A delayed diagnosis of salt-wasting congenital adrenal hyperplasia

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[Multiple endocrine neoplasia type 2B]

Item does not contain fulltextBACKGROUND: Multiple endocrine neoplasia type 2b (MEN2B) is a rare syndrome characterised by the occurrence of medullary thyroid carcinoma at a young age in all patients, and phaeochromocytoma at a later age in half of the patients. Once a medullary thyroid carcinoma causes symptoms, it has usually already metastasised to the lymph nodes and curative treatment is seldom possible at that stage. CASE DESCRIPTION: We present two patients who had phenotypical characteristics of the MEN2B syndrome from a young age: mucosal neuromas, ptosis, a marfanoid habitus, gastrointestinal problems and crying without tears. When the diagnosis was made, at the ages of 15 and 10 years respectively, both patients had already developed metastatic medullary thyroid carcinoma. CONCLUSION: Early recognition of the phenotype of MEN2B syndrome is crucial in order to be able to perform a prophylactic or curative thyroidectomy. The mucosal neuromas, which are usually present from infancy, are a particularly important characteristic

Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty

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Salivary morning androstenedione and 17alpha-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia

Contains fulltext : 152691.pdf (Publisher’s version ) (Open Access)BACKGROUND: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17alpha-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring. METHODS: We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21-hydroxylase deficiency. RESULTS: A-dione and 17OHP levels and its ratio 17OHP/A-dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46-4.41) during prepuberty; 2.36 nmol/L (0.63-8.89) for boys and 1.99 nmol/L (0.32-6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11-15 mg/m2/day. A-dione levels above the upper reference limit (URL), suggesting undertreatment, coincided with 17OHP levels >/=10 times URL. The percentage of A-dione levels above URL was 16% at ages 4-8 years, but increased to 31% for girls at 16 years and 46% for boys at 17 years. CONCLUSIONS: Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4-6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys.8 p

Adrenal Steroid Metabolites Accumulating in Congenital Adrenal Hyperplasia Lead to Transactivation of the Glucocorticoid Receptor

Item does not contain fulltextPatients with congenital adrenal hyperplasia (CAH) are often clinically less severely affected by cortisol deficiency than anticipated from their enzymatic defect. We hypothesize that adrenal steroid hormone precursors that accumulate in untreated or poorly controlled CAH have glucocorticoid activity and partially compensate for cortisol deficiency. We studied the in vitro effects of 17-hydroxyprogesterone (17OHP), progesterone (P), 21-deoxycortisol (21DF), and androstenedione (Delta4) on the human glucocorticoid receptor (hGR). Competitive binding assays were performed in HeLa cells. Nuclear translocation of the hGR was studied by transfection of COS-7 cells with a GFP-tagged hGR and fluorescence microscopy. Transactivation assays were performed in COS-7 cells and in HEK 293 cells after cotransfection with hGR and luciferase reporter vectors using a dual luciferase assay. 17OHP, P, and 21DF are able to bind to the hGR with binding affinities of 24-43% compared with cortisol. Delta4 has a low binding affinity. Incubation with 21DF led to complete nuclear translocation of the hGR, whereas treatment with 17OHP or P resulted in partial nuclear translocation. 21DF transactivated the hGR with an EC50 approximately 6 times the EC50 of cortisol. 17OHP and P transactivated the hGR with EC50s of more than 100 times the EC50 of cortisol. No hGR transactivation was detected after incubation with Delta4. 21DF, 17OHP, and P are able to bind, translocate, and transactivate the hGR in vitro and thus may have glucocorticoid activity. 21DF might have a clinically relevant agonistic effect on the hGR and could potentially partially compensate the cortisol deficiency in CAH patients.7 p

Supplementary Material for: Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

<b><i>Background:</i></b> 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). <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> 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

Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia

Item does not contain fulltextCONTEXT AND OBJECTIVE: We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH. DESIGN: Cross-sectional cohort study and translational research. INTERVENTION/MAIN OUTCOME MEASURES: Adrenal steroid precursor concentrations before and 60 minutes after ACTH administration to 24 untreated patients with CAH (3 to 46 years) with proven cortisol deficiency (&lt;500 nmol/L post-ACTH) measured by liquid chromatography-tandem mass spectrometry were compared with six control patients (Mann-Whitney U test). Glucocorticoid receptor (GR) activation was determined by dual-luciferase assays in human embryonic kidney cells transfected with the GR and exposed to increasing amounts of adrenal steroid precursors for 24 hours. RESULTS: Blood concentrations of the steroid precursors 11-deoxycortisol (457 nmol/L, P = 0.003), 11-deoxycorticosterone (55 nmol/L, P = 0.003), 17-hydroxyprogesterone (610 nmol/L, P &lt; 0.001), progesterone (29 nmol/L, P &lt; 0.001), and 21-deoxycortisol (73 nmol/L) were strongly elevated compared with control subjects. The GR was activated with comparable potency to cortisol by corticosterone and 21-deoxycortisol or with 4 to 100 times lower potency by 11-hydroxyprogesterone, 11-deoxycortisol, aldosterone, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone. CONCLUSIONS: We identified strongly elevated adrenal steroid precursor concentrations in blood from untreated patients with CAH and demonstrated glucocorticoid activity of these adrenal precursors in vitro, suggesting a possible role of these precursors in the clinical phenotype of these patients. Further studies are necessary to evaluate the role of these precursors in more detail

Absence of clinically relevant growth acceleration in untreated children with non-classical congenital adrenal hyperplasia.

Item does not contain fulltextBACKGROUND/AIMS: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. METHODS: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BA(c) = bone age - calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. RESULTS: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02-0.10). Mean BA(c) was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BA(c) was found. CONCLUSIONS: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BA(c) is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.6 p