Claudio E. Kater

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

CONTEXT Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.

Randomised controlled trial of growth effect of hydrocortisone in congenital adrenal hyperplasia

The influence of 15 or 25 mg/m2 of daily oral hydrocortisone with fludrocortisone 0.1 mg/day on growth and laboratory findings was evaluated in a prospective randomised crossover trial over 12 months in 26 children with 21-hydroxylase deficiency. Nine non-salt losers had fludrocortisone stopped for a further six month period. Height velocity was significantly decreased during treatment with 25 mg/m2 as compared with 15 mg/m2. This was the most sensitive indicator of corticosteroid treatment excess. A dose dependent effect upon plasma concentrations of 17-hydroxyprogesterone, testosterone, and androstenedione was found but increased values were still detected in more than half of the determinations made during the 25 mg/m2 period. Height velocity and 17-hydroxyprogesterone concentrations were positively correlated. Growth hormone response to clonidine stimulation and insulin-like growth factor-1 concentrations were both within reference values and there was no difference between treatment periods. Withdrawal of fludrocortisone did not result in any difference for the non-salt losers. It was concluded that 25 mg/m2 of hydrocortisone depressed growth in children with congenital adrenal hyperplasia, and that full suppression, or even normalisation, of plasma concentrations of 17-hydroxyprogesterone and androgens should not be considered a treatment goal, but instead an indication of corticosteroid treatment excess.

Cushing's syndrome in pregnancy: an overview

Cushings syndrome (CS) during pregnancy is a rare condition with fewer than 150 cases reported in the literature. Adrenal adenomas were found to be the commonest cause, followed by Cushings disease. The gestation dramatically affects the maternal hypothalamic-pituitary-adrenal axis, resulting in increased hepatic production of corticosteroid-binding globulin (CBG), increased levels of serum, salivary and urinary free cortisol, lack of suppression of cortisol levels after dexamethasone administration and placental production of CRH and ACTH. Moreover, a blunted response of ACTH and cortisol to exogenous CRH may also occur. Therefore, the diagnosis of CS during pregnancy is much more difficult. Misdiagnosis of CS is also common, as the syndrome may be easily confused with preeclampsia or gestational diabetes. Because CS during pregnancy is usually associated with severe maternal and fetal complications, its early diagnosis and treatment are critical. Surgery is the treatment of choice for CS in pregnancy, except perhaps in the late third trimester, with medical therapy being a second choice. There does not seem to be a rationale for supportive treatment alone.

Aldosterone-Producing Adrenocortical Carcinoma: Preoperative Recognition and Course in Three Cases

Three patients with primary aldosteronism due to adrenocortical carcinoma were studied, two with hyperaldosteronism alone and one also with hypercortisolism; in the later stages all three had hypersecretion of glucocorticoid and androgenic hormones. Although clinical presentations were similar to those of patients with benign adenoma, all had significantly higher concentrations of deoxycorticosterone and aldosterone and more profound hypokalemia. Stimulation with adrenocorticotropin in two patients showed a good cortisol response but no aldosterone response. The circadian rhythm for cortisol was normal but absent for aldosterone and deoxycorticosterone. Sequential 24-hour circadian studies in one patient showed that as the disease progressed, corticosterone and finally cortisol lost their circadian rhythms. Treatment with spironolactone, mitotane, or aminoglutethimide had transient clinical effects. The patients died 2 to 13 years later.

Growth hormone axis in cushing's syndrome.

All levels of the growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor (IGF) and IGF binding protein (IGFBP) axis are influenced by chronic hypercortisolism. Thus, there is a blunted response to GHRH alone or together with other stimuli associated with a marked suppression of endogenous GH secretion but accompanied by normal GHBP, normal to low IGF-1 and GHBPs 1 and 3 with the correspondent 41.5 and 38.5-kD molecular forms of the latter presenting values similar to normal. These findings may suggest enhanced GH sensitivity with normal or increased IGF-1 bioavailability to the correspondent tissue receptors. In conclusion, the glucocorticoid (GC)-induced target tissue resistance can neither be attributed to the suppression of the GH axis nor to changes in circulating GHBPs 1 and 3. However, it may be related either to the described 12-to-20-kD inhibitor(s) which antagonizes postbinding IGF-1 bioactivity (gene expression) and/or by the downmodulation of activator protein-1 (Fos/Jun) activity by the GC-GC receptor complex.

Cystic phaeochromocytoma is a distinctive subgroup with special clinical, imaging and histological features that might mislead the diagnosis.

To report and analyse cases of cyctic phaeochromocytoma at our institution and in previous publications, as adrenal cystic masses are usually associated with nonfunctional lesions, but they can be phaeochromocytoma.

Resposta divergente da testosterona e do cortisol séricos em atletas masculinos após uma corrida de maratona

Physical exercise alters homeostasis, as it requires prompt mobilization of metabolic sources. In this study, we measured serum testosterone (T) and cortisol (C) levels and the muscle-wastage enzymes CK, CKMB and LDH in 20 healthy male athletes (ages 25 to 40 years) in response to a marathon race (42.2 km). Venous blood samples were drawn in 3 different periods: (i) in the morning, 48 h before the competition (control), (ii) at the end of the race (end), and (iii) in the next morning, 20 h after the race (recovery). At the end, T was significantly lower (from 673 to 303 ng/dl) and C higher (from 20.3 to 42.5 µg/dl) as compared to the control period. At recovery, both were virtually identical to control levels. CK, CKMB and LDH were significantly higher at the end of the competition and even higher in the recovering period (except for CKMB), characterizing muscle wastage. CK and LDH disclosed a significant negative correlation with T (-0.412 and -0.546, respectively), whereas CKMB correlated positively with C (0.4521). We conclude that the inverse correlation observed between T and C levels, and the pattern of CK, CKMB and LDH increase, allow us to confirm that a marathon race may cause a marked physical stress, resulting in a distinct hormonal imbalance and severe cellular damage.

Superior discriminating value of ACTH‐stimulated serum 21‐deoxycortisol in identifying heterozygote carriers for 21‐hydroxylase deficiency

Background  Congenital adrenal hyperplasia caused by classic 21‐hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH‐stimulated values of 17‐hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21‐Deoxycortisol (21DF), an 11‐hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ.

Increased diagnostic probability of subclinical Cushing's syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus.

Endogenous Cushings Syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00 h and salivary and serum cortisol after a 1 mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253 ng/dL, 47 ng/dL, and 1.8 microg/dL, respectively for the 23:00 h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5-fold higher than in the remaining patients. After a confirmatory 2 mg x 2 day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population.

Cortisol, DHEAS and aging: resistance to cortisol suppression in frail institutionalized elderly.

Convincing evidences has linked the hypothalamus-pituitary-adrenal (HPA) axis to aging patterns. F excess is implicated in the development of frailty characteristics whereas DHEAS is positively correlated to successful aging. We compared serum F and DHEAS levels of independent community- living (successful group, 19 M and 28 F, 69 to 87 yr) with those of institutionalized elderly (frail group, 20 M and 30 F, 65 to 95 yr). Serum F was determined at 1) baseline (08:00 h, 16:00 h and 23:00 h), 2) after 2 overnight dexamethasone (DEX) suppression tests (DST, using 0.25 and 1.0 mg doses), and 3) 60 min after ACTH stimulation (250 μg i.v. bolus); serum DHEAS was determined at 08:00 h. Basal serum F at 08:00 h, 16:00 h and 23:00 h and serum DHEAS levels were similar in both groups; however F: DHEAS ratio at 08:00 h was higher in the frail, compared to the successful group (mean±SD: 0.55±0.53 and 0.35±0.41, respectively; p=0.04). In response to DST, F suppression was less effective in frail elderly after either 0.25 or 1.0 mg doses (9.0±6.0 and 2.0±0.9 μg/dl), as compared to the successful group (5.8±4.4 and 1.5±0.5 μg/dl) (p=0.01). In addition, a significant correlation was observed between post- DEX F levels (both doses) and parameters of cognitive and physical frailty. Normal and similar F levels were observed after ACTH stimulation in both groups. Our data suggest a deficient feedback regulation of the HPA axis in frail institutionalized elderly, as demonstrated by a higher set point for F suppression. This augmented HPA tonus enforces the hypothesis that even milder F excess may be related to characteristics of frailty in the elderly.