Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Neil Lawrence^{1

2}, Irina Bacila¹, Jeremy Dawson^{3

4}, Jillian Bryce^{5

5}, Salma R Ali^{5

5

6}, Erica L T van den Akker⁷, Tânia A S S Bachega⁸, Federico Baronio⁹, Niels H Birkebaek¹⁰, Walter Bonfig^{11

12}, Hedi C van der Grinten^{13

14}, Eduardo C Costa¹⁵, Liat de Vries¹⁶, Heba Elsedfy¹⁷, Ayla Güven¹⁸, Sabine Hannema^{19

20}, Violeta Iotova²¹, Hetty J van der Kamp²², María Clemente²³, Corina R Lichiardopol²⁴, Tatjana Milenkovic²⁵, Uta Neumann²⁶, Ana Nordenström^{27

28}, Şukran Poyrazoğlu²⁹, Ursina Probst-Scheidegger³⁰, Luisa De Sanctis^{31

32}, Rieko Tadokoro-Cuccaro³³, Ajay Thankamony³³, Ana Vieites³⁴, Zehra Yavaş³⁵, Syed Faisal Ahmed^{5

5

6}, Nils Krone^{1

2

36}

Affiliations

¹ Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
² Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
³ Institute of Work Psychology, Management School, University of Sheffield, Sheffield, UK.
⁴ School of Health and Related Research, University of Sheffield, Sheffield, UK.
⁵ Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK.
⁶ Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK.
⁷ Department of Pediatric Endocrinology, Sophia Children's Hospital, Erasmus Medical Centre, Rotterdam, the Netherlands.
⁸ Hormones and Molecular Genetics Laboratory LIM 42, Department of Internal Medicine, University of Sao Paulo, Sao Paulo, Brazil.
⁹ Department of Medical and Surgical Sciences, Pediatric Unit, Endo-ERN Center for Rare Endocrine Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.
¹⁰ Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
¹¹ Department of Pediatrics, Technical University Munich, Munich, Germany.
¹² Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria.
¹³ Department of Pediatric Endocrinology, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁴ Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁵ Pediatric Surgery Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁶ Institute for Diabetes and Endocrinology, Schneider's Children Medical Center of Israel, Petah-Tikvah, Israel.
¹⁷ Pediatrics Department, Ain Shams University, Cairo, Egypt.
¹⁸ Baskent University Istanbul Hospital, Pediatric Endocrinology, Istanbul, Turkey.
¹⁹ Department of Paediatric Endocrinology, Erasmus MC, Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Paediatrics, Leiden University Medical Centre, Leiden, the Netherlands.
²¹ Department of Paediatrics, Medical University of Varna, Varna, Bulgaria.
²² Pediatric Endocrinology Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands.
²³ Paediatric Endocrinology, Hospital Universitario Vall d'Hebron, CIBER de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain.
²⁴ Department of Endocrinology, University of Medicine and Pharmacy Craiova, Craiova, Romania.
²⁵ Department of Endocrinology, Institute for Mother and Child Healthcare of Serbia "Dr Vukan Čupić", Belgrade, Serbia.
²⁶ Institute for Experimental Pediatric Endocrinology and Center for Chronically Sick Children, Charite-Universitätsmedizin, Berlin, Germany.
²⁷ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
²⁹ Istanbul Faculty of Medicine, Paediatric Endocrinology Unit, Istanbul University, Istanbul, Turkey.
³⁰ Pediatric Department, Kantonsspital Winterthur, Winterthur, Switzerland.
³¹ Paediatric Endocrinology, Regina Margherita Children's Hospital, Torino, Italy.
³² Department of Public Sciences and Pediatrics, University of Torino, Torino, Italy.
³³ Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom Biomedical Campus, Cambridge, UK.
³⁴ Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
³⁵ Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey.
³⁶ Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

PMID: 35781728
PMCID: PMC9796837
DOI: 10.1111/cen.14796

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Neil Lawrence et al. Clin Endocrinol (Oxf). 2022 Nov.

. 2022 Nov;97(5):551-561.

doi: 10.1111/cen.14796. Epub 2022 Jul 11.

Authors

Affiliations

¹ Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
² Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
³ Institute of Work Psychology, Management School, University of Sheffield, Sheffield, UK.
⁴ School of Health and Related Research, University of Sheffield, Sheffield, UK.
⁵ Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK.
⁶ Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK.
⁷ Department of Pediatric Endocrinology, Sophia Children's Hospital, Erasmus Medical Centre, Rotterdam, the Netherlands.
⁸ Hormones and Molecular Genetics Laboratory LIM 42, Department of Internal Medicine, University of Sao Paulo, Sao Paulo, Brazil.
⁹ Department of Medical and Surgical Sciences, Pediatric Unit, Endo-ERN Center for Rare Endocrine Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.
¹⁰ Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
¹¹ Department of Pediatrics, Technical University Munich, Munich, Germany.
¹² Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria.
¹³ Department of Pediatric Endocrinology, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁴ Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁵ Pediatric Surgery Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁶ Institute for Diabetes and Endocrinology, Schneider's Children Medical Center of Israel, Petah-Tikvah, Israel.
¹⁷ Pediatrics Department, Ain Shams University, Cairo, Egypt.
¹⁸ Baskent University Istanbul Hospital, Pediatric Endocrinology, Istanbul, Turkey.
¹⁹ Department of Paediatric Endocrinology, Erasmus MC, Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Paediatrics, Leiden University Medical Centre, Leiden, the Netherlands.
²¹ Department of Paediatrics, Medical University of Varna, Varna, Bulgaria.
²² Pediatric Endocrinology Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands.
²³ Paediatric Endocrinology, Hospital Universitario Vall d'Hebron, CIBER de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain.
²⁴ Department of Endocrinology, University of Medicine and Pharmacy Craiova, Craiova, Romania.
²⁵ Department of Endocrinology, Institute for Mother and Child Healthcare of Serbia "Dr Vukan Čupić", Belgrade, Serbia.
²⁶ Institute for Experimental Pediatric Endocrinology and Center for Chronically Sick Children, Charite-Universitätsmedizin, Berlin, Germany.
²⁷ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
²⁹ Istanbul Faculty of Medicine, Paediatric Endocrinology Unit, Istanbul University, Istanbul, Turkey.
³⁰ Pediatric Department, Kantonsspital Winterthur, Winterthur, Switzerland.
³¹ Paediatric Endocrinology, Regina Margherita Children's Hospital, Torino, Italy.
³² Department of Public Sciences and Pediatrics, University of Torino, Torino, Italy.
³³ Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom Biomedical Campus, Cambridge, UK.
³⁴ Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
³⁵ Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey.
³⁶ Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

PMID: 35781728
PMCID: PMC9796837
DOI: 10.1111/cen.14796

Abstract

Objective: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4).

Design: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries.

Patients: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry.

Measurements: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM).

Results: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m² /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R² = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R² = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m² /day for every 1 point increase in weight standard deviation score.

Discussion: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Keywords: biomarkers; congenital adrenal hyperplasia; hydrocortisone; linear mixed-effects models.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
Comparison of each patient's most recent serum biomarkers between different centres. Absolute values plotted on logarithmic scale. Only centres with 10 or more patients with each biomarker are displayed. Horizontal lines correspond to median. Kruskal–Wallis comparison shows significant difference between centres (p < 0.05). (A) 17‐OH Progesterone, (B) androstenedione measured in patients under 12 years. Only 2 centres had 10 or more patients over 12 with D4 levels available for comparison, and Kruskal–Wallis comparison revealed no difference (p = 0.76).

**Figure 2**
Linear mixed effect models with random intercepts. Random effects stratify data into patient treated at level 1, and treatment centre at level 2. Dark line shows overall model fit. Central dark shading shows 95% confidence interval attributable to treatment centre, outer lighter shading shows remaining proportion attributable to individual patients. Dotted lines show individual model fit to each patient. (A) 17OHP on age. (B) Androstenedione on age. (C) Weight Standard Deviation Score (SDS) on age. (D) Body Mass Index (BMI) on age. (E) Total Daily Hydrocortisone (HC) on age. (F) Covariation of Weight SDS and Total Daily HC modelled with age. (G) Covariation of BMI SDS and Total Daily HC modelled with age.

See this image and copyright information in PMC

References

1. Sarafoglou K, Addo OY, Turcotte L, et al. Impact of hydrocortisone on adult height in congenital adrenal hyperplasia‐the Minnesota cohort. J Pediatr. 2014;164(5):1141‐1146.e1141. - PubMed
1. Claahsen‐van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics and management. Endocr Rev. 2022;43(1):91‐159. - PMC - PubMed
1. Bacila I, Freeman N, Daniel E, et al. International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I‐CAH registry. Eur J Endocrinol. 2021;184(4):553‐563. - PubMed
1. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW. Consensus statement on 21‐hydroxylase deficiency from the Lawson Wilkins pediatric endocrine society and the European society for paediatric endocrinology. J Clin Endocrinol Metab. 2002;87(9):4048‐4053. - PubMed
1. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21‐hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133‐4160. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Affiliations

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical