Two novel cases expanding the phenotype of SETD2-related overgrowth syndrome.

The SETD2-related overgrowth syndrome is also called "Luscan-Lumish syndrome" (OMIM 616831) with the clinical characteristics of intellectual disability, speech delay, macrocephaly, facial dysmorphism, and autism spectrum disorders. We report on two novel patients a 4.5-year-old boy and a 23-year-old female adolescent with a speech and language developmental delay, autism spectrum disorder and macrocephaly, who were both diagnosed with SETD2-related overgrowth syndrome due to de novo frameshift mutations in the SETD2 gene. Features not previously described which were present in either one of our patients were nasal polyps, a large tongue with creases, a high pain threshold, constipation, and undescended testicles. These features may be related to the syndrome and may need special attention in future patients. Additionally, prevention of obesity should be an important point of attention for patients diagnosed with a SETD2-related overgrowth syndrome.

[Fragile X syndrome: new therapeutic strategies]. / Fragiele-X-syndroom: nieuwe therapeutische strategieën.

BACKGROUND: Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy.
AIM: To present an overview of the development of targeted treatment for fxs.
METHOD: Several important publications were collected and indexed.
RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing.
CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement future therapeutic strategies and to facilitate research. In addition, this improves patient care, one example being the recent medical guideline for children with fxs.

Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series.

AIM: To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. METHODS: The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. RESULTS: We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. CONCLUSIONS: There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia.

Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Nonelective colon cancer resections in elderly patients: results from the dutch surgical colorectal audit.

AIMS: The aim of the study was to assess which factors contribute to postoperative mortality, especially in elderly patients who undergo emergency colon cancer resections, using a nationwide population-based database. METHODS: 6,161 patients (1,172 nonelective) who underwent a colon cancer resection in 2010 in the Netherlands were included. Risk factors for postoperative mortality were investigated using a multivariate logistic regression model for different age groups, elective and nonelective patients separately. RESULTS: For both elective and nonelective patients, mortality risk increased with increasing age. For nonelective elderly patients (80+ years), each additional risk factor increased the mortality risk. For a nonelective patient of 80+ years with an American Society of Anesthesiologists score of III+ and a left hemicolectomy or extended resection, postoperative mortality rate was 41% compared with 7% in patients without additional risk factors. CONCLUSIONS: For elderly patients with two or more additional risk factors, a nonelective resection should be considered a high-risk procedure with a mortality risk of up to 41%. The results of this study could be used to adequately inform patient and family and should have consequences for composing an operative team.

Mindfulness-Based Stress Reduction in Pre-symptomatic Genetic Frontotemporal Dementia: A Pilot Study.

Pre-symptomatic frontotemporal dementia (FTD) mutation carriers and first-degree family members that are 50% at-risk for FTD may experience symptoms of anxiety and depression as a result of the ambiguity of when or if symptoms of the disease will manifest. We conducted a pilot study to investigate the use of an online mindfulness-based stress reduction (MBSR) course to reduce symptoms of anxiety and depression in presymptomatic frontotemporal dementia (FTD) mutation carriers and individuals 50% at-risk. Seven known mutation carriers and six individuals 50% at-risk completed a standardized 8-week MBSR course, and filled out pre- and post and two-month follow-up questionnaires. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS). Measures of psychological distress (SCL-90-R), coping style (UCL), quality of life (SF-36) and mindfulness skills (FFMQ) were administered as secondary outcome. Group effects were analyzed with repeated measures ANOVA or Friedman's test, and the individual reliability change index (RCI) was calculated per participant for each outcome measure. Semi-quantitative data included an evaluation and process measure post-intervention. Significant decline was found on the HADS-A post-intervention and after 2 months (p = 0.01), with 54% and 62% of participants demonstrating a clinically significant RCI, respectively. On the HADS-D, significant decline was found 2 months post-intervention (p = 0.04), which was driven by 23% of participants whom had a clinically significant RCI. Additional changes were found between baseline and post-intervention on the seeking distraction and reassuring thoughts subscales of the UCL, the depression and interpersonal sensitivity subscales of the SCL, the observe subscale of the FFMQ, and on physical role limitations of the SF-36 (all p < 0.05). The process evaluation form indicated that the course was found beneficial by participants, and that they applied it in a wide range of everyday situations. This exploratory pilot study indicates the feasibility of MBSR in reducing anxiety and depression in presymptomatic FTD mutation carriers and 50% at-risk individuals. A randomized controlled trial is necessary to replicate these results.

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations.

Early-onset Parkinson's disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin.

Basal forebrain and hypothalamic connection to frontal and parietal cortex in the Rhesus monkey.

Horseradish peroxidase was injected in different parts of the frontal and parietal cortex in 17 rhesus monkeys. In all cases the enzyme was transported retrogradely to neurons in the substantia innominata and hypothalamus as well as in the thalamus. These new findings demonstrate that these cortical areas receive direct afferent fibers from limbic basal forebrain areas concerned with emotion and motivation.

Volume- or outcome-based referral to improve quality of care for esophageal cancer surgery in The Netherlands.

Recently, in The Netherlands esophageal resections for cancer are banned from hospitals with an annual volume less than 10. In this study we evaluate the validity of this specific volume cut-off, based on a review of the literature and an analysis of the available data on esophagectomies in our country. In addition, we compare the expected benefits of volume-based referral to the results of a regional centralization process based on differences in outcome (outcome-based referral).

Surgical adverse outcomes and patients' evaluation of quality of care: inherent risk or reduced quality of care?

BACKGROUND: Previous research has shown that sicker patients are less satisfied with their healthcare, but specific effects of adverse health outcomes have not been investigated. The present study aimed to assess whether patients who experience adverse outcomes, in hospital or after discharge, differ in their evaluation of quality of care compared with patients without adverse outcomes. METHOD: In-hospital adverse outcomes were prospectively recorded by surgeons and surgical residents as part of routine care. Four weeks after discharge, patients were interviewed by telephone about the occurrence of post-discharge adverse outcomes, and their overall evaluation of quality of hospital care and specific suggestions for improvements in the healthcare provided. RESULTS: Of 2145 surgical patients admitted to the Leiden University Medical Center in 2003, 1876 (88%) agreed to be interviewed. Overall evaluation was less favourable by patients who experienced post-discharge adverse outcomes only (average 19% lower). These patients were also more often dissatisfied (OR 2.02, 95% CI 1.24 to 3.31) than patients without adverse outcomes, and they more often suggested that improvements were needed in medical care (OR 2.07, 1.45 to 2.95) and that patients were discharged too early (OR 3.26, 1.72 to 6.20). The effect of in-hospital adverse outcomes alone was not statistically significant. Patients with both in-hospital and post-discharge adverse outcomes also found the quality of care to be lower (on average 33% lower) than patients without adverse outcomes. CONCLUSIONS: Post-discharge adverse outcomes negatively influence patients' overall evaluation of quality of care and are perceived as being discharged too early, suggesting that patients need better information at discharge.

Papillary thyroid carcinoma in a patient with sarcoidosis treated with minocycline.

Long-term treatment with minocycline is occasionally associated with the development of black thyroid syndrome in which thyroid cancer is frequently found. Here, we report a patient with cutaneous, pulmonary and thyroid sarcoidosis who developed papillary thyroid carcinoma in the presence of a black thyroid syndrome after being treated with minocycline for 2.5 years.

[Frankness regarding errors in medical care]. / Openheid over fouten in de gezondheidszorg.

In recent years, increasing attention has been given to the importance of disclosing medical errors. Many physicians are still reluctant to disclose errors and to discuss them with the patient. Recent legislative developments have reduced the existing uncertainty regarding the legal consequences of full disclosure. It is important that physicians are open and honest about the errors they make, that they apologise if necessary, and that measures are taken to prevent the same errors from happening again. Psychological factors hindering the full disclosure of errors require continued attention.

[Guideline 'Differentiated thyroid carcinoma', including diagnosis of thyroid nodules]. / Richtlijn 'Gedifferentieerd schildkliercarcinoom', inclusief de diagnostiek van de schildkliernodus.

Differentiated thyroid carcinoma is a rare disease. Appropriate diagnosis, treatment and follow-up are complex but greatly influence treatment outcomes and patient quality of life. Patients with differentiated thyroid carcinoma present in many hospitals throughout the Netherlands, underscoring the need for uniformity in diagnosis and treatment. This prompted the Dutch Society of Nuclear Medicine and the Dutch Endocrine Society to develop an evidence-based guideline that emphasises not only new scientific developments but also the organisation of care. Thyroid-stimulating hormone (TSH) assessment and fine needle aspiration cytology play a central role in the diagnostic assessment of a patient with a thyroid nodule. Ablation of residual thyroid tissue with radioiodine (1-131) is recommended for all patients who have undergone total thyroidectomy. Follow-up protocols distinguish between patients with a low risk of thyroid-carcinoma recurrence and those with a non-low risk of recurrence.

Effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences after treatment for early-stage invasive breast cancer: a meta-analysis and systematic review.

PURPOSE: To review the effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences in asymptomatic patients after treatment for early-stage invasive breast cancer. METHODS: Systematic review and meta-analysis. The proportion of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients was compared with the proportion of isolated locoregional recurrences in symptomatic patients. RESULTS: Twelve studies that involved a total of 5,045 patients and 378 isolated locoregional recurrences were identified. Pooling data showed an overall estimate of 40% of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients (95% CI, 35 to 45). Of these, 47% (95% CI, 39 to 54) were diagnosed after mastectomy, and 36% (95% CI, 28 to 43) were diagnosed after breast-conserving therapy (relative risk, 1.327; 95% CI, 1.014 to 1.738). Apart from differences in therapy, we have not been able to discern subgroups of patients for whom results were different. CONCLUSION: Approximately 40% of isolated locoregional recurrences are diagnosed during routine visits and routine tests in asymptomatic patients treated for early-stage invasive breast cancer. We could not assess whether these were detected by either physical examination or other tests, nor if the detection of asymptomatic isolated recurrences had any influence on potential for cure or quality of life. As the overall quality of the included studies and the overall incidence of isolated locoregional recurrences are low, this systematic review highlights the need for prospective comparative studies on cost-effective strategies for the follow-up of patients after a diagnosis of breast cancer.

Surgery groups differed in adverse outcome probabilities and can be used to adjust hospital comparisons.

BACKGROUND AND OBJECTIVE: In the Netherlands, all procedures in general surgery are categorized into 12 surgery groups by the Association of Surgeons of the Netherlands. The purpose of this study was to assess whether surgery groups differ in adverse outcome probabilities, to decide whether hospital comparisons on adverse outcomes should be adjusted for differences in surgery groups. METHODS: All surgical patients in one hospital discharged in 1997-1999 were included. Only the first operation during admission was included, with the assumption that successive operations were treatment of adverse outcomes. To avoid bias, only operations with procedures from the same surgery group were included. A total of 6,025 admissions were included and analyzed by a two-step multilevel analysis. RESULTS: Four surgery groups had fewer admissions with adverse outcomes than expected, and two groups had more. After adjustment for patient and operation characteristics, the remaining variance between surgery groups is still large. Similar results were found when differences in mortality were analyzed. CONCLUSION: Surgery group can therefore be used to adjust hospital comparisons for differences in surgical procedure mix.

Perioperative mortality of elective abdominal aortic aneurysm surgery. A clinical prediction rule based on literature and individual patient data.

BACKGROUND: Abdominal aortic aneurysm surgery is a major vascular procedure with a considerable risk of (mainly cardiac) mortality. OBJECTIVE: To estimate elective perioperative mortality, we developed a clinical prediction rule based on several well-established risk factors: age, gender, a history of myocardial infarction, congestive heart failure, ischemia on the electrocardiogram, pulmonary impairment, and renal impairment. METHODS: Two sources of data were used: (1) individual patient data from 246 patients operated on at the University Hospital Leiden (the Netherlands) and (2) studies published in the literature between 1980 and 1994. The Leiden data were analyzed with univariate and multivariate logistic regression. Literature data were pooled with meta-analysis techniques. The clinical prediction rule was based on the pooled odds ratios from the literature, which were adapted by the regression results of the Leiden data. RESULTS: The strongest adverse risk factors in the literature were congestive heart failure and cardiac ischemia on the electrocardiogram, followed by renal impairment, history of myocardial infarction, pulmonary impairment, and female gender. The literature data further showed that a 10-year increase in age more than doubled surgical risk. In the Leiden data, most multivariate effects were smaller than the univariate effects, which is explained by the positive correlation between the risk factors. In the clinical prediction rule, cardiac, renal, and pulmonary comorbidity are the most important risk factors, while age per se has a moderate effect on mortality. CONCLUSIONS: A readily applicable clinical prediction rule can be based on the combination of literature data and individual patient data. The risk estimates may be useful for clinical decision making in individual patients.

Intraoperative guidance in parathyroid surgery using near-infrared fluorescence imaging and low-dose Methylene Blue.

BACKGROUND: Identification of diseased and normal parathyroid glands during parathyroid surgery can be challenging. The aim of this study was to assess whether near-infrared (NIR) fluorescence imaging using administration of a low-dose Methylene Blue (MB) at the start of the operation could provide optical guidance during parathyroid surgery and assist in the detection of parathyroid adenomas. METHODS: Patients diagnosed with primary hyperparathyroidism planned for parathyroidectomy were included. Patients received 0.5 mg/kg MB intravenously directly after start of anesthesia. During the operation, NIR fluorescence imaging was performed to identify parathyroid adenomas. Imaging results were compared with a previous published feasibility study in which 12 patients received MB after intraoperative identification of the adenoma. RESULTS: A total of 13 patients were included in the current study. In 10 of 12 patients with a histologically proven adenoma, the adenoma was fluorescent. Mean signal to background ratio was 3.1 ± 2.8. Mean diameter of the resected lesions was 17 ± 9 mm (range 5-28 mm). Adenomas could be identified up to 145 minutes after administration, which was the longest timespan until resection. Interestingly, in 3 patients, a total of 6 normal parathyroid glands (median diameter 2.5 mm) with a signal to background ratio of 1.8 ± 0.4 were identified using NIR fluorescence imaging. CONCLUSION: Early administration of low-dose MB provided guidance during parathyroidectomy by identifying both parathyroid adenomas and normal parathyroid glands. In patients in whom difficult identification of the parathyroid adenoma is expected or when normal glands have to be identified, the administration of MB may improve surgical outcome.

Yeast artificial chromosome cloning of the Xq13.3-q21.31 region and fine mapping of a deletion associated with choroideremia and nonspecific mental retardation.

Microscopically detectable deletions and X;autosome translocations have previously facilitated the construction of a high-resolution interval map of the Xq21 region. Here, we have generated three yeast artificial chromosome contigs spanning approximately 7 megabases of the Xq13.3-q21.31 region. In addition, a novel deletion associated with choroideremia and mental retardation was identified and mapped in detail. The proximal deletion endpoint was positioned between the loci DXS995 and DXS232, which enabled us to confirm the critical region for a locus involved in mental retardation. The distal deletion endpoint is situated in the Xq21.33 band, which allowed us to refine the order of several markers in this region.