Christiaan F. Mooij

Unfavourable trends in cardiovascular and metabolic risk in paediatric and adult patients with congenital adrenal hyperplasia

Context  As a result of the introduction of treatment with glucocorticoids and mineralocorticoids, now 60 years ago, congenital adrenal hyperplasia has become a lifelong chronic disease. Whether long‐term treatment of the disease leads to long‐term side effects remains unknown. In this respect, especially cardiovascular risk seems to be important.

A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1).

CONTEXT Cytochrome P450 side-chain cleavage enzyme (CYP11A1) facilitates the first and rate-limiting step of steroidogenesis. Only nine patients with CYP11A1 deficiency have been described. All patients presented with adrenal insufficiency (AI) and disorder of sex development in 46,XY individuals. OBJECTIVE Our objective was to define the pathogenic consequences of a novel CYP11A1 mutation (p.R451W) found in two brothers with isolated adrenal insufficiency. PATIENTS The two brothers (46,XY) presented with AI and normal male genital development. The older boy first presented with signs and symptoms suggestive of AI at the age of 2.8 yr but was only diagnosed at the age of 4.1 yr during an adrenal crisis. The younger brother was diagnosed with AI at the age of 2.5 yr while being clinically asymptomatic. Both boys had entirely normal appearance of their external genitalia. RESULTS The novel p.R451W mutation and five published missense CYP11A1 mutations were characterized employing two in vitro approaches using the natural substrate cholesterol and the intermediate 22R-hydroxycholesterol, respectively. Pregnenolone generation was measured by highly specific liquid chromatography tandem mass spectrometry. p.R451W had 30% of wild-type activity consistent with the clinical phenotype in our patients. Two previously published mutations (p.L222P and p.A359V) had 2- to 3-fold higher in vitro activities than originally reported, correlating better with the associated phenotypes. CONCLUSIONS We provide the first evidence that partial CYP11A1 deficiency has to be considered as a differential diagnosis in clinically isolated adrenal insufficiency. Our assays demonstrate a tighter genotype-phenotype correlation in CYP11A1 deficiency than previous in vitro studies.

Characterization of the molecular genetic pathology in patients with 11β‐hydroxylase deficiency

Steroid 11β‐hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD.

Blood Pressure in the First Year of Life in Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: A Pilot Study

Aims: Evaluation of blood pressure in the first year of life in children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Methods: Twenty-four children were included. Retrospective blood pressure values, fludrocortisone dosages, and serum renin, 17-hydroxyprogesterone (17-OHP) and androstenedione levels in the first year of life were evaluated. Blood pressure values were compared to reference values. Correlations between blood pressures and serum renin levels, and the dosage of fludrocortisone were calculated. Results: Mean peak systolic blood pressure values were generally not elevated, most values were around the 50th percentile, except incidentally higher mean peak systolic blood pressure values most below the 95th percentile. No significant correlations between blood pressure and serum renin, androstenedione and 17-OHP levels and fludrocortisone dosage were found. Conclusion: In this pilot studyin CAH patients, blood pressure values do not seem to be elevated in the first year of life. Further investigations are necessary to evaluate blood pressure in the first year of life in CAH patients in more detail.

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia.

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to accumulation of steroid precursors and adrenal androgens. These steroids may have a biological effect on the steroid receptor with clinical consequences on diagnostics and treatment in CAH patients. Therefore, we analysed the effect of accumulated steroids [17-hydroxyprogesterone (17OHP), progesterone, androstenedione and testosterone] on aldosterone-mediated transactivation of the human mineralocorticoid receptor (hMR). Methods: A transactivation assay using transiently transfected COS7 cells was employed. Cells were co-transfected with hMR-cDNA, MMTV-luciferase and renilla-luciferase expression vectors. Transfected cells were incubated with six different steroid concentrations in addition to aldosterone (10-10M). Luciferase and renilla activities were measured to quantify hMR transactivation. Results: Linear regression analysis showed statistically significant linear inhibition of transactivation of the hMR by 10-10M aldosterone in the presence of increasing 17OHP [F(1,5) = 11.34, p = 0.019] and progesterone [F(1,5) = 11.08, p = 0.021] concentrations. In contrast, neither androstenedione nor testosterone affected hMR transactivation by aldosterone at a concentration of 10-10M. Conclusion: Our study shows for the first time that neither androstenedione nor testosterone has a biological effect on aldosterone-mediated transactivation of the hMR. 17OHP and progesterone have an anti-mineralocorticoid effect in vitro that may clinically lead to an increased requirement of mineralocorticoids in poorly controlled CAH patients.

Cardiovascular health, growth and gonadal function in children and adolescents with congenital adrenal hyperplasia

After the introduction of replacement therapy with glucocorticoids and mineralocorticoids in the 1950s, congenital adrenal hyperplasia (CAH) is no longer a life-limiting condition. However, due to the successful introduction of medical steroid hormone replacement, CAH has become a chronic condition, with associated comorbidities and long-term health implications. The aim of treatment is the replacement of mineralocorticoids and glucocorticoids and the normalisation of elevated androgen concentrations. Long-term consequences of the condition and current treatment regimens include unfavourable changes in the cardiovascular risk profile, impaired growth, testicular adrenal rest tumours (TART) in male and subfertility in both male and female patients with CAH. Optimising replacement therapy in patients with CAH remains challenging. On one hand, treatment with supraphysiological doses of glucocorticoids might be required to normalise androgen concentrations and decrease size or presence of TARTs. On the other hand, treatment with supraphysiological doses of glucocorticoids is associated with an increased prevalence of unfavourable cardiovascular and metabolic risk profiles as well as impaired longitudinal growth and gonadal function. Therefore, treatment of children and adults with CAH requires an individualised approach. Careful monitoring for early signs of complications is already warranted during paediatric healthcare provision to prevent and reduce the impact of comorbidities in later life.

Cardiovascular and metabolic risk in pediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency

Abstract Background: The aim of the study was to evaluate the cardiovascular and metabolic risk profile in pediatric patients with congenital adrenal hyperplasia (CAH). Methods: A cross-sectional study was performed in 27 CAH patients (8–16 years). Blood samples were taken to evaluate circulating cardiovascular risk (CVR) markers. Insulin resistance (IR) was evaluated by homeostatic model assessment (HOMA)-IR. Blood pressure (BP) was evaluated by office BP measurements and 24-h ambulatory BP measurements (24-h ABPM). Dual energy X-ray absorptiometry (DXA) scans were performed in patients >12 years. Results: Body mass index (BMI) standard deviation score (SDS) was elevated (0.67), with seven patients being overweight and four obese. DXA scans showed percentage body fat SDS of 1.59. Office BP levels were higher than reference values. Twenty-four hour ABPM showed systolic hypertension (n=5), while 11 patients had a non-dipping BP profile. HOMA-IR was >75th percentile in 12 patients. Conclusions: CAH patients develop an unfavorable CVR profile already in childhood with increased BMI, increased fat mass, elevated BP levels, a non-dipping BP profile and IR compared to population reference values.