Congenital Adrenal Hyperplasia in Children: A Pilot Study of Steroid Hormones Expressed as Sex- and Age-Related Standard Deviation Scores

Abstract

<b><i>Introduction:</i></b> Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease predominantly caused by 21-hydroxylase deficiency. Clinical management in children includes glucocorticoid and often mineralocorticoid treatment alongside monitoring outcomes such as an­thro­po­metry, pubertal status, blood pressure, and biochemistry. <b><i>Objective:</i></b> The objective of this pilot study was to present the use of 17-hydroxyprogesterone (17-OHP) and androgen metabolites expressed as standard deviation (SD) scores rather than actual concentrations as a tool in the management of children with CAH as well as in research settings. <b><i>Methods:</i></b> The study was a retrospective, longitudinal study that took place in a single, tertiary center and included 38 children and adolescents aged 3–18 years with CAH due to 21-hydroxylase deficiency. Biochemical measurements of 17-OHP, androstenedione, dehydroepiandrosterone-sulphate (DHEAS), and testosterone using liquid chromatography-tandem mass spectrometry were expressed as SD scores, and outcomes such as genotype, height, bone maturation, blood pressure, and treatment doses were extracted from patient files. <b><i>Results:</i></b> The majority (86%) of CAH patients had 17-OHP measurements above +2 SD during standard hydrocortisone therapy, receiving an average daily hydrocortisone dose of 12.6 mg/m<sup>2</sup>. Androstenedione concentrations were mostly within ±2 SD, whereas DHEAS values were below –2 SD in 47% of patients. <b><i>Conclusions:</i></b> Applying sex- and age-related SD scores to 17-OHP and androgen metabolite concentrations allows for monitoring of hydrocortisone treatment independent of age, sex, assay, and center. We propose that 17-OHP and androgen metabolites expressed as SD scores be implemented as a unifying tool that simplifies research and, in the future, also optimal management of treatment.

The Application of Principal Component Analysis on Clinical and Biochemical Parameters Exemplified in Children With Congenital Adrenal Hyperplasia

“…The inclusion criteria were genetically verified CAH due to 21-hydroxylase deficiency and measurements of the following four steroid metabolites at each included visit: 17-OHP; dehydroepiandrosterone-sulphate (DHEAS); androstenedione; and testosterone. As previously reported in detail ( 15 ), the following information extracted from patient files, when available, was also included: A) clinical information: anthropometry (i.e. height corrected for target height [height SD score minus target height SD score] and body-mass index [BMI]), systolic and diastolic blood pressure, and total glucocorticoid dose per body surface area without regard to timing of dosages throughout the day, and B) biochemical information: serum concentrations of sex-hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).…”

“…In this study the total CAH cohort included 33 patients aged 0.3 to 18.9 years. This cohort was described in a recent publication focusing on the use of standard deviation (SD) scores in the management of CAH ( 15 ). However, one patient with an additional diagnosis of 45,X/46,XY mosaicism was excluded, as this condition could potentially influence the PCA, while a second patient was excluded due to lack of clinical information.…”

“…height corrected for target height [height SD score minus target height SD score] and body-mass index [BMI]), systolic and diastolic blood pressure, and total glucocorticoid dose per body surface area without regard to timing of dosages throughout the day, and B) biochemical information: serum concentrations of sex-hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Except for glucocorticoid dose, all included variables were expressed as sex- and age-adjusted SD scores to enable comparison of all data entries across sexes and different ages as previously described ( 15 ).…”

“…Serum 17-OHP and the adrenal androgens (DHEAS, androstenedione, and testosterone) were measured by liquid chromatography tandem-mass spectrometry-based (LC-MS/MS) with inter-assay coefficients of variation (CVs) ranging from 1.4 to 2.5% ( 15 ). These androgens were included as they are part of routine follow-up in our clinic.…”

“…The use of the Generalized Additive Model for Location, Scale, and Shape (GAMLSS) to obtain SD scores has previously been described for height and BMI ( 17 ), blood pressure ( 15 ), 17-OHP and the adrenal androgens ( 15 ), and LH and FSH ( 18 ). Based on healthy participants aged 0.2 to 20.0 years of age ( 19 ), reference curves were established for SHBG (1068 males, 668 females).…”