, Petr E. Jira, Marlies Kempers, Michiel N. Kerstens, Mohamed M. Khalifa, Birgit Koehler, Dominique Maiter, Shelly Nielsen, Stephen M. O'Riordan, Christian L. Roth, Kate P. Shane, Martin Silink, Nike M. M. L. Stikkelbroeck, Elizabeth Sweeney, Maria Szarras-Czapnik, John R. Waterson, Lori Williamson, Michaela F. Hartmann, Norman F. Taylor, Stefan A. Wudy, Ewa M. Malunowicz, Cedric H. L. Shackleton, Wiebke Arlt^*, M.J. Smith

^*Corresponding author for this work

Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.

Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.

Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.

Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17 alpha-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 1846, XX and seven of 1246,XY individuals. Homozygosity for p.A287P was invariably associated with 46, XX DSD but normal genitalia in 46, XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.

Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing. (J Clin Endocrinol Metab 97: E257-E267, 2012)

Original language	English
Pages (from-to)	E257-E267
Number of pages	11
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	97
Issue number	2
DOIs	https://doi.org/10.1210/jc.2011-0640
Publication status	Published - Feb-2012

Keywords

ANTLEY-BIXLER-SYNDROME
RETINOIC ACID HOMEOSTASIS
CYTOCHROME-P450 OXIDOREDUCTASE
DISORDERED STEROIDOGENESIS
STEROID-METABOLISM
ABNORMAL STEROL
MUTATIONS
GENE
VASCULOGENESIS
IDENTIFICATION

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10.1210/jc.2011-0640

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Krone, N., Reisch, N., Idkowiak, J., Dhir, V., Ivison, H. E., Hughes, B. A., Rose, I. T., O'Neil, D. M., Vijzelaar, R., Smith, M. J., MacDonald, F., Cole, T. R., Adolphs, N., Barton, J. S., Blair, E. M., Braddock, S. R., Collins, F., Cragun, D. L., Dattani, M. T., ... Smith, M. J. (2012). Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency. Journal of Clinical Endocrinology and Metabolism, 97(2), E257-E267. https://doi.org/10.1210/jc.2011-0640

Krone, Nils ; Reisch, Nicole ; Idkowiak, Jan ; Dhir, Vivek ; Ivison, Hannah E. ; Hughes, Beverly A. ; Rose, Ian T. ; O'Neil, Donna M. ; Vijzelaar, Raymon ; Smith, Matthew J. ; MacDonald, Fiona ; Cole, Trevor R. ; Adolphs, Nicolai ; Barton, John S. ; Blair, Edward M. ; Braddock, Stephen R. ; Collins, Felicity ; Cragun, Deborah L. ; Dattani, Mehul T. ; Day, Ruth ; Dougan, Shelley ; Feist, Miriam ; Gottschalk, Michael E. ; Gregory, John W. ; Haim, Michaela ; Harrison, Rachel ; Olney, Ann Haskins ; Hauffa, Berthold P. ; Hindmarsh, Peter C. ; Hopkin, Robert J. ; Jira, Petr E. ; Kempers, Marlies ; Kerstens, Michiel N. ; Khalifa, Mohamed M. ; Koehler, Birgit ; Maiter, Dominique ; Nielsen, Shelly ; O'Riordan, Stephen M. ; Roth, Christian L. ; Shane, Kate P. ; Silink, Martin ; Stikkelbroeck, Nike M. M. L. ; Sweeney, Elizabeth ; Szarras-Czapnik, Maria ; Waterson, John R. ; Williamson, Lori ; Hartmann, Michaela F. ; Taylor, Norman F. ; Wudy, Stefan A. ; Malunowicz, Ewa M. ; Shackleton, Cedric H. L. ; Arlt, Wiebke ; Smith, M.J. / Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 2. pp. E257-E267.

@article{45890e26609543e38febcf88d01a1f8d,

title = "Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency",

abstract = "Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17 alpha-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 1846, XX and seven of 1246,XY individuals. Homozygosity for p.A287P was invariably associated with 46, XX DSD but normal genitalia in 46, XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing. (J Clin Endocrinol Metab 97: E257-E267, 2012)",

keywords = "ANTLEY-BIXLER-SYNDROME, RETINOIC ACID HOMEOSTASIS, CYTOCHROME-P450 OXIDOREDUCTASE, DISORDERED STEROIDOGENESIS, STEROID-METABOLISM, ABNORMAL STEROL, MUTATIONS, GENE, VASCULOGENESIS, IDENTIFICATION",

author = "Nils Krone and Nicole Reisch and Jan Idkowiak and Vivek Dhir and Ivison, {Hannah E.} and Hughes, {Beverly A.} and Rose, {Ian T.} and O'Neil, {Donna M.} and Raymon Vijzelaar and Smith, {Matthew J.} and Fiona MacDonald and Cole, {Trevor R.} and Nicolai Adolphs and Barton, {John S.} and Blair, {Edward M.} and Braddock, {Stephen R.} and Felicity Collins and Cragun, {Deborah L.} and Dattani, {Mehul T.} and Ruth Day and Shelley Dougan and Miriam Feist and Gottschalk, {Michael E.} and Gregory, {John W.} and Michaela Haim and Rachel Harrison and Olney, {Ann Haskins} and Hauffa, {Berthold P.} and Hindmarsh, {Peter C.} and Hopkin, {Robert J.} and Jira, {Petr E.} and Marlies Kempers and Kerstens, {Michiel N.} and Khalifa, {Mohamed M.} and Birgit Koehler and Dominique Maiter and Shelly Nielsen and O'Riordan, {Stephen M.} and Roth, {Christian L.} and Shane, {Kate P.} and Martin Silink and Stikkelbroeck, {Nike M. M. L.} and Elizabeth Sweeney and Maria Szarras-Czapnik and Waterson, {John R.} and Lori Williamson and Hartmann, {Michaela F.} and Taylor, {Norman F.} and Wudy, {Stefan A.} and Malunowicz, {Ewa M.} and Shackleton, {Cedric H. L.} and Wiebke Arlt and M.J. Smith",

year = "2012",

month = feb,

doi = "10.1210/jc.2011-0640",

language = "English",

volume = "97",

pages = "E257--E267",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "ENDOCRINE SOC",

number = "2",

}

Krone, N, Reisch, N, Idkowiak, J, Dhir, V, Ivison, HE, Hughes, BA, Rose, IT, O'Neil, DM, Vijzelaar, R, Smith, MJ, MacDonald, F, Cole, TR, Adolphs, N, Barton, JS, Blair, EM, Braddock, SR, Collins, F, Cragun, DL, Dattani, MT, Day, R, Dougan, S, Feist, M, Gottschalk, ME, Gregory, JW, Haim, M, Harrison, R, Olney, AH, Hauffa, BP, Hindmarsh, PC, Hopkin, RJ, Jira, PE, Kempers, M, Kerstens, MN, Khalifa, MM, Koehler, B, Maiter, D, Nielsen, S, O'Riordan, SM, Roth, CL, Shane, KP, Silink, M, Stikkelbroeck, NMML, Sweeney, E, Szarras-Czapnik, M, Waterson, JR, Williamson, L, Hartmann, MF, Taylor, NF, Wudy, SA, Malunowicz, EM, Shackleton, CHL, Arlt, W & Smith, MJ 2012, 'Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 2, pp. E257-E267. https://doi.org/10.1210/jc.2011-0640

Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency. / Krone, Nils; Reisch, Nicole; Idkowiak, Jan; Dhir, Vivek; Ivison, Hannah E.; Hughes, Beverly A.; Rose, Ian T.; O'Neil, Donna M.; Vijzelaar, Raymon; Smith, Matthew J.; MacDonald, Fiona; Cole, Trevor R.; Adolphs, Nicolai; Barton, John S.; Blair, Edward M.; Braddock, Stephen R.; Collins, Felicity; Cragun, Deborah L.; Dattani, Mehul T.; Day, Ruth; Dougan, Shelley; Feist, Miriam; Gottschalk, Michael E.; Gregory, John W.; Haim, Michaela; Harrison, Rachel; Olney, Ann Haskins; Hauffa, Berthold P.; Hindmarsh, Peter C.; Hopkin, Robert J.; Jira, Petr E.; Kempers, Marlies; Kerstens, Michiel N.; Khalifa, Mohamed M.; Koehler, Birgit; Maiter, Dominique; Nielsen, Shelly; O'Riordan, Stephen M.; Roth, Christian L.; Shane, Kate P.; Silink, Martin; Stikkelbroeck, Nike M. M. L.; Sweeney, Elizabeth; Szarras-Czapnik, Maria; Waterson, John R.; Williamson, Lori; Hartmann, Michaela F.; Taylor, Norman F.; Wudy, Stefan A.; Malunowicz, Ewa M.; Shackleton, Cedric H. L.; Arlt, Wiebke; Smith, M.J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 2, 02.2012, p. E257-E267.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

AU - Krone, Nils

AU - Reisch, Nicole

AU - Idkowiak, Jan

AU - Dhir, Vivek

AU - Ivison, Hannah E.

AU - Hughes, Beverly A.

AU - Rose, Ian T.

AU - O'Neil, Donna M.

AU - Vijzelaar, Raymon

AU - Smith, Matthew J.

AU - MacDonald, Fiona

AU - Cole, Trevor R.

AU - Adolphs, Nicolai

AU - Barton, John S.

AU - Blair, Edward M.

AU - Braddock, Stephen R.

AU - Collins, Felicity

AU - Cragun, Deborah L.

AU - Dattani, Mehul T.

AU - Day, Ruth

AU - Dougan, Shelley

AU - Feist, Miriam

AU - Gottschalk, Michael E.

AU - Gregory, John W.

AU - Haim, Michaela

AU - Harrison, Rachel

AU - Olney, Ann Haskins

AU - Hauffa, Berthold P.

AU - Hindmarsh, Peter C.

AU - Hopkin, Robert J.

AU - Jira, Petr E.

AU - Kempers, Marlies

AU - Kerstens, Michiel N.

AU - Khalifa, Mohamed M.

AU - Koehler, Birgit

AU - Maiter, Dominique

AU - Nielsen, Shelly

AU - O'Riordan, Stephen M.

AU - Roth, Christian L.

AU - Shane, Kate P.

AU - Silink, Martin

AU - Stikkelbroeck, Nike M. M. L.

AU - Sweeney, Elizabeth

AU - Szarras-Czapnik, Maria

AU - Waterson, John R.

AU - Williamson, Lori

AU - Hartmann, Michaela F.

AU - Taylor, Norman F.

AU - Wudy, Stefan A.

AU - Malunowicz, Ewa M.

AU - Shackleton, Cedric H. L.

AU - Arlt, Wiebke

AU - Smith, M.J.

PY - 2012/2

Y1 - 2012/2

N2 - Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17 alpha-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 1846, XX and seven of 1246,XY individuals. Homozygosity for p.A287P was invariably associated with 46, XX DSD but normal genitalia in 46, XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing. (J Clin Endocrinol Metab 97: E257-E267, 2012)

AB - Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17 alpha-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 1846, XX and seven of 1246,XY individuals. Homozygosity for p.A287P was invariably associated with 46, XX DSD but normal genitalia in 46, XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing. (J Clin Endocrinol Metab 97: E257-E267, 2012)

KW - ANTLEY-BIXLER-SYNDROME

KW - RETINOIC ACID HOMEOSTASIS

KW - CYTOCHROME-P450 OXIDOREDUCTASE

KW - DISORDERED STEROIDOGENESIS

KW - STEROID-METABOLISM

KW - ABNORMAL STEROL

KW - MUTATIONS

KW - GENE

KW - VASCULOGENESIS

KW - IDENTIFICATION

U2 - 10.1210/jc.2011-0640

DO - 10.1210/jc.2011-0640

M3 - Article

VL - 97

SP - E257-E267

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 2

ER -