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Contains fulltext : 245825.pdf (Publisher’s version ) (Closed access) BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery). INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. FUNDING: US National Institutes of Health.

BackgroundPathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma–paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.MethodsThree independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes.ResultsTruncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (pSDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (pConclusionsSDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.

Pheochromocytoma and Paraganglioma Pheochromocytoma and paraganglioma are related tumors that differ mainly in location; pheochromocytomas are adrenal, and paragangliomas can be anywhere else. The ...

Background: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. Methods: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC’s photometric method. Results: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. Conclusions: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.

© 2019 Elsevier Ltd. All rights reserved., Background: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. Methods: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. Findings: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range

Delayed gastric emptying (DGE) after Ivor-Lewis esophagectomy occurs postoperatively in up to 50% of the patients. This pyloric dysfunction can lead to severe secondary complications postoperatively such as early aspiration, pneumonia or may even have an impact on anastomotic healing and therefore leakage. Early detection of DGE is essential to prevent further complications. The common treatment postoperatively is endoscopic pyloric balloon dilatation (EPBD) after symptoms already occurred. In our work, we analyzed patients who received a preoperative EPBD during the routine restaging endoscopy and compared those patients to a control group to analyze if preoperative EPBD may prevent postoperative DGE and secondary additional complications. We performed a single-center retrospective analysis of 115 patients who received an Ivor-Lewis esophagectomy by the same surgeon between June 2015 and October 2017. Out of these 115 patients, 91 (79.1%) patients received EPBD preoperatively during the staging/restaging endoscopy (PDG, pyloric dilatation group). In 24 (20.9%) patients, preoperative EPBD was not performed due to stenotic esophageal tumors or logistic reasons (NDG, non-pyloric dilatation group). Data of the PDG and NDG group were compared regarding the rate of postoperative DGE as well as DGE and EPBD related complications. In total, 21 (18.3%) patients developed pyloric dysfunction requiring a total of 27 EPBD during follow-up. There were 12 (13.2%) patients in the PDG and 9 (37.5%) patients in the NDG (p = 0.014), respectively. DGE-related complications such as anastomotic leaks (p = 0.466), pulmonary complications (p = 0.466) and longer median hospital stay (p = 0.685) were more frequent in the NDG group; however this difference did not reach statistical significance. The success rate for postoperative EPBD with 20-mm balloons was lower (58.5%) compared to the usage of 30-mm balloons (93.3%). All pre- and postoperative EPBD were performed without any complications. Preoperative EPBD is feasible, safe and can be combined with restating endoscopy. It seems that preoperative EPBD reduces the incidence of DGE and can prevent the need for early postoperative endoscopic interventions. Our recommendation is therefore to perform an EPBD preoperatively when possible to reduce postoperative complications to a minimum. For postoperative EPBD, we recommend the use of the 30-mm balloon due to lower redilatation rates.

Background Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. Methods We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905–1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. Results We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. Conclusions The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.

Background The importance of high quality preprocedural bowel preparation is widely acknowledged, but suboptimal bowel cleansing still occurs in up to 20 % of all colonoscopy patients. The aim of this study was to evaluate the performance of a novel intraprocedural cleaning device for cleaning poorly prepared colons. Methods This multicenter feasibility study included patients aged 18 – 75 years who were referred for colonoscopy. Intraprocedural cleaning was performed in patients after a limited preprocedural bowel preparation regimen (2 days of dietary restrictions and 2 × 10 mg bisacodyl). The primary outcome was the proportion of adequately prepared patients (Boston Bowel Preparation scale [BBPS] ≥ 2 in each segment) before and after segmental washing with the new device. Secondary outcomes included: cecal intubation rate, procedure time, system usability, patient satisfaction, and safety. Results 47 patients (42.6 % male), with a median age of 61 years (interquartile range [IQR] 46 – 67 years), were included at three clinical sites. Cecal intubation was achieved in 46/47 patients (97.9 %). The cleaning device significantly improved the proportion of patients with adequate bowel cleansing (from 19.1 % to 97.9 %; P Conclusions This feasibility study suggests that the intraprocedural cleaning device appears to be safe and effective in cleaning poorly prepared colons to an adequate level, allowing a thorough colorectal examination.

The calcium signalling and hedgehog (HH) signalling pathways operate in the primary cilium. Abnormalities in these pathways cause autosomal dominant polycystic kidney disease (ADPKD) and naevoid basal cell carcinoma syndrome (NBCCS) respectively. Several reports have proposed that hyperactivation of the HH pathway in animal models of polycystic kidney disease affects normal renal development and renal cyst phenotype. A family with 2 cases (a proband and her sister) of ADPKD and NBCCS coinheritance led us to investigate whether interactions may be present in the 2 pathways. The effect of HH pathway hyperactivation (due to c.573C>G mutation on PTCH1 gene that cause NBCCS) on renal ADPKD progression in the proband was compared to 18 age- and sex-matched ADPKD patients in a 9-year, prospective, follow-up study. Blood pressure, total kidney volume, estimated glomerular filtration rate, plasma copeptin, urine excretion of albumin, total protein and monocyte chemoattractant protein-1 (MCP-1) were analysed. Data for the sibling was not available. In the ADPKD group, blood pressure and estimated glomerular filtration rate were within normal values, and total kidney volume and MCP-1 increased (p < 0.01) throughout the study. In comparison, during the 9-year follow-up, the proband showed persistent hypertension (from 125/85 to 140/95 mm Hg), low total kidney volume (75 and 61% of median ADPKD), and a ninefold increase in urine MCP-1. We found no differences in urine excretion of albumin or plasma copeptin values. These results suggest that HH hyperactivation may play a minimal role in ADPKD progression. These observations can help to clarify the clinical impact of affected pathways in renal development and cystogenesis in humans.

Introduction Gastroparesis (GP) is defined as delayed gastric emptying (GE) without any obstruction of the pylorus. It can be divided into idiopathic, diabetic, post surgical and rare causes. Electronic gastric stimulation (EGS) – Enterra Medtronic™ – is a part of GP therapy. Although its positive impact has been reported in open label trials, randomized controlled trials failed in demonstrating a positive outcome. The aim of this pilot study was to establish a reliable prediction for permanent gastric stimulation. Patients and procedure 6 female patients underwent laparoscopic implantation of 2 temporary electrodes. The Enterra™ system was connected and taped to the skin. Baseline and postoperative gastroparesis cardinal symptom index (GCSI), a validated index for GP therapy, was assessed. Response to EGS was defined as a 50% decrease of baseline GCSI. Results 4 of 6 patients responded to temporary EGS. 3 of 4 responders underwent permanent implantation. 1 non-responder received a permanent Enterra™ at another institution. After a median follow up time of 9 months the responder group GCSI remained low, whereas the non-responder GCSI had increased. Moreover, the health care system was saved € 30,678.03 by this test stimulation concept. Conclusion Laparoscopic implantation of a temporary EGS system predicts the outcome of permanent gastric stimulation and is cost-saving.

Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access. In the setting of a prospective study (1/2001–12/2016), 42 consecutive children and adolescents (33 m, 9 f) were operated on. Thirty-seven patients (88%) suffered from inherited diseases. Twenty-six patients had PH, 11 presented retroperitoneal PGL, and five patients suffered from both. Altogether, 70 tumours (mean size 2.7 cm) were removed (45 PH, 25 PGL). All operations were performed by a minimally invasive access (retroperitoneoscopic, laparoscopic, extraperitoneal). Partial adrenalectomy was the preferred procedure for PH (31 out of 39 patients). Twenty patients received α-receptor blockade preoperatively. One patient died after induction of anaesthesia due to cardiac arrest. All other complications were minor. Conversion to open surgery was necessary in two cases with PGL. Median operating time for unilateral PH was 55 min, in bilateral cases 125, 143 min in PGs, and 180 min in combined cases. Median blood loss was 20 ml (range 0–1000). Blood transfusion was necessary in two cases. Intraoperative, systolic peak pressure was 170 ± 39 mmHg with α-receptor blockade and 191 ± 33 mmHg without α-receptor blockade (p = 0.41). The median post-operative hospital stay was 3 days. After a mean follow-up of 8.5 years, two patients presented ipsilateral recurrence (after partial adrenalectomy). All patients with bilateral PH (n = 13) are steroid independent post-operatively. PH and PGL in children and adolescents should preferably be removed by minimally invasive surgery. Partial adrenalectomy provides long-term steroid independence in bilateral PH and a low rate of (ipsilateral) recurrence. α-Receptor blockade may not be necessary in these patients.

Objective Cervical cancer precursor screening by HPV testing has a low positive predictive value for advanced lesion. HPV16 RNA patterns characteristic for HPV16-transformed cells but based on laborious, cost-intensive singleplex NASBA reactions promised high value in triaging HPV16 DNA-positive women. Methods We developed two high-throughput reverse transcriptase quantitative (RT-q) PCR assays for the HPV16 transcripts E6*I, E1^E4 and E1C and the cellular transcript ubiquitin C and analysed RNA of 158 singly HPV16 DNA-positive cervical cell samples archived in PreservCyt buffer for the presence of transformation-associated HPV16 RNA patterns, i.e., upregulation of E6*I relative to E1^E4 and/or presence of E1C. Results HPV16 RNA pattern analyses classified 85% of 58 samples diagnosed ≤CIN1 (no cytologically and histologically detectable cervical lesion or CIN grade 1) as negative and 90% of 59 samples diagnosed as ≥CIN3 (CIN grade 3 or invasive cancer) as positive. Among 41 CIN grade 2 samples representing an intermediate lesion group, 49% were HPV16 RNA patterns-positive. Interestingly, 3 of 4 HPV16 RNA patterns-positive lesions initially diagnosed as ≤CIN1 at follow-up 5–24months later had progressed to ≥CIN2. Conclusions We successfully developed and validated a second generation of HPV16 RNA patterns assay by rapid RT-qPCR as triage marker for HPV16 DNA-positive women offering clinical utility to distinguish between the need for immediate colposcopy and continued observation. Limited follow-up data suggests that HPV16 RNA patterns-positivity in ≤CIN1 lesions can predict disease progression.

BACKGROUND As we emerge into the genomic medicine era, the epidemiology of diseases is taken for granted. Accurate prevalence figures, especially of rare diseases (RDs, ≤50/100,000), will become even more important for purposes of health care and societal planning. We noticed that the numbers of affected individuals in regionally established registries for mainly hereditary RDs do not align with published estimated and expected prevalence figures. We therefore hypothesized that such non-population-based means overestimate RDs and sought to address this by recalculating prevalence for an important 'common' hereditary disease, autosomal-dominant polycystic kidney disease (ADPKD) whereby presumed-prevalence is 100-250/100,000 METHODS: The Else-Kroener-Fresenius-ADPKD-Study in south-west Germany with a population of 2,727,351 inhabitants was established with the cooperation of all nephrology centres. Furthermore, general practitioners, internists, urologists, human geneticists and neurosurgery centres were contacted with questionnaires for demographic, family and kidney function data. Germline-mutation screening of susceptibility genes PKD1 and PKD2 was offered. Official population data for 2010 were used for overall and kidney function-adjusted prevalence estimations. RESULTS A total of 891 subjects, 658 index-cases and 233 relatives, aged 10-89 (mean 52), were registered, with >90% response rate, 398 by nephrologists and 493 by non-nephrologists. Molecular-genetic analyses contributed to confirmation of the diagnosis in 57%. The overall prevalence of ADPKD was 32.7/100,000 reaching a maximum of 57.3/100,000 in the 6th decade of life. CONCLUSIONS Prevalence of ADPKD is overestimated by 2- to 5-fold and close to the limit of RDs which may be of broad clinical, logistic and policy implications.

Objective: The purpose was to determine the growth rate of succinate dehydrogenase subunit (SDHx) gene-related paragangliomas based on computed tomography (CT) measurements. Methods: Twenty-seven patients with SDHx mutations who underwent subsequent CT examinations were enrolled in the study. Tumors were classified as head and neck (HNP), thoracic, or abdominal/pelvic paragangliomas (PGLs). The percentage volume increase and volume doubling time were estimated. Results: We analyzed 56 PGLs (21 with SDHD, 6 with SDHB mutations) in 27 patients (16 men, 11 women; mean age 37.7 years). The estimated median of the follow-up was 23 months. Twenty-two (39.3%) PGLs were located in the abdomen, 8 (14.3%) in the thorax, and 26 (46.4%) in the head and neck region. The median volume growth rate was estimated at 10.4% per year (interquartile range lIQR]: -1.3; 36.3). The volume doubling time was estimated as 7.01 (2.24;+∞) years. By tumor site, the estimated medians of the annual volume growth rates were 13.6% (IQR:0.8 -30.4) for HNP, -6.06% (IQR: -1.79;47.32) for thoracic PGLs, and 10.5% (IQR: -2.2;44.6) for abdominal PGLs. The volume doubling time was 5.44 years (2.61; 87.0) for HNP, 11.8 years (1.79;+∞) for thoracic PGLs, and 6.94 years (1,88;+∞) for abdominal PGLs. There was no significant difference in the volume growth rate according to tumor location or initial size (P>.7 and P = .07, respectively) or gene mutation type (SDHB vs. SDHD, P>.8). Conclusion: PGLs related to SDHx mutations are slowly growing tumors. There were no correlations between tumor location, growth rate or initial size over a 23-month follow-up period. Abbreviations: CT = computed tomography HNP = head and neck paraganglioma IQR = interquartile range PGL = paraganglioma PPGL = pheochromocytoma and paraganglioma SDH = succinate dehydrogenase

Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with hereditary paraganglioma and pheochromocytoma. Although most mutations in SDHB, SDHC and SDHD are intraexonic variants, large germline deletions may represent up to 10% of all variants but are rarely characterized at the DNA sequence level. Additional phenotypic effects resulting from deletions that affect neighboring genes are also not understood. We performed multiplex ligation-dependent probe amplification, followed by a simple long-range PCR 'chromosome walking' protocol to characterize breakpoints in 20 SDHx-linked paraganglioma-pheochromocytoma patients. Breakpoints were confirmed by conventional PCR and Sanger sequencing. Heterozygous germline deletions of up to 104 kb in size were identified in SDHB, SDHC, SDHD and flanking genes in 20 paraganglioma-pheochromocytoma patients. The exact breakpoint could be determined in 16 paraganglioma-pheochromocytoma patients of which 15 were novel deletions. In six patients proximal genes were also deleted, including PADI2, MFAP2, ATP13A2 (PARK9), CFAP126, TIMM8B and C11orf57. These genes were either partially or completely deleted, but did not modify the phenotype. This study increases the number of known SDHx deletions by over 50% and demonstrates that a significant proportion of large gene deletions can be resolved at the nucleotide level using a simple and rapid method.

Background. Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. Methods. Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. Results. Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. Conclusion. Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. (C) 2015 Wiley Periodicals, Inc.

Systemic analysis of somatic mutations of other susceptibility genes in syndromic tumors as well as apparently sporadic tumors in well-characterized specimens is lacking. Its clinical relevance has not been studied. Our objective was to determine the frequency of second allele inactivation in syndromic tumors and determine the frequency and potential clinical impact of somatic mutations and loss of heterozygosity (LOH) of the known susceptibility genes in syndromic and sporadic tumors. Nine tumor specimens from clinically characterized VHL mutation, five from SDHB mutation, four from SDHD mutation, two from RET mutation carriers, and eight from apparently sporadic cases were analyzed. Tumor DNA mutation screening of the SDHx, VHL, and RET genes and LOH analyses of the SDHx and VHL genes were performed. The Yates-corrected chi-squared test was used for comparison of the clinical data and the molecular-genetic results. Second allele inactivation in tumors was identified in 83 % of VHL, 80 % of SDHB, and 50 % of SDHD specimen. High prevalence of VHL (6/6, p = 0.024) and SDHB (7/7, p = 0.018) somatic mutations has been identified in the sporadic group compared to all others. In the group of the VHL tumors the SDHB somatic events were significantly lower (2/6; p = 0.045). In 18/19 (95 %) of cases, we were able to demonstrate the presence of at least two concomitant affected susceptibility genes. We conclude that LOH is the most prevalent second allele-inactivating event. SDHB and VHL somatic mutation might play a role in the sporadic forms of tumor development. There is no clinical impact of mutation screening or LOH analysis of tumor specimens.

The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel–Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA–D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European–American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.

To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas.F-18 DOPA PET examinations were performed in 9 patients with 7 pheochromocytomas and 4 head and neck paragangliomas using a dedicated PET scanner. The acquisition started with a dynamic single-bed scan in the tumor region over the first 60 minutes after tracer injection followed by a late time whole-body scan at approximately 130 minutes. Standard uptake values (SUVs) were calculated in tumors, surrounding background, and adjacent normal tissues of relevance. Furthermore, kinetic analysis was performed using a 2-compartment model with rate constants for uptake (K1'), release (k2'), metabolism (k3'), and reverse reaction (k4') for region of interest and pixel-wise analysis.All tumors show a marked increased F-18 DOPA uptake, which was visually detectable and distinguishable from the surrounding tissue. The SUV is significantly lower in neck paraganglioma compared with abdominal pheochromocytomas. Mean time-activity curves of F-18 DOPA in tumors show a rapid uptake of the tracer. Already 2 minutes after the injection, the activity in the tumor is beyond that of the blood pool. The average maximum value (SUVmean = 8.2) has already been reached after 20 minutes. Afterward, a very slight decrease of the tumor SUV starts, which still amounts to 80% of the maximum value after 132 minutes. Due to the continuous decrease of activity in the background tissue, the tumor-to-background ratio of SUVs shows a constant increase within the entire period of examination. The mean values of apparent kinetic constants obtained by region of interest analysis averaged over all tumors are as follows: K1' = 2.89 ± 2.56 min(-1), k2' = 2.59 ± 2.81 min(-1), k3' = 0.301 ± 0.395 min(-1), and k4' = 0.044 ± 0.043 min(-1).Pheochromocytoma and paraganglioma take up F-18 DOPA very quickly. At best, the acquisition for static clinical PET imaging of paraganglioma with F-18 DOPA can start at 20 minutes postinjection for maximum uptake in tumors. Separation of tumor, background, and adjacent normal tissues is feasible due to their differences in SUV values and kinetics. The kinetic analysis demonstrates an F-18 DOPA accumulation within the tumor due to considerable differences between the rate constants of uptake and metabolism. Second, in contradiction to healthy brain, paraganglionic tumors show a reversible F-18 DOPA metabolism.

Cortical-sparing adrenalectomy in bilateral pheochromocytomas offers a postoperative corticoid-free course and has to be balanced against the risk of local recurrence. In this study we report our experience with the minimally invasive cortical-sparing adrenalectomy in patients with bilateral pheochromocytomas. From January 1996 to February 2011, 66 patients (45 men, 21 women; mean age 36 ± 16 years) were treated for bilateral pheochromocytomas. Fifty-seven patients (88%) were affected by genetic diseases. In 32 patients surgery was synchronously performed on both side, in 34 cases adrenalectomy followed previous surgery. All in all, 101 operations (47 right, 54 left) were conducted using the retroperitoneoscopic access (n = 97) or the laparoscopic route (n = 4). The mortality in our series was zero. Postoperative complications included one patient with a bleeding requiring reoperation and one patient developing a cerebral stroke on the fifth postoperative day. The mean operative time was 67 ± 26 min for unilateral adrenalectomy and 128 ± 68 min for bilateral surgery (range 25–300 min). A cortical-sparing resection was possible in 89 procedures resulting in a corticoid-free postoperative course in 60 patients (91%). A postoperative corticosteroid substitution therapy was necessary in six patients. During a median follow-up period of 48 months, one patient showed a persistent disease and needed reoperation, none developed a recurrent disease. Cortical-sparing surgery for bilateral pheochromocytomas has a low recurrence rate and avoids lifelong cortisone substitution therapy in the majority of cases.

Hereditary pheochromocytoma is associated with germline mutations of a set of susceptibility genes to which the TMEM127 gene has recently been added. Patients with TMEM127 mutations have been thus far exclusively identified with adrenal tumors.A population-based series of 48 consecutive individuals from the European-American Pheochromocytoma Paraganglioma Registry with multiple paraganglial tumors and, of these, one extraadrenal paraganglial tumor were selected for this study. They all had normal results when screened for germline mutations of the genes RET, VHL, SDHB, SDHC, and SDHD. Germline mutation analysis of the TMEM127 gene included a search for intragenic mutations and large rearrangements.Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor.TMEM127 germline mutations confer risks of extraadrenal paraganglial tumors in addition to the documented adrenal pheochromocytoma. Thus, surveillance for extraadrenal and adrenal paraganglial tumors is likely warranted in TMEM127 mutation carriers, although the true prevalence should be evaluated in patients with extraadrenal paraganglial tumors.

Item does not contain fulltext Our objective is to outline the utility of adrenal venous sampling (AVS) with measurements of metanephrine to normetanephrine ratios for diagnostic localization of phaeochromocytoma in a patient with normal plasma levels of catecholamines. A 53-year-old-woman was referred for evaluation of recurrent pheochromocytoma following a right adrenalectomy 14 years earlier. Diagnosis of recurrent disease was established from elevations in plasma metanephrines with normal levels of catecholamines. Magnetic resonance imaging indicated two 1-2 cm masses in the right surgical bed and another 1-1.5 cm mass in the left adrenal. These masses were negative on (123)I-metaiodobenzylguanidine scintigraphy. There was no evidence of a hereditary syndrome. We, therefore, carried out two investigational approaches to identify the tumor masses. Hybrid positron emission tomography/computed tomography with (68)Ga-DOTATOC ((68)Ga-DOTATOC-PET/CT) confirmed the presence of recurrent disease in the right surgical bed and also suggested additional left adrenal involvement. Normal plasma catecholamines precluded the use of adrenal venous sampling (AVS) with catecholamine measurements. Hence, we performed AVS with measurements of plasma metanephrines, which were 4- to 7-fold higher in the left adrenal vein than in central venous plasma. We observed a reversal of the normally high metanephrine to normetanephrine ratio (mean value +/- SD 5.28 +/- 1.86; range 3.36-8.84, n = 13) to 0.73, establishing the presence of a left adrenal pheochromocytoma. Surgical pathology confirmed bilateral disease. This case highlights a scenario where a combination of (68)Ga-DOTATOC-PET/CT and AVS with measurement of the metanephrine to normetanephrine ratio was crucial for the preoperative assessment of a patient with bilateral pheochromocytoma.

OBJECTIVE The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver. RESEARCH DESIGN AND METHODS To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals. RESULTS The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver. CONCLUSIONS These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

Cancer genetics is fundamental for preventive medicine, in particular in pheochromocytoma-associated syndromes. Variants in two susceptibility genes, SDHC and RET, were found in a kindred with head and neck paraganglioma. This observation of coincident DNA variants, both reported as pathogenic, in two known susceptibility genes prompted the question of their pathogenic relevance.Our objective was to elucidate the pathogenic role of the detected variants and study the prevalence of such variants.Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.Analysis of germline mutation screening results for all pheochromocytoma-paraganglioma susceptibility genes, including RET [multiple endocrine neoplasia type 2 (MEN 2)] and VHL [von Hippel-Lindau disease (VHL)]. Cases in which more than one DNA variant was found were clinically reevaluated, and cosegregation of the disease with the variant was analyzed within the registrants' families. A total of 1000 controls were screened for the presence of detected variants, and in silico analyses were performed.Three variants were identified, RET p.Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser. The frequencies of RET p.Ser649Leu (0.07%) and p.Tyr791Phe (0.9%) compared with controls excluded the two variants' role in the etiology of MEN 2 and VHL. None of the carriers of the RET variants who underwent prophylactic thyroidectomy showed medullary thyroid carcinoma. Clinical reinvestigation of 18 variant carriers excluded MEN 2. VHL variant p.Pro81Ser, also previously described as a mutation, did not segregate with the VHL in one family. In silico analyses for these variants predicted unmodified protein function.RET p.Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser are definitely not pathogenic mutations for VHL and MEN 2. Misinterpretation results in irreversible clinical consequences.

Aspergillusperitonitis is a rare life-threatening complication of peritoneal dialysis (PD). We report a case of symptomaticNeosartorya pseudofischeriperitonitis in a 60-year-old woman treated by continuous ambulatory peritoneal dialysis (CAPD) for 13 months, who performed peritoneal exchanges independently. This is believed to be the first published case ofN. pseudofischeriin an elderly patient. Comprehensive treatment included early removal of the PD catheter and the use of voriconazole (200 mg Vfend twice daily) for a period of 5 weeks. This case supports the need for more effective prophylaxis and treatment of non-Candidafungal infections in CAPD patients. Our conclusions from this case and a review of the literature are that infection with this fungus can cause substantial morbidity and is best treated with prompt catheter removal, aggressive antifungal therapy with voriconazole or amphotericin B, and vigilant observation for complications. Our report describes for what is believed to be the first time the administration of voriconazole to treat aNeosartoryaperitonitis case.

There is a high frequency of germline mutations in patients with pheochromocytomas and paragangliomas. This article describes a patient with a pheochromocytoma and a novelSDHCmutation. The authors highlight the importance of genetic testing in patients with the pheochromocytoma–paraganglioma syndrome. Background A 46-year-old man presented with headaches, paroxysmal palpitations, anxiety and hypertension. The patient had undergone surgery for a retroperitoneal tumor at the age of 31 years, when histological examination revealed an extra-adrenal pheochromocytoma. The patient's 68-year-old mother had a history of a carotid body tumor, which had been resected when she was 34 years old. She was diagnosed with a meningioma at 54 years of age and a jugular paraganglioma at 68 years of age. Investigations A 24h urine catecholamine assay was performed. CT imaging of the abdomen and 123I-labeled metaiodobenzylguanidine scintigraphy revealed a right pheochromocytoma and left adrenal incidentaloma. An inherited neoplasia syndrome was suspected and molecular genetic analyses were performed. Diagnosis Right adrenal pheochromocytoma and left adrenal nonfunctioning incidentaloma, as part of a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa). Management Predictive testing, with genetic counseling. Management included surgical resection of the existing pheochromocytoma. The patient continues to be monitored with MRI scans of the neck, thorax, abdomen and pelvis every 1–2 years and an annual 24h urine collection for the measurement of metanephrines and catecholamines.

Background A 12-year-old girl presenting with intermittent epigastric pains and diarrhea was referred to our clinic. Diagnostic workup revealed nonfunctional bilateral adrenal pheochromocytomas as well as a neuroendocrine tumor of the pancreatic head. This is the first report on the combination of a neuroendocrine pancreatic tumor with adrenal pheochromocytoma in a pediatric patient with von Hippel–Lindau (VHL) disease. Methods von Hippel–Lindau disease was confirmed by molecular genetic analysis of peripheral blood lymphocytes, which revealed the mutation VHL c. 695 G > A. The family history showed also VHL disease in the mother who carried the same mutation. Results and Conclusion Open laparotomy, organ-sparing enucleation of pheochromocytoma, and pylorus-preserving resection of the pancreatic head tumor were successfully performed. After an uneventful postoperative course, the child fully recovered. She was free of further manifestations of VHL disease 30 months after surgery.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

This study was designed to search for risk factors predicting mortality of patients with Wegener's granulomatosis (WG) treated on the intensive care unit (ICU).Seventeen patients admitted to the ICU of an University Hospital for an acute illness related to WG were analysed retrospectively over 4 years. A variety of clinical and laboratory variables were recorded. Contingency table analyses, univariate logistic regression, and discriminate analysis were performed to determine which factors influenced a negative outcome.Reasons for ICU admission were respiratory failure (n = 10), severe haemoptysis (n = 13), sepsis (n = 9), acute renal failure (n = 6), and gastrointestinal bleeding (n = 1). Patients were treated for a median of 6 days (range 4-121 days). During the stay in the ICU, five patients died within 24-121 days (overall mortality 29.4%). Causes of death were cerebral haemorrhage (n = 2), pulmonary embolism (n = 1), and sepsis (n = 2). Significantly associated with death were: Acute Physiology and Chronic Health Evaluation II (APACHE II) score24 [p = 0.004, odds ratio (OR) 0.568, 95% confidence interval (CI) 0.327-0.989], period of time in the ICU10 days (p = 0.001, OR 0.795, 95% CI 0.589-1.072), and treatment with cyclophosphamide during the stay in the ICU (p = 0.013, OR 0.799, 95% CI 0.651-0.980). No association was found for higher age, C-reactive protein (CRP), pulmonary involvement, serum creatinine, and requirement of haemodialysis.The prognosis for WG patients in the ICU is serious, but the majority can survive. To achieve a more favourable outcome, patients should stay in the ICU for as short a time as possible. The occurrence of renal failure did not influence the outcome in our patients.

Since 1971 German women aged 20 years and older can annually participate in the gynecological cancer screening program free of charge. As part of this program a cervical smear is taken for testing. The Federal Joint Committee (Gemeinsamer Bundesausschuss, GBA) is planning to change this system so that women aged over 30 years can either choose to continue with annual cytological screening using a cervical smear or can primarily opt for a human papillomavirus (HPV) test every 5 years. Women who are HPV positive will receive a supplementary cytological examination as a triage method. In Germany classification of the cytological results is based on the third revision of the Munich nomenclature (Münchner Nomenklatur, MN III), which has been in operation since 1 January 2015. The number of accredited cytology institutions and of cytologists has changed considerably since 2008. There has been a marked increase in the number of pathologists by 28.4%, which is a promising trend. The number of tests carried out has remained relatively constant; however, an increasing number of tests are now being performed in large laboratories.

Although deceptively simple, the etio-pathogenesis of pheochromocytoma represents a clinical and molecular genetic investigative challenge. Here, we summarize, from a historical point of view, the 22-year-long studies initiated at the University of Freiburg, which developed from a local experience to a national and finally an international effort. All research activities are translational and clinical and hence, registry based and intended to improve the outcome of the patients, whether by improved detection, prevention, or treatment. Major clinical steps are the prospective study on hormone tests and imaging techniques for adrenal and extra-adrenal abdominal tumors as well as the concept of organ sparing and endoscopic tumor resection. Further, we introduced 18-fluoro-dopa positron emission tomography. Population-based registries were used in order to identify germline mutations in the susceptibility genes VHL, RET, SDHB, and SDHD in non-syndromic pheochromocytoma. We differentiated distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Finally, we identified predictors and prevalence of paraganglioma syndromes associated with mutations of the SDHC gene.

OBJECTIVE: Hemangioblastomas are histologically benign lesions that occur sporadically or as a manifestation of von Hippel-Lindau disease (VHL). The treatment strategy of these neoplasms is complicated by their unpredictable growth patterns and the often irreversible neurological deficits they may cause. This study aims to outline the neurosurgical treatment options and to address the ongoing debate of surgical timing in pediatric patients with VHL. PATIENTS AND METHODS: Thirteen consecutive pediatric patients (mean age 15.1 years) who were surgically treated for intracranial (n=8) or spinal hemangioblastomas (n=5) were included in this study (range of clinical follow up 12-86 months). Ten patients were affected by von Hippel-Lindau and three were with sporadic tumors. Serial examinations, preoperative MRI studies, and operative findings were reviewed. RESULTS: Patients with cerebellar and intramedullary hemangioblastomas did not develop additional neurological deficits postoperatively. Two patients with brainstem tumors exhibited transient hemiparesis and caudal nerve palsy, respectively. Both patients recovered completely from their postoperative deficits. Preoperatively symptomatic patients with spinal tumors did not deteriorate nor improve after surgery. During the observed follow-up periods, no tumor recurrences were observed. CONCLUSION: Central nervous system (CNS) hemangioblastomas in pediatric patients can be surgically treated with low morbidity. Based on our experience, we recommend considering also the surgical removal of asymptomatic hemangioblastomas with proven radiological progression to prevent the development of permanent neurological deficits. Molecular screening of every pediatric patient and family is mandatory to enable the detection of extraneurological tumors and the development of an efficient therapeutic strategy.

Objective: To report our experience with Laparoscopic Partial Adrenalectomy (LPA) for recurrent tumours in patients with hereditary phaeochromocytoma. Patients and methods: Five patients with hereditary phaeochromocytoma (4 with von Hippel-Lindau disease and 1 with Multiple Endocrine Neoplasia 2B), who had undergone adrenal surgery previously, presented with recurrent adrenal tumours. One patient was pregnant at 20 weeks of gestation. All patients underwent hormonal evaluation, genetic screening and imaging with CT or MRI, metaiodobenzylguanidine (MIBG) scintigraphy. Results: Of the 7 attempted LPA in five patients, five procedures (71%) were successfully completed and total adrenalectomy was needed on two occasions. The adrenal vein could be spared in all patients except one. There were no intra-operative complications. The adrenal function was adequate in all patients without need for steroid supplementation except one patient who lost both adrenals eventually. There was no correlation between the preservation of adrenal vein and adrenocortical function. Conclusion: Laparoscopic partial adrenalectomy is feasible, safe and effective in recurrent phaeochromocytoma, despite previous adrenal surgery and is technically easier if the previous approach had been laparoscopic as well. Patients with hereditary phaeochromocytoma are prone for recurrent tumours and may need repeated surgical procedures. Hence, minimally invasive approach is ideal for these patients.

Objective Paragangliomas represent neoplasms of neural crest origin that arise from paraganglia. Mutations in the gene encoding succinate dehydrogenase subunit D (SDHD) are responsible for a percentage of hereditary paragangliomas. We previously described a group of 271 pheochromocytoma patients, 11 of whom had mutations of the SDHD gene. The objective of this study was to find out whether those 11 patients had additional paragangliomas. Study design Ten patients participated in our clinical screening program that included MRI of the skull base and neck, thorax, and abdomen, as well as an 18 Fluoro-DOPA positron emission tomography (DOPA-PET). Results Five patients presented with head and neck paragangliomas, 1 patient with a thoracic paraganglioma, and 2 patients with intraabdominal paragangliomas. Conclusions The screening for paragangliomas in patients with mutations of the SDHD gene offers the chance to diagnose those tumors in an early stage. Significance Because morbidity after surgical resection increases with tumor size, early surgery will minimize the potential risks.

Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHB and SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novo promoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (PVHL and SDHD mutations) and sporadic phaeochromocytomas.

The retroperitoneoscopic approach is a standardized operative procedure for primary adrenal gland tumors. It allows direct access with a detailed view of the adrenal gland. Thereby, a clear differentiation between normal and neoplastic adrenal tissue is often possible, which permits a planned partial resection of the gland in selected cases. Between July 1994 and November 2003 325 posterior retroperitoneoscopic adrenalectomies were performed for primary benign adrenal gland tumors (106 Conn's adenomas, 83 pheochromocytomas, 76 Cushing's adenomas, 60 nonfunctioning tumors; size: 2.8 +/- 1.5 cm; site: 160 right, 165 left) in 318 patients (122 M, 196 F, age: 49.0 +/- 14.3 years). In 96 patients 100 tumors were removed by partial adrenalectomy (30 Conn's adenomas, 33 pheochromocytomas, 20 Cushing's adenomas, 17 nonfunctioning tumors; site: 61 right, 59 left) maintaining tumor-free parts of the adrenal gland. Of this group, 15 patients suffered from bilateral adrenal neoplastic diseases. During the same period, 225 total adrenalectomies (76 Conn's adenomas, 50 pheochromocytomas, 56 Cushing's adenomas, 34 nonfunctioning tumors; site: 109 right, 116 left) were performed in 224 patients. There was no mortality. Major complications were seen in 1.8%, minor complications in 14.5%. Three conversions were necessary to an open or a laparoscopic approach (2 patients and 1 patient, respectively). There are no differences between the two groups (total versus partial adrenalectomy) with regard to tumor size (2.8 +/- 1.6 cm versus 2.8 +/- 1.5 cm), operating time (80 +/- 44 minutes versus 79 +/- 42 minutes), and blood loss (33 +/- 71 ml versus 29 +/- 31 ml). In all patients with partial adrenalectomy, biochemical healing was proven. Fourteen of 15 patients with bilateral diseases had preservation of adrenocortical function. After a mean follow up of 51 months (range: 7-120 months) local recurrence or relapse of the initial diseases was noticed in 6 patients after total adrenalectomy: in 4 patients with Conn's syndrome and bilateral hyperplasia, and in 2 patients with malignant pheochromocytoma and adrenocortical carcinoma, respectively. Our data demonstrate that partial adrenalectomy is a safe procedure not only perioperatively but also in the long-term follow-up.

Nephronophthisis (NPH) is an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and tubular cysts. NPH leads to end-stage renal failure in the first 2 decades of life. Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4. The NPHP1 gene encodes nephrocystin; NPHP2, inversin; NPHP3, nephrocystin-3; and NPHP4, nephrocystin-4. We report 3 siblings from a consanguineous family with NPH who were previously described as carrying a homozygous mutation in the NPHP4 gene. Renal imaging showed cysts in the children. The histological picture of NPHP4 showed the same characteristic features as those known for NPHP1 and NPHP3. Progression to end-stage renal disease occurred between the ages of 17 and 22 years. None of the renal transplants showed recurrence of the disease. Retinitis pigmentosa was absent in all affected family members.

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains. Background Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). Methods Haplotype analaysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. Results In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. Conclusion We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD , in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.

The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of theSDHA,SDHB,SDHC,SDHD,SDHAF2,VHL,RET,TMEM127, andMAXgenes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each inSDHAandSDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.

The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice.Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated.Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation.Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

WOS: 000410676400011, PubMed ID: 28384794, IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation., Deutsche Krebshilfe Grant from the German Cancer Foundation [107995]; Arthur Blank Foundation; Sondra J and Stephen R Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic; Fondazione Cassa di Risparmio di Trento e Rovereto; Janos Bolyai Research FellowshipHungarian Academy of Sciences; National Medical Research CouncilMedical Research Council UK (MRC), This study was supported in part by Deutsche Krebshilfe Grant 107995 from the German Cancer Foundation (Dr Neumann), the Arthur Blank Foundation (Dr Eng), the Sondra J and Stephen R Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic, a grant of the Fondazione Cassa di Risparmio di Trento e Rovereto (Dr Opocher), the Janos Bolyai Research Fellowship (Dr Patocs), and a Transition Award from the National Medical Research Council (Dr Ngeow).

The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using (99m)Tc-[HYNIC, Tyr3]-octreotide (TOC) and 123I-metaiodobenzylguanidine (mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers.All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis.We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malignant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively).SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG SPECT.

The diagnostic confusion in differentiating the various causes of renal cystic diseases in adults is well documented. This confusion can include misclassifications between autosomal dominant polycystic kidney disease (ADPKD) and von Hippel-Lindau disease (VHL). We describe such a case of VHL. A review of the literature and of the patients in our database regarding typical features of each disease, mean age of onset, and frequency of these features was undertaken to provide helpful differentiating features. Pancreatic cysts are one differentiating feature. In VHL, pancreatic cysts can occur in 70% of patients, often are multiple, and rarely may cause exocrine or endocrine insufficiency. Pancreatic islet cell tumors occur. In ADPKD, pancreatic cysts are found in only 9% of patients, usually are single and asymptomatic, generally occur in conjunction with cystic liver disease, and are not found in children or unaffected family members. Pancreatic malignancies do not occur with increased frequency in ADPKD. A different pattern, especially in patients without a strong family history of ADPKD, may be a clue to VHL masquerading as ADPKD. Genetic mutation screening of the VHL gene should be used in these patients.

Summary Because of the excessive production of catecholamines, surgery for pheochromocytoma carries a certain risk that can be reduced by accurate preoperative evaluation and by pretreatment with or blockers. The authors' experience and that of other groups suggests that this inherent risk is not enhanced by the laparoscopic approach, and that, following successful surgery, patients benefit from the minimal invasiveness of this technique. Most surgeons recommend the transperitoneal approach that allows direct access to the adrenal vein, facilitating early ligation. This recommendation does not apply to other pathologies of the adrenal gland. Bilateral adrenal tumors are only seen in patients with familial pheochromocytomas. In this setting, adrenal-sparing surgery should be considered, which can also be performed laparoscopically. Previous adrenal surgery is not a contraindication but will render the procedure more difficult. Laparoscopic excision of paragangliomas is also technically feasible. Laparoscopic adrenal surgery for pheochromocytoma is a difficult and demanding task that must be performed by an experienced surgeon in cooperation with a team of specialists including an internist, endocrinologist, and anesthesiologist.

Background Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. Objective To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. Design and methods We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. Setting Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. Participants Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. Main outcome measures The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. Results Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. Conclusions Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Autosomal recessive polycystic kidney disease (ARPKD) is usually characterized by early onset chronic renal failure due to innumerable dilated collecting ducts. Hepatic fibrosis is an obligate sign. Here, for the first time, we report a 31-year-old female with ARPKD who was diagnosed with symptomatic multiple intracranial aneurysms, a manifestation previously only known to be associated with autosomal dominant polycystic kidney disease (ADPKD).