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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4888-4895
Copyright © 2006 by The Endocrine Society

Altered 24-Hour Blood Pressure Profiles in Children and Adolescents with Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Thomas M. K. Völkl, Diemud Simm, Jörg Dötsch, Wolfgang Rascher and Helmuth G. Dörr

Divisions of Pediatric Endocrinology (T.M.K.V., D.S., H.G.D.) and Nephrology (J.D., W.R.), Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054 Erlangen, Germany

Address all correspondence and requests for reprints to: Professor Helmuth G. Dörr, M.D., Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Loschgestrasse 15, 91054 Erlangen, Germany. E-mail: hgdoerr{at}kinder.imed.uni-erlangen.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters.

Design: Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work.

Results (Median, Range): The median body mass index of the cohort was significantly elevated [1.09 SD score (SDS), –2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, –1.5–4.1; 0.63 SDS, –0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (–0.81 SDS, –2.6 to 3.2) and normal during the night (0.11 SDS, –2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1–22.8) but not diastolic blood pressure (17.2%, 0.90–25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (rs = 0.271–0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin.

Conclusions: Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CONGENITAL ADRENAL HYPERPLASIA (CAH) due to 21-hydroxylase deficiency results in glucocorticoid deficiency with or without involvement of the mineralocorticoid system with a consecutively increased stimulation of the CRH-ACTH axis and raised production of androgens and steroid precursors before the enzyme defect (1, 2). Inadequate therapy may cause short-term and long-term complications such as electrolyte imbalances, Addisonian crisis, accelerated bone maturation, short stature, hirsutism and virilization, and decreased fertility (1, 3). Recent studies provide evidence that these patients are at high risk of becoming overweight and obese (4, 5).

In CAH patients, there are several factors, primarily related to glucocorticoid and mineralocorticoid deficiency or iatrogenic overtreatment, that may interfere with the physiological control of blood pressure (BP). It is well known that patients with Conn’s syndrome have hypertension due to mineralocorticoid excess, whereas mineralocorticoid insufficiency causes hypotension (6, 7). Excessively elevated glucocorticoid levels also affect the mineralocorticoid receptor (8). Moreover, there is increasing evidence that adrenomedullar function is altered in CAH patients (9, 10), which might have a negative impact on the sympathogenic regulation of BP. In addition, obesity is strongly associated with hypertension. In this context, leptin and insulin have been proposed to play a role in the development of overactivity of the sympathetic nervous system related to obesity (11). However, there is limited information available on BP in CAH patients. Preliminary data on 24-h BP profiles measured in a clinical setting suggested an increased risk of hypertension (12).

Therefore, the aim of this study was to analyze ambulatory 24-h BP profiles in a cohort of 55 children and adolescents with classical CAH, during a couple of days off school or work, spent at home. We evaluated possibly contributing factors such as body mass index (BMI), skinfold thickness, glucocorticoid and mineralocorticoid medication, and skeletal maturation. Additionally, the implications of laboratory parameters like serum 17-hydroxyprogesterone (17-OHP), 24-h urine ratio of pregnanetriol to tetrahydrocortisone, saliva 17-OHP, serum leptin, and insulin levels were investigated.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We included 55 Caucasian children and adolescents (32 females, 23 males), aged between 5 and 19 yr, who presented regularly at our outpatient endocrine unit. All individuals had classical CAH with 21-hydroxylase deficiency [salt wasting (SW); n = 45; simple virilizing (SV); n = 10] and received glucocorticoid substitution therapy with hydrocortisone (HC; n = 40), prednisone (PR; n = 12), or dexamethasone (DX; n = 3). HC was given thrice daily (~50% of the daily dosage in the early morning, 25% at noon, and 25% in the evening); PR was given twice and DX once daily. The diagnosis was confirmed in all patients with molecular genetic analyses by direct sequencing (n = 4, patients presented with neonatal Addisonian crisis but had no detectable mutation on the second allele). Fifty-three patients additionally received fludrocortisone (FC; twice daily) due to mineralocorticoid insufficiency. The quality of therapy was monitored during follow-up visits every 3–6 months by clinical presentation and laboratory measurements according to current guidelines (follow-up median 10.3 yr; range 4.2–19) (13). At the time of the analysis, none of them had obvious signs of any acute or chronic disease, nor did they receive any other medication. There was no reported history of parental hypertension.

Study design

The cross-sectional data of all patients were prospectively ascertained during a regular follow-up visit to our outpatient endocrine unit. All patients presented over a 12-month period between July 2004 and June 2005 on a day off school or work, mostly on Fridays. All of them were seen between 0800 and 0900 h after an overnight fast. The study was approved by our institutional review board. All subjects and parents gave their informed consent.

Physical examination included evaluation of height (Harpenden stadiometer), weight (without clothes except underwear), and pubertal status (Tanner stages). Height SD scores (SDS) were calculated using German references (14). BMI and SDS were calculated adjusted for age and sex according to current German reference data (15). According to the Childhood Group of the International Obesity Task Force, a BMI greater than 2.0 SDS was defined as obesity (16, 17). Subscapular skinfold thickness was measured with Holtain Tanner-Whitehouse skinfold calipers (Holtain Ltd., Crosswell, Crymych, UK).

The clinic BP and heart rate at the time of presentation were oscillometrically measured (CBPM; DINAMAP ProCare Monitor, GE Medical Systems, Tampa, FL). These values were transformed into SDS matched for age or height, sex, and population (18, 19).

Equivalent HC dosages (eHC4,30) were calculated for PR and DX (factors 4 and 30, respectively). With respect to recently published data, we alternatively calculated equivalent HC dosages (eHC15,70) multiplying by factors 15 (PR) and 70 (DX) (20, 21). In a subgroup of children (n = 36), bone age was assessed by an experienced observer using the atlas method of Greulich and Pyle, which has been found to be reliable for central European children (22). For evaluation of the current status of skeletal maturation, we calculated the difference between bone age and chronological age [bone age delay = bone age (BA) minus chronological age (CA) in years]. Fasting blood sampling was performed for monitoring the therapy. Serum or plasma was then separated by centrifugation and stored at –20 C until assay.

Ambulatory 24-h BP profiles (ABPM)

Ambulatory measurements within the home setting on a couple of days off school or work (24 h, starting between 0800 and 0900 h) were undertaken in each patient with a standard oscillometric ABPM device (Mobil-O-Graph; I.E.M., Stolberg, Germany), which is accurate according to the British Hypertension Society and the Association for the Advancement of Medical Instrumentation protocol criteria (23).

The most appropriate of three cuff sizes was applied to the nondominant arm. The patients pursued their normal daily activities but were instructed to rest the arm during recordings and note special events. Readings were taken every 15 min during the day and every 30 min at night (modified protocol 1). A minimum of 50 recordings had to be obtained during the study period. Initial cuff inflation increased step-wise to the systolic level. All subsequent inflations were programmed to be 5 mm Hg higher than the previous measured systolic BP (auto-feedback-logic). The monitor detected two pulses at each pressure step during deflation of the cuff (beat-compare-technology). These pulses had to be similar and match a certain height and duration to become part of the envelope curve calculation. Measurements that produced a pulse pressure of less than 20 mm Hg or a heart rate of less than 40 beats per min (bpm) were regarded as errors and automatically excluded by the recorder. If any of the parameters was not correctly measured, the measurement was repeated within 3 min. Because directly measured BP values were obtained as mean arterial pressure by the device, systolic and diastolic BP values were calculated via algorithms.

All measured and calculated values were transformed into SDS matched for age (index CA) or height (cm, index H), sex, population, and the same oscillometric method (SpaceLabs Monitor 90207; SpaceLabs Medical Inc., Redmond, WA) (18, 19, 24).

Laboratory methods

All serum parameters were measured with commercially available assays: Serum leptin levels by RIA [Mediagnost, Reutlingen, Germany; intraassay coefficient of variation (CV): 7.3%; sensitivity: 32 ng/liter]. Serum insulin levels were measured by ELISA (Diagnostics Systems Laboratories, Sinsheim, Germany; intra- and interassay CV: <7%; sensitivity: 0.26 mU/liter; conversion factor from milliunits per liter to micrograms per liter: 0.04). Serum levels of active renin were determined by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA; intra- and interassay CV: <10%; sensitivity: 0.9 ng/liter).

Saliva was collected before the morning tablet (0700 h) and stored frozen until measurement. Serum and saliva 17-OHP levels were determined with a commercial RIA (Diagnostics Systems Laboratories; adapted to the use of saliva as sample matrix as previously described) (25). Intra- and interassay CVs were less than 8%; sensitivity was 0.02 µg/liter (the conversion factor from micrograms per liter to nanomoles per liter was 3.03).

Levels of pregnanetriol and tetrahydrocortisone in specimens of urine collected during 24 h were simultaneously determined by isotope dilution/gas chromatography-mass spectrometry procedure. Deuterium-labeled analogs of the analytes served as internal standards. Intra- and interassay CVs were less than 6.0%; sensitivity was 10 pg.

Statistical analysis

Normality was tested using the Shapiro-Wilk test (P > 0.05). CA (years), height (SDS), BMI (SDS), BA delay (years), FC dosage (µg/m2 BSA), and serum insulin (mU/liter) had a Gaussian distribution, whereas Tanner stage (n), skinfold thickness (millimeters), eHC dosages (milligrams per square meter BSA), and all other laboratory and ABPM/clinical BP level- (CBPM) derived (mm Hg, bpm, SDS) variables did not.

To compare each variable between genders, clinical forms (SV, SW), and other subgroups, Mann-Whitney U test was used where appropriate. Different variables within the same subjects were compared with the Wilcoxon matched pairs test. To assess significant deviations from a hypothetical value, we used the Wilcoxon signed rank test. Because ABPM/CBPM variables were not distributed normally, Spearman (rs) correlation coefficients were assessed for the relation analysis between two parameters. Observed and expected frequencies were compared with the {chi}2 test.

All tests were performed two-tailed and a P < 0.05 was considered to be significant. For calculation and presentation, we used the GraphPad Prism software (version 4.03; GraphPad Software Inc., San Diego, CA).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient group

Detailed clinical data are shown in Table 1Go. The BMI of the whole group ranged between –2.45 and 3.77 SDS (mean 1.05 ± 1.4 SD) and was significantly above zero SDS (P < 0.0001). Fifteen subjects (27.3%; female = 7, male = 8) had a BMI greater than 2.0 SDS, indicating a significantly higher frequency of obesity in CAH patients than expected for the normal population (expected: 2.27%; P < 0.0001), and almost half of the patients (n = 26, 47.3%) presented with overweight as defined by a BMI greater than 90th percentile. There was no significant difference in age and BMI between genders and clinical form (SW vs. SV).


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  		TABLE 1. Clinical and laboratory cohort data of CAH children and adolescents

 
ABPM and CBPM

Mean daytime and nighttime systolic BP levels expressed as SDS for CA and height were significantly elevated (P < 0.0001). After adjustment to sex and CA, 11% (n = 6) of all patients had a mean daytime systolic BP above the 97th centile (P = 0.0006) and 80% (n = 40) above the 50th centile, respectively (P = 0.0007). Nighttime BP showed a similar pattern (n = 7 > 97th centile, P = 0.0001; n = 35 > 50th centile, P = 0.043). In contrast, daytime diastolic BP levels were significantly decreased (P < 0.001), whereas nighttime diastolic BP was normal. Accordingly, there was a normal nocturnal drop of systolic BP (12.8%) and a significantly decreased nocturnal drop of diastolic levels (17.2%, P < 0.001; Table 2Go, Figs. 1Go and 2Go, and supplemental figure and table, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).


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  		TABLE 2. BP and HRs (SDS for CA and height) of the cohort

 

Figure 1
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  		FIG. 1. Daytime systolic (upper panel) and diastolic (middle panel) BP and HR (lower panel) values (individual means). Filled squares (boys, left panels) or circles (girls, right panels) indicate overweight patients (BMI > 90th centile). Lines refer to –2.0 (2.3rd centile), –1.0 (16th centile), 0 (50th centile), +1.0 (84th centile), and +2.0 SDS (97.7th centile), in ascending order. DT, Daytime; dia, diastolic; sys, systolic.

 

Figure 2
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  		FIG. 2. Nighttime systolic (upper panel) and diastolic (middle panel) BP and HR (lower panel) values (individual means). Filled squares (boys, left panels) or circles (girls, right panels) indicate overweight patients (BMI > 90th centile). Lines refer to –2.0 (2.3rd centile), –1.0 (16th centile), 0 (50th centile), +1.0 (84th centile), and +2.0 SDS (97.7th centile), in ascending order. NT, Nighttime; dia, diastolic; sys, systolic.

 
The CBPM at the time of presentation showed elevated systolic BP levels in girls (P < 0.001) but not boys. Diastolic levels were decreased in boys (P < 0.01) and normal in girls. Compared with ambulatory daytime levels of the 24-h BP profiles, the clinic systolic and diastolic BP was significantly higher (P < 0.01) in girls but not boys (Table 2Go).

As shown in Table 3Go, some BP variables were correlated positively with CA and the progress of puberty (Tanner stages). There was no significant difference in any 24-h BP SDS variable between genders and clinical form (SW vs. SV).


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  		TABLE 3. Correlation analyses (Spearman rs, P values) between BP and HR variables and clinical data

 
All in all, only one patient (CA 9.5 yr) showed a highly pathological BP profile (mean values: daytime BP 154/81 mm Hg, heart rate (HR) 99 bpm; nighttime BP 131/76 mm Hg, HR 79 bpm; serum renin concentration 6 ng/liter) with the need of antihypertensive medication (atenolol 0.6 mg/kg·d).

Overweight and obesity

BMI (SDS) was positively correlated with skinfold thickness (millimeters, rs = 0.818, P < 0.0001). Twenty-three (88.5%, P < 0.0001 > 50%) of the overweight but only 17 (58.6%, not significant) of the normal-weight children had daytime systolic BP levels over the 50th centile (SDSCA). In contrast, 24 (82.8%, P < 0.0004) of the normal-weight but only 17 (65.4%, not significant) of the overweight children had daytime diastolic BP levels below the 50th centile (SDSCA). There were no significant results in both groups for HR SDSCA (Fig. 1Go).

Systolic nighttime BP levels showed a similar pattern (overweight group: 73.1%, > 50th centile, P < 0.0186; normal-weight group: 58.6%, not significant; SDSCA), whereas there were no significant results in both groups for diastolic BP SDSCA. Nineteen (73.1%, P < 0.0186) of the overweight but only 17 (58.6%, not significant) of the normal-weight children had elevated nighttime HRs (SDSCA) over the 50th centile (Fig. 2Go). Several BP variables, but not the HR, were correlated with BMI and skinfold thickness (Table 3Go).

Serum leptin and insulin

Serum leptin was positively correlated with skinfold thickness (rs = 0.800, P < 0.0001), BMI SDS (rs = 0.502, P < 0.0001), Tanner stage (rs = 0.502, P < 0.0001), and CA (rs = 0.348, P < 0.0001). Serum insulin was also positively correlated with skinfold thickness (rs = 0.285, P = 0.0353), BMI SDS (rs = 0.306, P = 0.0331), and Tanner stage (rs = 0.288, P = 0.0230) but not CA. There was no significant difference between girls and boys in both hormones. Several BP variables, but not the HR, were correlated with leptin and insulin in a similar pattern as skinfold thickness and BMI (Table 3Go).

Medication and metabolic control

Classic equivalent HC (eHC4,30) dosage ranged between 5.6 and 29.6 mg/m2 (Table 1Go). BP and HR variables did not differ between children receiving HC, PR, or DX. There was no significant difference between the subjects with a lower (eHC4,30 < 15 mg/m2, n = 30) or higher (eHC4,30 > 15 mg/m2, n = 25) dosage in any BP or HR variable (SDSCA), except for daytime diastolic BP (median, range; – 1.03 SDSCA, – 2.6 to 3.0; – 0.48 SDSCA, – 2.5 to 1.9; P = 0.035). Accordingly, eHC4,30 was also positively correlated with daytime diastolic BP SDSCA (rs = 0.332, P = 0134) but with none of the other variables (Table 3Go). In contrast, fludrocortisone dosage was not correlated with any of the BP or HR variables (Table 1Go).

In addition, calculations with the alternative equivalent HC (eHC15,70) dosage revealed the same results, except for a significant correlation with nighttime diastolic BP (Table 3Go). Because there is, first, also a strong correlation of these two BP parameters with CA and, second, most of the older patients are receiving PR and DX, these findings most likely reflect an overestimation of eHC by the factors 15 and 70 and therefore represent multicollinearity (Table 3Go).

To estimate the influence of metabolic control at the time of BP assessment, we made correlation analyses between serum renin, serum 17-OHP, morning saliva 17-OHP, 24-h urine pregnanetriol, 24-h urine pregnanetriol to tetrahydrocortisone ratio (only in patients with hydrocortisone), and the BA delay (BA minus CA in years) and all BP and HR variables: there was no correlation regarding any of these parameters (Table 1Go). There was no significant difference between the patients with either low (<fifth percentile, n = 9) or elevated (>95th percentile, n = 9) serum renin concentrations according to age-specific reference values (26) in any BP variable.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our data showed an increased risk of systolic hypertension in children and adolescents with classical CAH due to 21-hydroxylase deficiency, compared with current German references recorded from 1254 girls and boys using the same oscillometric method and precision according to the British Hypertension Society protocol (18, 19, 23, 24). Analyses of nocturnal dipping revealed an insufficient diastolic but a normal systolic BP decrease. However, the results of systolic and diastolic dipping had a wide range and should be considered with caution because most of our patients dipped within the normal range. Preliminary oscillometrically measured data published by Roche et al. (12) also suggested elevated systolic BP levels in CAH children (n = 38, aged 6.1–18.2 yr). Mean diastolic levels were also reported to be elevated but less significantly. Overall, this study had some limitations regarding the reference group. It was assembled of metaanalyzed data of nine different studies as far back as the 1970s and provided reference values from single BP measurements using a mercury sphygmomanometer or a Doppler device. Another limiting factor of this study might be the clinical setting of measurements. A recent longitudinal study in 5292 adults confirms the superiority of ambulatory over clinical measurements (12, 27, 28, 29, 30). A second study with CAH patients comprised only a small cohort of 11 patients (31).

Generally, references for 24-h BP in children and adolescents are corrected for CA or height. Because CAH patients show a significantly different growth pattern, compared with the normal population, SDS for height calculations should be interpreted with care (32, 33).

Further investigation of underlying factors revealed overweight and obesity as major factors contributing to systolic hypertension. Indeed, the mean systolic levels were normotense within the normal-weight subgroup. Weiss et al. (34) also demonstrated a predominant influence of the BMI SDS on the ambulatory measured systolic but not the diastolic BP in children and adolescents. The principles of obesity-associated hypertension have recently been reviewed, focusing on new mechanisms involved (11). In brief, overactivity of the sympathic nervous system has been highlighted to play a key role in obesity-hypertension (35). Among others, leptin acts in the hypothalamus to increase BP through activation of the sympathic nervous system. A similar effect has also been shown for insulin (36, 37). Both hormones exhibit high serum levels in obesity (34). In agreement, our study also showed elevated serum leptin and insulin levels that were closely correlated to BMI and age (38, 39). As previously shown, the leptin levels are not significantly higher in CAH, compared with the reference population, after adjustment for sex, age, and BMI (4).

In contrast, the mean diastolic levels of the obese children were normal and decreased within the normal weight, probably reflecting a tendency to hypotension. Because the renin-angiotensin-aldosterone axis is affected in CAH, mineralocorticoid insufficiency might contribute to hypotension in these patients. The pathophysiology of salt loss in the distal nephron, due to failure of the mineralocorticoid receptor mediated sodium uptake, is well known (7). Besides this mechanism, there is increasing evidence for additional nongenomic-type action of mineralocorticoid receptors, e.g. on the heart and blood vessels (7, 40). A second approach to explain our findings might be a general risk of adrenomedullar insufficiency in CAH. Merke et al. (9) showed reduced levels of plasma epinephrine, metanephrine, and normetanephrine as well as urinary excretion of epinephrine in CAH patients but normal values for plasma norepinephrine and urinary norepinephrine. The histological and ultrastructural analyses of adrenal glands in these CAH patients confirmed incomplete formation and structural changes of the adrenal medulla (9, 10).

Another factor in the regulation of BP is assigned to the exogenous steroid replacement therapy. High glucocorticoid levels have mineralocorticoid effects, probably due to the saturation of the 11ß-hydroxysteroid dehydrogenase 2 enzyme, which normally converts cortisol to cortisone (8, 41). Furthermore, the role of the hypothalamic-pituitary-adrenal axis on fetal programming and epigenetic effects should also be taken into account in CAH patients (42, 43). However, we did not find any correlations between BP and the current substitution therapy, except for equivalent hydrocortisone dosage and daytime diastolic levels. Roche et al. (12) also found no correlations for these variables.

The effectiveness of glucocorticoid substitution therapy over a period of years is not easy to assess. Monitoring serum and urinary laboratory parameters cover only a few days or weeks, whereas advanced skeletal maturation as an index of poor metabolic control might be more representative over a longer period of time (4). As an additional parameter, we calculated the pregnanetriol to tetrahydrocortisone ratio, which has been shown to be less correlated with age than urine pregnanetriol or serum 17-OHP levels (44, 45, 46). Similarly to the study of Roche et al. (12), we did not find any correlation of the 24-h BP profiles with these parameters.

In conclusion, our data are supportive of two major findings in children and adolescents with CAH: obesity-associated systolic hypertension and, on the other hand, a trend to diastolic hypotension in normal-weight patients. The former factor indicates the need for weight management programs, whereas the second one requires careful monitoring and a tight stress management. However, our paper can touch only on several potentially influencing factors. Further studies are needed, focusing for example on the role of the adrenal medulla and the sympathetic activity.


   Acknowledgments
 
We are grateful for having been provided with five additional Mobil-O-Graph devices (I.E.M.) and the time of study and technical support by Mrs. B. Diegeler-Gatignon and Mr. Alexander Wolf. We appreciate the technical assistance of Mrs. Jutta Biskupek-Sigwart and the help of our study nurse, Mrs. Diana Striegel.


   Footnotes
 
Parts of this study were presented at the 7th Joint Meeting of the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society, Lyon, France, September 21–24, 2005.

Disclosure summary: T.M.K.V., D.S., and W.R. have nothing to declare. J.D. received lecture fees from various companies (less than $10,000 per 2 yr). H.G.D. consults for KIGS Germany Advisory Board (Pfizer, less than $1,000 per year) and received lecture fees from various companies (less than $10,000 per 2 yr).

First Published Online September 26, 2006

Abbreviations: ABPM, Ambulatory 24-h BP profile; BA, bone age; BMI, body mass index; BP, blood pressure; CA, chronological age; CAH, congenital adrenal hyperplasia; CBPM, clinical BP level; CV, coefficient of variation; DX, dexamethasone; eHC, equivalent HC dosages; FC, fludrocortisone; HC, hydrocortisone; HR, heart rate; 17-OHP, 17-hydroxyprogesterone; PR, prednisone; SDS, SD score; SV, simple virilizing; SW, salt wasting.

Received May 17, 2006.

Accepted September 18, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. New MI 2004 An update of congenital adrenal hyperplasia. Ann NY Acad Sci 1038:14–43[Abstract/Free Full Text]
  2. White PC, Speiser PW 2000 Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291[Abstract/Free Full Text]
  3. Hughes IA 1998 Congenital adrenal hyperplasia—a continuum of disorders. Lancet 352:752–754[CrossRef][Medline]
  4. Völkl TMK, Simm D, Beier C, Dörr HG 2006 Obesity among children and adolescents with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 117:e98–e105
  5. Cornean RE, Hindmarsh PC, Brook CG 1998 Obesity in 21-hydroxylase deficient patients. Arch Dis Child 78:261–263[Abstract/Free Full Text]
  6. Kühnle U, Lewicka S, Fuller PJ 2004 Endocrine disorders of sodium regulation. Role of adrenal steroids in genetic defects causing sodium loss or sodium retention. Horm Res 61:68–83[CrossRef][Medline]
  7. Fuller PJ, Young MJ 2005 Mechanisms of mineralocorticoid action. Hypertension 46:1227–1235[Abstract/Free Full Text]
  8. Chemaitilly W, Wilson RC, New MI 2003 Hypertension and adrenal disorders. Curr Hypertens Rep 5:498–504[Medline]
  9. Merke DP, Chrousos GP, Eisenhofer G, Weise M, Keil MF, Rogol AD, Van Wyk JJ, Bornstein SR 2000 Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343:1362–1368[Abstract/Free Full Text]
  10. Charmandari E, Eisenhofer G, Mehlinger SL, Carlson A, Wesley R, Keil MF, Chrousos GP, New MI, Merke DP 2002 Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency. J Clin Endocrinol Metab 87:3031–3037[Abstract/Free Full Text]
  11. Rahmouni K, Correia ML, Haynes WG, Mark AL 2005 Obesity-associated hypertension: new insights into mechanisms. Hypertension 45:9–14[Abstract/Free Full Text]
  12. Roche EF, Charmandari E, Dattani MT, Hindmarsh PC 2003 Blood pressure in children and adolescents with congenital adrenal hyperplasia (21-hydroxylase deficiency): a preliminary report. Clin Endocrinol (Oxf) 58:589–596[CrossRef][Medline]
  13. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW 2002 Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res 58:188–195[CrossRef][Medline]
  14. Reinken L, Stolley H, Droese W, van Oost G 1980 [Longitudinal data of physical growth of healthy children. II. Height, weight, skinfold thickness of children aged 1.5–16 years]. Klin Padiatr 192:25–33[Medline]
  15. Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geiß HC, Hesse V, von Hippel A, Jaeger U, Johnsen D, Korte W, Menner K, Müller G, Müller JM, Niemann-Pilatus A, Remer T, Schaefer F, Wittchen H-U, Zabransky S, Zellner K, Ziegler A, Hebebrand J 2001 Perzentile für den body-mass-index für das kindes- und jugendalter unter heranziehung verschiedener deutscher stichproben. Monatsschr Kinderheilkd 149:807–818[CrossRef]
  16. Wabitsch M 2000 [Obesity in childhood and adolescence: recommendations of a United States of America task force for diagnosis and therapy]. Klin Padiatr 212:287–296[Medline]
  17. Barlow SE, Dietz WH 1998 Obesity evaluation and treatment: Expert Committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 102:E29
  18. Wühl E, Witte K, Sörgel M, Mehls O, Schaefer F 2002 Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 20:1995–2007[CrossRef][Medline]
  19. Soergel M, Kirschstein M, Busch C, Danne T, Gellermann J, Holl R, Krull F, Reichert H, Reusz GS, Rascher W 1997 Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: a multicenter trial including 1141 subjects. J Pediatr 130:178–184[CrossRef][Medline]
  20. Punthakee Z, Legault L, Polychronakos C 2003 Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency. J Pediatr 143:402–405[CrossRef][Medline]
  21. Rivkees SA, Crawford JD 2000 Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics 106:767–773[Abstract/Free Full Text]
  22. Groell R, Lindbichler F, Riepl T, Gherra L, Roposch A, Fotter R 1999 The reliability of bone age determination in central European children using the Greulich and Pyle method. Br J Radiol 72:461–464[Abstract]
  23. Jones CR, Taylor K, Chowienczyk P, Poston L, Shennan AH 2000 A validation of the Mobil O Graph (version 12) ambulatory blood pressure monitor. Blood Press Monit 5:233–238[CrossRef][Medline]
  24. O’Brien E, Mee F, Atkins N, O’Malley K 1991 Accuracy of the Labs 90207 determined by the British Hypertension Society protocol. J Hypertens 9:573–574[Medline]
  25. Krüger C, Breunig U, Biskupek-Sigwart J, Dörr HG 1996 Problems with salivary 17-hydroxyprogesterone determinations using the Salivette device. Eur J Clin Chem Clin Biochem 34:926–929[Medline]
  26. Krüger C, Rauh M, Dörr HG 1998 Immunoreactive renin concentrations in healthy children from birth to adolescence. Clin Chim Acta 274:15–27[CrossRef][Medline]
  27. Rascher W 1997 Blood pressure measurement and standards in children. Nephrol Dial Transplant 12:868–870[Free Full Text]
  28. Anonymous 1987 Report of the Second Task Force on Blood Pressure Control in Children—1987. Task Force on Blood Pressure Control in Children. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics 79:1–25[Abstract/Free Full Text]
  29. Verdecchia P, Angeli F 2005 How can we use the results of ambulatory blood pressure monitoring in clinical practice? Hypertension 46:25–26[Free Full Text]
  30. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den HE, McCormack P, Staessen JA, O’Brien E 2005 Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension 46:156–161[Abstract/Free Full Text]
  31. de Silva KS, Kanumakala S, Brown JJ, Jones CL, Warne GL 2004 24-hour ambulatory blood pressure profile in patients with congenital adrenal hyperplasia—a preliminary report. J Pediatr Endocrinol Metab 17:1089–1095[Medline]
  32. Frisch H, Waldhauser F, Lebl J, Solyom J, Hargitai G, Kovacs J, Pribilincova Z, Krzisnik C, Battelino T 2002 Congenital adrenal hyperplasia: lessons from a multinational study. Horm Res 57(Suppl 2):95–101
  33. Merke DP, Bornstein SR 2005 Congenital adrenal hyperplasia. Lancet 365:2125–2136[CrossRef][Medline]
  34. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S 2004 Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374[Abstract/Free Full Text]
  35. Vaz M, Jennings G, Turner A, Cox H, Lambert G, Esler M 1997 Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation 96:3423–3429
  36. Mark AL, Correia ML, Rahmouni K, Haynes WG 2004 Loss of leptin actions in obesity: two concepts with cardiovascular implications. Clin Exp Hypertens 26:629–636[CrossRef][Medline]
  37. Rahmouni K, Morgan DA, Morgan GM, Liu X, Sigmund CD, Mark AL, Haynes WG 2004 Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest 114:652–658[CrossRef][Medline]
  38. Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP 2002 Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab 87:2114–2120[Abstract/Free Full Text]
  39. Poyrazoglu S, Gunoz H, Darendeliler F 2003 Serum leptin levels in patients with 21-hydroxylase deficiency before and after treatment. Turk J Pediatr 45:33–38[Medline]
  40. Okoshi MP, Yan X, Okoshi K, Nakayama M, Schuldt AJ, O’Connell TD, Simpson PC, Lorell BH 2004 Aldosterone directly stimulates cardiac myocyte hypertrophy. J Card Fail 10:511–518[CrossRef][Medline]
  41. Dötsch J, Dörr HG, Stalla GK, Sippell WG 2001 Effect of glucocorticoid excess on the cortisol/cortisone ratio. Steroids 66:817–820[CrossRef][Medline]
  42. Moritz KM, Boon WM, Wintour EM 2005 Glucocorticoid programming of adult disease. Cell Tissue Res 322:81–88[CrossRef][Medline]
  43. Matthews SG 2002 Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 13:373–380[CrossRef][Medline]
  44. Vierhapper H, Nowotny P, Waldhausl W, Frisch H 1985 Capillary gas chromatography as a tool for characterization of urinary steroid excretion in patients with congenital adrenal hyperplasia. J Steroid Biochem 22:363–369[CrossRef][Medline]
  45. Homoki J, Solyom J, Teller WM 1988 Detection of late onset steroid 21-hydroxylase deficiency by capillary gas chromatographic profiling of urinary steroids in children and adolescents. Eur J Pediatr 147:257–262[CrossRef][Medline]
  46. Homoki J, Solyom J, Wachter U, Teller WM 1992 Urinary excretion of 17-hydroxypregnanolones in patients with different forms of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. Eur J Pediatr 151:24–28[CrossRef][Medline]




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