The Results of CHD7 Analysis in Clinically Well-Characterized Patients with Kallmann Syndrome

Item does not contain fulltextCONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients

Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. Patients and Methods: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. Conclusion: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients' impaired QOL and of the impact of unemployment on QOL

MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients

Contains fulltext : 170909.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up. METHODS: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. RESULTS: A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001). CONCLUSIONS: Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors

TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing’s disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease

Adult Patients with Congenital Adrenal Hyperplasia Have Elevated Blood Pressure but Otherwise a Normal Cardiovascular Risk Profile

Contains fulltext : 96615.pdf (publisher's version ) (Open Access)OBJECTIVE: Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin). RESULTS: 24-Hour systolic (126.3 mmHg+/-15.5 vs 124.8 mmHg+/-15.1 in controls, P = 0.019) and diastolic (76.4 mmHg+/-12.7 vs 73.5 mmHg+/-12.4 in controls, P<0.001) blood pressure was significantly elevated in CAH patients compared to the control population. CAH patients had higher HDL cholesterol levels (P<0.01), lower hsCRP levels (P = 0.03) and there was a trend toward elevated adiponectin levels compared to controls. Other cardiovascular risk factors were similar in both groups. CONCLUSION: Adult CAH patients have higher ambulatory blood pressure compared to healthy matched controls. Other cardiovascular risk markers did not differ, while HDL-cholesterol, hsCRP and adiponectin levels tended to be more favorable

A prediction model for primary aldosteronism when the salt loading test is inconclusive

Objective: To develop a prediction model to confirm or exclude primary aldosteronism (PA) in patients with an inconclusive salt loading test (SLT). Context: Diagnosis in patients with a suspicion of PA can be confirmed using an SLT. In case of inconclusive test results the decision about how to manage the patient is usually based on contextual clinical data. Design: We included a retrospective cohort of 276 patients in the final analysis. Methods: All patients underwent an SLT between 2005 and 2016 in our university medical center. The SLT was inconclusive (post-infusion aldosterone levels 140–280 pmol/L) in 115 patients. An expert panel then used contextual clinical data to diagnose PA in 45 of them. Together with 101 patients with a positive SLT this resulted in a total of 146 patients with PA. A total of 11 variables were used in a multivariable logistic regression analysis. We assessed internal validity by bootstrapping techniques. Results: The following variables were independently associated with PA: more intense potassium supplementation, lower plasma potassium concentration, lower plasma renin concentration before SLT and higher plasma aldosterone concentration after SLT. The resulting prediction model had a sensitivity of 84.4% and a specificity of 94.3% in patients with an inconclusive SLT. The positive and negative predictive values were 90.5 and 90.4%, respectively. Conclusions: We developed a prediction model for the diagnosis of PA in patients with an inconclusive SLT that results in a diagnosis that was in high agreement with that of an expert panel

Decreased Aerobic Exercise Capacity After Long-Term Remission From Cushing Syndrome: Exploration of Mechanisms.

BACKGROUND: Although major improvements are achieved after cure of Cushing syndrome (CS), fatigue and decreased quality of life persist. This is the first study to measure aerobic exercise capacity in patients in remission of CS for more than 4 years in comparison with matched controls, and to investigate whether the reduction in exercise capacity is related to alterations in muscle tissue. METHODS: Seventeen patients were included. A control individual, matched for sex, estrogen status, age, body mass index, smoking, ethnicity, and physical activity level was recruited for each patient. Maximal aerobic capacity (VO2peak) was assessed during incremental bicycle exercise to exhaustion. In 8 individually matched patients and controls, a percutaneous muscle biopsy was obtained and measures were made of cross-sectional areas, capillarization, and oxphos complex IV (COXIV) protein content as an indicator of mitochondrial content. Furthermore, protein content of endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated on serine1177 and of the NAD(P)H-oxidase subunits NOX2, p47phox, and p67phox were measured in the microvascular endothelial layer. FINDINGS: Patients showed a lower mean VO2peak (SD) (28.0 [7.0] vs 34.8 [7.9] ml O2/kg bw/min, P < .01), maximal workload (SD) (176 [49] vs 212 [67] watt, P = .01), and oxygen pulse (SD) (12.0 [3.7] vs 14.8 [4.2] ml/beat, P < .01) at VO2peak. No differences were seen in muscle fiber type-specific cross-sectional area, capillarization measures, mitochondrial content, and protein content of eNOS, eNOS-P-ser1177, NOX2, p47phox, and p67phox. INTERPRETATION: Because differences in muscle fiber and microvascular outcome measures are not statistically significant, we hypothesize that cardiac dysfunction, seen in active CS, persists during remission and limits blood supply to muscles

Results of endoscopic transsphenoidal pituitary surgery in 40 patients with a growth hormone-secreting macroadenoma

Contains fulltext : 96290.pdf (Publisher’s version ) (Open Access)OBJECTIVE: Transsphenoidal pituitary surgery (TS) is the primary treatment of choice for patients with acromegaly. Macroadenomas (>1 cm) are more difficult to resect than microadenomas (remission rate +/- 50% compared to +/- 90%). Besides the conventional microscopic TS, the more recently introduced endoscopic technique is nowadays frequently used. However, no large series reporting on its results have yet been published. We evaluated the outcome of endoscopic TS in 40 patients with a growth hormone (GH)-secreting macroadenoma treated in our hospital between 1998 and 2007. METHODS: Medical records were retrospectively reviewed. Remission was defined as disappearance of clinical symptoms of acromegaly, normal serum insulin-like growth factor-1 levels (</=2 SD) and serum GH levels suppressed to <2 mU/l after an oral glucose tolerance test within the first 4 months after TS. RESULTS: In four patients TS aimed at debulking of the tumour. In the remaining 36 patients, remission was achieved in 20 patients. In the first 5 years remission was achieved in 6 out of 18 patients (33%) compared to 14 out of 22 patients (63%) in the following 5 years (p = 0.06). Thirteen patients had a mild perioperative complication. Before TS 15 patients received hormonal substitution therapy compared to 12 patients (33%) after TS. CONCLUSION: Endoscopic TS is a good primary therapeutic option for patients with a GH-secreting macroadenoma, resulting in a remission rate of up to 63% in experienced hands. This technique can potentially improve the outcome of TS in these patients

Relating circulating thyroid hormone concentrations to serum interleukins-6 and -10 in association with non-thyroidal illnesses including chronic renal insufficiency

<p>Abstract</p> <p>Background</p> <p>Because of the possible role of cytokines including interleukins (IL) in systemic non-thyroidal illnesses' (NTI) pathogenesis and consequently the frequently associated alterations in thyroid hormone (TH) concentrations constituting the euthyroid sick syndrome (ESS), we aimed in this research to elucidate the possible relation between IL-6 & IL-10 and any documented ESS in a cohort of patients with NTI.</p> <p>Methods</p> <p>Sixty patients and twenty healthy volunteers were recruited. The patients were subdivided into three subgroups depending on their underlying NTI and included 20 patients with chronic renal insufficiency (CRI), congestive heart failure (CHF), and ICU patients with myocardial infarction (MI). Determination of the circulating serum levels of IL-6 and IL-10, thyroid stimulating hormone (TSH), as well as total T4 and T3 was carried out.</p> <p>Results</p> <p>In the whole group of patients, we detected a significantly lower T3 and T4 levels compared to control subjects (0.938 ± 0.477 vs 1.345 ± 0.44 nmol/L, p = 0.001 and 47.9 ± 28.41 vs 108 ± 19.49 nmol/L, p < 0.0001 respectively) while the TSH level was normal (1.08+0.518 μIU/L). Further, IL-6 was substantially higher above controls' levels (105.18 ± 72.01 vs 3.35 ± 1.18 ng/L, p < 0.00001) and correlated negatively with both T3 and T4 (r = -0.620, p < 0.0001 & -0.267, p < 0.001, respectively). Similarly was IL-10 level (74.13 ± 52.99 vs 2.64 ± 0.92 ng/ml, p < 0.00001) that correlated negatively with T3 (r = -0.512, p < 0.0001) but not T4. Interestingly, both interleukins correlated positively (r = 0.770, p = <0.001). Moreover, IL-6 (R²= 0.338, p = 0.001) and not IL-10 was a predictor of low T3 levels with only a borderline significance for T4 (R²= 0.082, p = 0.071).</p> <p>By subgroup analysis, the proportion of patients with subnormal T3, T4, and TSH levels was highest in the MI patients (70%, 70%, and 72%, respectively) who displayed the greatest IL-6 and IL-10 concentrations (192.5 ± 45.1 ng/L & 122.95 ± 46.1 ng/L, respectively) compared with CHF (82.95 ± 28.9 ng/L & 69.05 ± 44.0 ng/L, respectively) and CRI patients (40.05 ± 28.9 ng/L & 30.4 ± 10.6 ng/L, respectively). Surprisingly, CRI patients showed the least disturbance in IL-6 and IL-10 despite the lower levels of T3, T4, and TSH in a higher proportion of them compared to CHF patients (40%, 45%, & 26% vs 35%, 25%, & 18%, respectively).</p> <p>Conclusion</p> <p>the high prevalence of ESS we detected in NTI including CRI may be linked to IL-6 and IL-10 alterations. Further, perturbation of IL-6 and not IL-10 might be involved in ESS pathogenesis although it is not the only key player as suggested by our findings in CRI.</p

Exercise Improves Insulin Sensitivity in the Absence of Changes in Cytokines.

PURPOSE: The benefits of aerobic exercise training on insulin sensitivity in subjects with the metabolic syndrome (MetS) are, at least in part, associated with changes in cytokines. Recent studies identified novel cytokines (e.g. fractalkine, omentin and osteopontin) that are strongly involved in glucose homeostasis and therefore potentially contribute in the exercise-induced changes in insulin sensitivity. Therefore, we aim to examine changes in skeletal muscle RNA expression and plasma levels of novel cytokines after exercise training, and correlate these changes to the exercise-induced changes in insulin sensitivity. METHODS: Women with the metabolic syndrome (MetS, n=11) and healthy women (n=10) participated in a 6-month aerobic exercise training intervention (3/week, 45min per session at 65%-85% of individual heart rate reserve). Before and after training, we examined insulin sensitivity (M-value during hyperinsulinemic euglycaemic clamp), circulating blood levels of cytokines (venous blood sample; leptin, adiponectin, omentin, fraktalkin, osteopontin). Skeletal muscle RNA-expression of these cytokines (muscle biopsy) was examined in two subgroups (MetS n=6; healthy women n=6). RESULTS: At baseline, plasma levels of omentin (85.8±26.2ng/ml) and adiponectin (5.0±1.7μg/ml) levels were significantly higher in controls compared to MetS (51.1±27.1; 3.6±1.1 respectively), and leptin levels were lower in controls (18.7±11.5ng/ml vs 53.0±23.5). M-value was significantly higher in controls (8.1±1.9mg/kg/min) than in MetS (4.0±1.7). Exercise training significantly improved M-values in both groups (P0.05). CONCLUSION: Whilst exercise training successfully improves insulin sensitivity in MetS and healthy women, we found no change in plasma and mRNA expression levels of novel cytokines