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It is well documented that deteriorating heart function due to deposition of ceroid lipopigment is a significant co-morbidity in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease) although the exact disease mechanisms remain unknown in any NCL form. An increasing frequency of cardiac conduction disorders including severe bradycardia and sinus arrest is seen in the late teens, as is a left ventricular hypertrophy in the early 20s. Only a few case reports of pacemaker implantation have been published, and so far, no long-term follow-up study exists. As new treatment options emerge, more patients will live longer and the need for pacemaker will likely increase, why knowledge of long-term outcome is needed. In the present study, we present the course of six patients from the original Danish CLN3-heart population study (n = 29) published in 2011 in whom pacemaker implantation was indicated from a cardiac point of view. In two cases, the families deselected pacemaker implantation. In four males, aged 19-29 years, all having a good general condition, a dual-chamber pacemaker (St. Jude Medical™ Accent/Assurity MRI™) was implanted in general anesthesia without any complications. At follow-up 9 years later, three were still alive. According to the parents' opinion they still have a good quality of life, now 26, 30, and 36 years old. Pacemaker treatment is safe and may have great impact on quality of life. However, the medical indication for pacemaker treatment is relative and it is important that various aspects, including the patient's general condition and family preferences, are thoroughly discussed before making the final decision.

Background Low-grade optic pathway glioma (OPG) develops in 15–20% of children with neurofibromatosis type 1 (NF1). OPGs are symptomatic in 30–50% and one-third of these require treatment. A few studies have suggested female sex as a risk factor for visual impairment associated with NF1-OPG. This descriptive study investigated the correlation between NF1-OPG growth, sex and visual impairment. Method We based our cross-sectional study on a systematic, retrospective data collection in a NF1 cohort of children and adolescents below 21 years of age followed at Center for Rare Diseases, Aarhus University Hospital, Denmark. For each patient with OPG a medical chart review was performed including demographics, ophthalmological examinations and magnetic resonance imaging (MRI) of OPG. Results Of 176 patients with NF1 (85 females, 91 males), we identified 21 patients with OPG (11.9%) with a preponderance of females, p = 0.184. Eight females (62%) and one male (13%) had visual impairment at the last ophthalmological evaluation. Five out of 21 children with OPG (24%) underwent diagnostic MRI because of clinical findings at the ophthalmological screening. Nine children (43%) had symptoms suggestive of OPG and seven (33%) experienced no OPG-related symptoms before the diagnostic MRI. Of eight children diagnosed with OPG ≤ two years of age, one had visual impairment. Of 13 children diagnosed > two years of age, eight had visual impairment; in each group, four of the children were treated with chemotherapy. The study suggested no correlation between NF1-OPG growth and sex. Conclusion Our data suggest sex as a risk factor for visual impairment, while an OPG diagnose ≤ two years of age was a protective factor for visual impairment. Females with NF1-OPG had a higher prevalence of visual impairment outcome compared to males. Interestingly, our data also suggest a better response to treatment in children with OPG diagnosed ≤ two years of age compared to older children. The findings in our study suggest sex as a potential prognostic factor for visual impairment.

PurposeThe Danish neurofibromatosis 1 (NF1) cohort was initiated to study health-related, socioeconomic and psychological consequences of living with the monogenetic disorder NF1 using a nationwide and population-based approach.ParticipantsThe cohort includes all 2467 individuals in Denmark who were hospitalised with or due to NF1 from 1977 to 2013 or registered in the RAREDIS Database (1995–2013), a national clinical database for rare diseases, or both. A comparison cohort matched to individuals with NF1 on sex and date of birth was identified in the Civil Registration System (n=20 132).Findings to dateAll cohort members were linked to the unique Danish registries to obtain information on hospital contacts, birth outcomes, education and partnership. A questionnaire was completed by 244 of the 629 adult cohort members with NF1 registered in the RAREDIS Database to evaluate the psychosocial and emotional burden. Further, neuropsychological tests were performed on 103 adult cohort members with NF1 and 38 adult population comparisons. To date, six studies have been published. Individuals with NF1 had an increased risk for (1) hospitalisation for disorders affecting all organ systems of the body throughout all decades of life, (2) psychiatric disorders, (3) attaining a short or medium long education and (4) not forming a life partner. Women with NF1 had an increased risk for spontaneous abortions and stillbirths. Finally, adults with NF1 had an impaired quality of life and a high need for professional support for physical, psychological and work-related problems, which was partly associated with disease severity and visibility.Future plansThe cohort will regularly be updated with newly diagnosed patients in the RAREDIS Database as well as with outcome information in the Danish registries. New studies are in progress to assess other medical and socioeconomic dimensions of living with NF1.

Introduction: Children treated for cancer with a central venous catheter are often bothered by scarring. We studied whether glucocorticosteroid during patch occlusion has a beneficial effect on scar outcome in children and adolescents treated for neoplastic disease. Methods: A double-blinded placebo-controlled randomized clinical trial was performed. The main outcome was the Vancouver Scar Scale (VSS). Secondary outcomes were scar width and scar quality measured using the Patient and observer scar assessment (POSAS). The patients were divided into an intervention groups and a control group. The intervention group was randomized into two groups; Active and placebo group. The active treatment consisted of cream with glucocorticosteroid and fusidic acid. The placebo treatment consisted of cream with fusidic acid. Both groups were also treated with a silicone gel patch for three months after central venous catheter removal. The control group did not receive any specific skin care. Results: Assessment at 6 months were completed for 44 in the intervention group (21 in the active and 23 in the placebo group) and 47 in the comtrol group. The intervention group had a significantly lower VSS and a smaller scar compared to the control group (p = 0.00, p = 0.02). The POSAS by the patients and the study nurse showed no significant difference between the intervention and control groups (p = 0.84, p= 0.36). Conclusions: Silicone gel sheet alone or in combination with application of glucocorticosteroid during sheet occlusion improved scar outcome after removal of central venous catheter in children treated for neoplastic diseases.

BackgroundThe mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications.MethodA systematic retrospective data collection in a MNF1 cohort from one of two Danish national centers of NF1 Expertise was completed. Data collected included demographics, clinical features including NF1 diagnostic criteria and NF1-associated complications. Recent literature in the field was reviewed.ResultsWe identified 17 patients with MNF1 with a median age of 37 years [4; 66]. Eleven (65%) were females. Five patients (30%) had a plexiform neurofibroma. The median age at detection of plexiform neurofibroma was 30 years [14; 60]. Nine (53%) had at least one NF1-related complication; scoliosis, hypertension, ADHD, learning disability, language delay, autism and delay in gross and fine motor function development. We reviewed nine articles. In total, 126 cases were described within three case-series. Nineteen (15%) had a plexiform neurofibroma and in total, 23 NF1-associated complications were reported including language delay, learning disability and skeletal abnormalities. Furthermore, from the literature it was evident that the diagnosing of MNF1 varies among physicians and across countries.ConclusionPatients with MNF1 present with plexiform neurofibromas and other NF1-related complications with a frequency requiring that follow-up of MNF1 patients should be in accordance with the standard NF1 guideline in both childhood and adulthood. Physicians should be aware of cognitive impairment as a complication to MNF1. To develop a specific MNF1 follow-up guideline, there is a need for an international consensus on the diagnostic criteria for MNF1 and a follow-up study conducted in a larger MNF1 cohort.

This case report describes a three-year-old boy with delayed development of language, who developed erythema migrans. Soon after peroral antibiotics was initiated, he also had loss of motoric function, and he developed ataxia. Neuroborreliosis was diagnosed, and antibiotic treatment was changed to intravenous. There was no gain of his motoric skills. A test was made for lysosomal storage disease, and neuronal ceroid lipofuscinosis type 2 was found. The patient started intraventricular enzyme substitution treatment as the first patient in Denmark. Treatment has shown to reduce the progression of functional decline.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden.

Background When an infection is suspected in a child with cancer and a central venous line (CVL), cultures are often only obtained from the CVL and not from a peripheral vein (PV). This study was undertaken to evaluate the importance of concomitant blood cultures from the CVL and a PV. Procedure Clinical data and the results of all cultures taken concomitantly from the CVL and a PV were registered prospectively in children admitted with fever from April 2008 to December 2012 at the Department of Pediatrics at Aarhus University Hospital Skejby. Results During the study period 654 paired cultures obtained from the CVL and from a PV within two hour of each other were included. A true bloodstream infection (BSI) was registered in 112 episodes. In 20 (17%) out of 112, true BSI growth of a microorganism was detected only in the culture from a PV including seven cases of Escherichia coli and three cases of Staphylococcus aureus. In 52 episodes the same microorganism was cultured from both the CVL and a PV. Twenty-four of these episodes were classified as catheter-related bloodstream infections (CRBSI) using differential time to positivity. In total, 64 (57%) of all true BSI were defined as CRBSI. Conclusions Blood cultures should be obtained from a PV in addition to cultures from CVL at the onset of fever in pediatric patients with cancer in order to maximize the findings of true BSIs. The frequency of CRBSI may be over-estimated if blood cultures are drawn from CVL only. Pediatr Blood Cancer 2015;62:99–102. © 2014 Wiley Periodicals, Inc.

Central venous catheters (CVC) are an inevitable part of thetreatment of children with cancer. Although many attempts havebeen made to reduce the risk of catheter-related infections, CVCsremain a major risk factor of bloodstream infections [1–4]. Stud-ies have shown that biofilm develops quickly once a CVC isinserted into a patient [5]. Bacteria living in a biofilm can bevery difficult to eradicate and are likely to be involved in casesof recurrent CRBSI [5,6].Heparin is often used to lock the catheter to prevent clottingwhen the catheter is not in use although heparin may enhance thegrowth of bacteria and the biofilm formation [7]. A Cochranereview has found prophylactic antibiotic catheter-lock to be ben-eficial in preventing CRBSI, but it is not routinely recommendeddue to the risk of selecting resistant microorganisms [8,9].Taurolidine is derived from the naturally occurring amino-sulphonic acid taurinamide and formaldehyde [10]. Taurolidineand its active metabolites contain an activeN-methylol groupthat cross-links with the protein part of the bacterial cell walland thereby neutralizes endotoxins and probably also to someextent exotoxins [11,12]. Taurolidine has also been reported tohave anti-adherence properties [13] and may reduce biofilmformation [14–16]. The substance has shown a broad spectrumof antimicrobial activity against both gram-positive and gram-negative bacteria as well as fungi. Taurolidine used as a cathe-ter-lock has shown efficacy in preventing CRBSI in adultpatients [17,18]. One non-randomized study of the use oftaurolidine as a catheter-lock in children with cancer reducedthe rate of gram-positive bloodstream infections [19]. Nointrinsic microbial resistance towards taurolidine has beenreported [20].We report the result of a prospective, randomized, controlledopen-label study in which CVCs locked with a taurolidine solu-tion were compared to CVCs locked with a standard heparinsolution.

Background High-dose cytarabine has been associated with a high frequency of viridans group streptococcal (VGS) bacteraemia. VGS bacteraemia causes considerable morbidity and mortality. The Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML protocols use higher cumulated doses of cytarabine and more chemotherapy series (n = 6) than other protocols with the potential increased risk of severe VGS infections. Procedure Medical records of all Danish children enrolled on the NOPHO-AML-2004 protocol between January 2004 and September 2011 (n = 45) were retrospectively reviewed and all febrile episodes were registered. Results Following 236 courses of chemotherapy, 112 positive blood cultures were registered. VGS were found in 38% of all positive blood cultures. Infectious episodes with VGS resulted in more days of fever and intravenous antibiotic therapy compared with infections caused by other microorganisms. VGS were involved in 45% of all episodes categorized as sepsis (n = 51) and in 67% of life-threatening bloodstream infections (n = 9). Penicillin resistance was found in 40% of the VGS strains. No significant difference was observed in the proportion of VGS isolated following courses with low-dose cytarabine versus courses with high-dose cytarabine. Conclusions VGS were the most commonly isolated pathogens causing the most severe infections and the majority of life-threatening infections. A substantial proportion of the strains were resistant to penicillin. The high rate of VGS seemed independent of high-dose cytarabine but was more likely caused by the intensive chemotherapy treatment leading to severe mucositis and neutropenia. Pediatr Blood Cancer 2013; 60: 1154–1160. © 2012 Wiley Periodicals, Inc.

The purpose of the study was to assess the risk of first-time bloodstream infection (BSI) according to type of central venous catheter (CVC) during induction therapy in children with acute lymphoblastic leukemia (ALL). Patients eligible for our analysis were all newly diagnosed children with ALL treated at 3 pediatric centers in Denmark between 2008 and 2014. A total of 136 patients were followed from initial CVC placement until first BSI, CVC removal, death, or day 28, whichever occurred first. Thirty-nine BSIs were detected, of which 67% were gram-positive infections, and 59% met the criteria for being CVC associated. The 28-day cumulative incidence of BSI was similar in 77 patients with a nontunneled CVC (28%; 95% confidence interval, 19%-40%) and in 59 patients with a tunneled CVC with external lines (TE) (33%; 95% confidence interval, 23%-47%). Subgroup analyses showed that gram-negative blood isolates occurred more frequently in patients with a TE, and that lower incidences of BSI were detected in patients older than 9 years with a TE, and in patients with T-ALL. It is concluded that the type of CVC inserted at diagnosis has no impact upon the risk of BSI in patients with ALL undergoing induction therapy.

When an infection is suspected in a child with cancer and a central venous line (CVL), cultures are often only obtained from the CVL and not from a peripheral vein (PV). This study was undertaken to evaluate the importance of concomitant blood cultures from the CVL and a PV.Clinical data and the results of all cultures taken concomitantly from the CVL and a PV were registered prospectively in children admitted with fever from April 2008 to December 2012 at the Department of Pediatrics at Aarhus University Hospital Skejby.During the study period 654 paired cultures obtained from the CVL and from a PV within two hour of each other were included. A true bloodstream infection (BSI) was registered in 112 episodes. In 20 (17%) out of 112, true BSI growth of a microorganism was detected only in the culture from a PV including seven cases of Escherichia coli and three cases of Staphylococcus aureus. In 52 episodes the same microorganism was cultured from both the CVL and a PV. Twenty-four of these episodes were classified as catheter-related bloodstream infections (CRBSI) using differential time to positivity. In total, 64 (57%) of all true BSI were defined as CRBSI.Blood cultures should be obtained from a PV in addition to cultures from CVL at the onset of fever in pediatric patients with cancer in order to maximize the findings of true BSIs. The frequency of CRBSI may be over-estimated if blood cultures are drawn from CVL only.

To determine if the catheter lock taurolidine can reduce the number of catheter-related bloodstream infections (CRBSI) in pediatric cancer patients with tunneled central venous catheters (CVC).During a study period of 34 months, 129 newly placed tunneled CVCs in 112 patients were randomly assigned to standard lock with heparin solution or experimental lock with a taurolidine solution (ClinicalTrials.gov Identifier NCT00735813).Sixty-five CVCs were included in the standard group and 64 CVCs in the experimental group. The groups were comparable regarding patients' characteristics. A total number of 72 bloodstream infections of which 33 were CRBSIs were observed during 39,127 CVC-days. A lower rate of CRBSI (0.4 per 1,000 CVC-days) was observed in the experimental arm compared with the standard arm (1.4 per 1,000 CVC-days, incidence rate ratio (IRR) = 0.26; 95% confidence interval (CI) 0.09-0.61; P = 0.001). A lower rate of total bloodstream infections (1.2 per 1,000 CVC-days) was also observed in the experimental arm compared with the standard arm (2.5 per 1,000 CVC-days, IRR = 0.49; 95% CI 0.29-0.82; P = 0.004). Median interval from catheter insertion until first CRBSI was significantly lower in the standard group (156 days, range 12-602) compared with the experimental group (300 days, range 12-1,176; P = 0.02). Premature removal of the CVC due to infection and overall CVC survival were similar in the two study groups.Locking of long-term tunneled CVC with taurolidine significantly reduces catheter-related bloodstream infections in children with cancer.

High-dose cytarabine has been associated with a high frequency of viridans group streptococcal (VGS) bacteraemia. VGS bacteraemia causes considerable morbidity and mortality. The Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML protocols use higher cumulated doses of cytarabine and more chemotherapy series (n = 6) than other protocols with the potential increased risk of severe VGS infections.Medical records of all Danish children enrolled on the NOPHO-AML-2004 protocol between January 2004 and September 2011 (n = 45) were retrospectively reviewed and all febrile episodes were registered.Following 236 courses of chemotherapy, 112 positive blood cultures were registered. VGS were found in 38% of all positive blood cultures. Infectious episodes with VGS resulted in more days of fever and intravenous antibiotic therapy compared with infections caused by other microorganisms. VGS were involved in 45% of all episodes categorized as sepsis (n = 51) and in 67% of life-threatening bloodstream infections (n = 9). Penicillin resistance was found in 40% of the VGS strains. No significant difference was observed in the proportion of VGS isolated following courses with low-dose cytarabine versus courses with high-dose cytarabine.VGS were the most commonly isolated pathogens causing the most severe infections and the majority of life-threatening infections. A substantial proportion of the strains were resistant to penicillin. The high rate of VGS seemed independent of high-dose cytarabine but was more likely caused by the intensive chemotherapy treatment leading to severe mucositis and neutropenia.

Taurolidine has demonstrated inhibition of biofilm formation in vitro. The aim of this study was to compare the effect of catheter locking with taurolidine vs heparin in biofilm formation in central venous catheters. Forty-eight children with cancer were randomized to catheter locking by heparin (n = 22) or taurolidine (n = 26), respectively. After removal, catheters were examined by standardized scanning electron microscopy to assess quantitative biofilm formation. Biofilm was present if morphologically typical structures and bacterial cells were identified. Quantitative and semi-quantitative cultures were also performed. Biofilm was identified in 23 of 26 catheters from the taurolidine group and 21 of 22 catheters from the heparin group. A positive culture was made of six of the catheters locked with taurolidine and heparin, respectively (p = 0.78). The rate of catheter-related bloodstream infections (CRBSI) was 0.1 per 1000 catheter-days using taurolidine and 0.9 per 1000 catheter-days using heparin (p = 0.03). This randomized trial confirmed that the use of taurolidine as catheter-lock compared with heparin reduced the rate of CRBSIs; this reduction was not related to a reduction in the intraluminal biofilm formation and the rate of bacterial colonization detected by scanning electron microscopy in the two groups.

Central venous catheters (CVC) are an essential part of the treatment of children with haematological and oncological diseases. Unfortunately, CVC also represent a major risk factor of bloodstream infections. Catheter-related bloodstream infections (CRBSI) in children are often diagnosed based on blood cultures from the CVC only. Most CRBSI can be treated without catheter removal. On suspicion of CRBSI empirical antibiotic treatment with piperacillin-tazobactam, meropenem or ampicillin in combination with gentamicin is recommended. The systemic treatment can be combined with catheter-lock therapy.

A six-month old girl presented with repetitive episodes of vomiting. Soon after admission to hospital she had convulsions. Computertomography showed a tumour in the third ventricle. She was non-radically operated. Histology showed an atypical teratoid/rhabdoid tumour (AT/RT). No active treatment was initiated, and the patient died three months later. AT/RT is a very rare tumor of the brain. It occurs primarily in early childhood. AT/RT is a very aggressive and rapidly progressing tumour.