Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Monitoring of regional tissue oxygenation with near-infrared spectroscopy during the early postoperative course after superior cavopulmonary anastomosis.

OBJECTIVES: Near-infrared spectroscopy (NIRS) offers continuous non-invasive monitoring of regional tissue oxygenation. We evaluated NIRS monitoring during the postoperative course after superior cavopulmonary anastomosis in patients with hypoplastic left heart syndrome and anatomically related malformations. METHODS: Cerebral (cSO(2)) and somatic (sSO(2)) tissue oxygenations were recorded for 48 h and compared with routine measures of intensive care monitoring. Changes in parameters in the case of postoperative complications were evaluated. RESULTS: Data were obtained from 32 patients. Median age at operation was 2.9 (1.5-10.0) months and weight was 5.3 ± 1.0 kg. Postoperative complications occurred in 7 patients (pulmonary artery thrombus n = 4, pneumothorax n = 1, cardiopulmonary resuscitation n = 1 and low-cardiac output n = 1). cSO(2) was 44 ± 14% at the end of the operation and reached its minimum of 40 ± 11% 2 h later (P = 0.018). Overall, cSO(2) was depressed early after surgery and increased from a mean of 42 ± 11% during the first 4 postoperative hours to 57 ± 8% in the last 4 h of the study period (P < 0.001). The sSO(2) decreased from 77 ± 11% during the early postoperative course to 68 ± 9% within the later course (P < 0.001). The cSO(2) correlated with the arterial partial pressure of oxygen (pO(2), r = 0.364, P < 0.001), with the arterial oxygen saturation (SaO(2), r = 0.547, P < 0.001) and with the central venous oxygen saturation providing the strongest correlation (SvO(2), r = 0.686, P < 0.001). Analysis of agreement between cSO(2) and SvO(2) measurements revealed a mean bias of 0.97 with limits of agreement between 19.8 and -17.9%. Inclusion of both cSO(2) and sSO(2) into a linear regression model slightly improved the prediction of SvO(2) from NIRS values (r = 0.706, P < 0.001). The mean values of cSO(2), sSO(2), SaO(2) and SvO(2) during the early postoperative period were lower in patients with complications (cSO(2): 45 ± 9 vs 29 ± 5%, P < 0.001; sSO(2): 80 ± 11 vs 70 ± 6%, P = 0.004; SaO(2): 76 ± 8 vs 66 ± 6%, P = 0.004; SvO(2): 48 ± 14 vs 32 ± 6%, P < 0.001). CONCLUSIONS: NIRS technology allows inferring the global oxygenation from continuous non-invasive measurements of regional tissue oxygenation. The cSO(2) is lowered in the early postoperative course. Lower cSO(2) values in the early postoperative course may be predictive of postoperative complications.

Digital necroses and vascular thrombosis in severe spinal muscular atrophy.

Infantile spinal muscular atrophy (SMA) caused by homozygous SMN1 gene deletions/mutations is characterized by neuronal loss and axonopathy of motor neurons. We report two unrelated patients with severe SMA type I who had only one SMN2 copy and developed ulcerations and necroses of the fingers and toes. Sural nerve biopsy was normal in patient 1, whose affected skin displayed necroses and thrombotic occlusions of small vessels. Corresponding to a mouse model and other patients with similar findings, we believe that severe survival motor neuron (SMN) deficiency may present as vasculopathy.

Hypothermia in a combined intoxication with doxepin and moclobemide in an adolescent.

OBJECTIVE: Intoxication with antidepressants, frequently encountered in pediatric emergency medicine, can often lead to life threatening situations. While hyperthermia, hypertonicity and rigidity are symptoms indicative of a serotonin syndrome triggered by an intoxication with serotonin reuptake inhibitors or monoamine oxidase inhibitors, cardiotoxicity, coma and ECG changes are typical of an intoxication with tricyclic antidepressants. CASE REPORT: Hypothermia (instead of the expected hyperthermia) is described for the first time as a persistent symptom during the course of a combined moclobemide-doxepin intoxication in an attempted suicide of a 16-year-old adolescent. DISCUSSION: The administration of serotonin reuptake inhibitors alone or in combination with other medication which increases the level of 5-hydroxytryptamine, i.e. serotonin, in the synaptic cleft mainly leads to hyperthermia. According to a recent study, however, the application of a selective 5-HT(1a) agonist to transgenic mice with a prominent overexpression of the 5-HT(1a) receptor lead to immobility and hypothermia. These findings might help to explain the hypothermia observed in the case of the intoxicated 16-year-old. CONCLUSION: Intoxication with antidepressants should not be excluded a priori in a hypothermic patient who displays other clinical signs of the said intoxication.

Norovirus infections in preterm infants: wide variety of clinical courses.

BACKGROUND: Norovirus is an important cause of nonbacterial acute gastroenteritis in all ages. Atypical courses are described. Clinical symptoms are diarrhea, vomiting, nausea, abdominal cramps, fever and malaise. Apart from three recent short reports we describe for the first time an outbreak of norovirus in a tertiary Neonatal Intensive Care Unit. FINDINGS: The typical symptoms of norovirus infection are in part also seen in premature born infants but with a different pattern and a huge variety of clinical courses. Vomiting is not the main symptom of norovirus infection in premature infants but distended abdomen and other symptoms such as apnea, gastric remainders or sepsis like appearance. The course in premature born patients could be explained by an immunocompromised mice model. Extensive hygienic measures were necessary to control the outbreak without closing the Neonatal Intensive Care Unit. CONCLUSION: Norovirus infection in premature infants shows an impressive pattern of a wide variety of clinical courses. Only the consequent use of different hygienic pattern can lead to elimination of norovirus.

Outcome of very low birthweight infants after introducing a new standard regime with the early use of nasal CPAP.

In this paper, a retrospective study was performed to find out whether the introduction of early nasal continuous positive airway pressure (nCPAP) as a new standard regime of very low birthweight infants will lead to a decreasing tracheal intubation and ventilation rate, as well as to a lower incidence of bronchopulmonary dysplasia in a tertiary-level perinatal centre. Ninety-three infants (study group) with early nCPAP as the first respiratory support were compared to 63 infants (historical control group) born before the use of early nCPAP. No statistically significant differences were found in the baseline characteristics. The main results of the study include reduced intubation mainly in infants with a birthweight <1,000 g (study group): 58% vs. 81% (p < 0.05). The mean duration of ventilation was 248 h (control group) vs. 128 h (study group) (p < 0.001) and 437 h vs. 198 h in infants <1,000 g (p < 0.001). There was significantly reduced incidence of bronchopulmonary dysplasia from 55% to 18% for all surviving infants (p < 0.001), and for infants <1,000 g, it was 90% vs. 30% (p < 0.001). No significant differences for other outcome criteria were noted, but a significant reduction in the use of central i.v. lines, fluids, drugs, volume expansion, sedation, catecholamines, surfactant, steroids and buffer, as well as antibiotics, was observed (p < 0.05). Therefore, we can conclude that early nCPAP is an easy-to-use and safe procedure for very low birthweight infants to treat respiratory distress.

Impedance index or standard anthropometric measurements, which is the better variable for predicting fat-free mass in sick children?

AIM: To compare the predictive value of impedance index (ZI, height2/impedance) with anthropometric measurements for estimating fat-free mass (FFM). METHODS: FFM of 120 white paediatric children (46 males, 74 females), aged 2.5-18 years was measured by using dual energy X-ray absorptiometry. Weight, height, mid-upper arm circumference (MUAC), skinfold thickness (biceps, triceps, subscapular and suprailiac) and bioelectrical impedance were also obtained. Stepwise multiple regression analysis and residual plots were performed to determine the most significant variables to predict FFM. RESULTS: The single best predictor of FFM was ZI, which explained 96.2% of the variance in FFM (r = 0.981, SEE = 2.15 kg). Addition of weight to the model containing ZI increased the explained variance of FFM to 96.6% (r = 0.983, SEE = 2.03 kg). BMI and MUAC were the poorest predictors of FFM: r = 0.422, SEE = 10.2 kg and r = 0.621, SEE = 8.93 kg, respectively. CONCLUSION: Impedance index is a more significant single predictor of FFM than other anthropometric measurements. The predictive accuracy of bioelectrical impedance analysis-based prediction equations for FFM was improved by addition of weight.

Use of bioelectrical impedance analysis and anthropometry to measure fat-free mass in children and adolescents with Crohn disease.

OBJECTIVES: To investigate the precision of published prediction equations for fat-free mass (FFM) from bioimpedance measurements in children with Crohn disease using dual-energy X-ray absorptiometry (DXA) as an in vivo gold standard. METHODS: Fat-free mass of 49 white boys and girls ages 7.3 to 16.9 y suffering from Crohn disease was measured by DXA. Body weight, height and bioimpedance measurements were also collected. FFM measured by DXA (FFM(DXA)) was compared with FFM predicted by the only 5 published prediction equations available for children and adolescents. An equation was developed for predicting FFM and was validated using a bootstrap method. RESULTS: When correlating predicted FFM with FFM(DXA), Schaefer's equation showed the highest R2 (0.950), the smallest standard error of estimate (SEE) (2.05 kg) and the smallest percentage error (0.28%). Our prediction equation for estimating FFM was FFM = 0.652 Ht2/Z + 0.0385 Wt + 0.586 Age - 0.327, R2 = 0.951, SEE = 2.08, P < 0.0005, where Ht2/Z is the impedance index in cm2/ohm, Wt is body weight in kilograms, age is in years. R2 value from bootstrap method was 0.950 +/- 0.01 (95% confidence interval 0.927-0.968), indicating an acceptable validation of the derived formula. CONCLUSIONS: The formula of Schaefer is the best for predicting FFM. The present study provides a new prediction equation for estimating FFM in children with Crohn disease that may be used in clinical settings in which more sophisticated body composition measuring equipments are not available.

Body composition of preterm infants measured during the first months of life: bioelectrical impedance provides insignificant additional information compared to anthropometry alone.

UNLABELLED: Detailed knowledge of body composition in preterm neonates during their later postnatal period may be important for the treatment process. However, little consideration has been given to test whether bioelectrical impedance analysis (BIA) is a useful bedside method to predict fat-free mass (FFM). The aim of the study is to assess whether BIA is a bedside method to measure FFM in preterm neonates. FFM of 118 white subjects (51 males, 67 females), mean gestational age of 30.1+/-3.1 weeks and birth weight of 1.26+/-0.47 kg, was measured at a gestational age of 38.6+/-3.8 weeks and actual body weight of 2.6+/-0.54 kg using dual energy X-ray absorptiometry (FFM(DXA)). Weight (W), height (Ht), and bioelectric impedance (I) measurements were collected. Multiple regression analysis was performed to develop prediction equations to estimate FFM with impedance index (Ht(2)/I, cm(2)/Omega) and W (kg) as predictor variables. Bootstrap analysis was performed for validating the derived prediction equations. Correlations between FFM(DXA) and weight were 0.96, 0.98, and 0.97 in boys, girls, and both sexes, respectively. Those between FFM(DXA) and Ht(2)/I were: 0.73, 0.81, and 0.79. Equations used to predict FFM (kg) were for boys: FEM = 0.05Ht(2)/I + 0.68W + 0.40(R2 = 0.919) and for girls: FFM = 0.04Ht(2)/I + 0.71W + 0.29(R2 = 0.957). CONCLUSIONS: In preterm neonates, weight is a more effective predictor of FFM than impedance index. The study provides a bedside procedure for estimating FFM, mainly based on anthropometric parameters rather than BIA.

Restrictive dermopathy associated with transposition of the great arteries and microcolon: a rare neonatal entity with new symptoms.

BACKGROUND: Restrictive dermopathy is a very rare autosomal recessive skin disorder. The typical pathologic findings are striking: microstomia, micrognathia, thin but very tight translucent skin that tears spontaneously, and arthrogryposis multiplex. The mechanisms behind this disease are unknown. OBSERVATIONS: We describe for the first time a newborn girl with restrictive dermopathy, transposition of the great vessels, and microcolon. She had thin shiny skin with nearly no compliance indicating restrictive dermopathy. Additional dysmorphic findings included enlarged fontanelle, hypertelorism, absent eyelashes, small pinched nose, microstomia, micrognathia, dysplastic ears, pterygium colli, dyplastic fingers and toes with upper- and partial lower-limb flexion contractures, dysplastic genitalia, and muscular hypotonia. She also had left transposition of the great artery with small atrial septal defect, bilateral hypoplasia of the first rib, and congenital stenosis of the small bowel with microcolon. CONCLUSIONS: The pathogonomic diagnostic features remain reduced dermal thickness and nearly complete absence of elastic fibers in the dermis. In mice, a defective fatty acid transport protein 4 gene (Fatp4) leads to clear signs of restrictive dermopathy by influencing the arrangement of the lipids in the epidermis. Whether the left transposition of the great artery is associated with restrictive dermopathy or represents an additional malformation of multifactorial, polygenetic, or monogenetic cause remains open.

Tendonitis in variant hyperimmunoglobulinaemia D and periodic fever syndrome--a rare disease with a new symptom.

UNLABELLED: Hyperimmunoglobulinaemia D syndrome (HIDS) is defined as recurrent fever, generalised lymphadenitis, abdominal pain, arthritis and raised polyclonal serum IgD >100 IU/ml. The cause is a mutation in the mevalonate kinase gene. Other periodic fever syndromes are known. We report a new patient and describe orbital tendonitis as a hitherto unreported symptom CONCLUSION: Without any underlying cause, the tendonitis must be seen as new symptom of variant hyperimmunoglobulinaemia D syndrome. We speculate that the inflammation of the Tenon spatium is similar to the process of inflammation of the connective tissue in the joint in hyperimmunoglobulinaemia D syndrome where deposits of C3 and IgM are present. Variant hyperimmunoglobulinaemia D syndrome can be present in one family.

Renal excretion of 8-oxo-7,8-dihydro-2(')-deoxyguanosine: degradation rates of RNA and metabolic rate in humans.

Renally excreted 8-oxo-7,8-dihydro-2(')-deoxyguanosine (oxo(8)dG) is a potential marker of oxidative DNA damage by reactive oxygen species. Whole-body degradation rates of t- and rRNA are potential indicators of the resting metabolic rate (RMR). Excretion rates of oxo(8)dG and degradation rates of t- and rRNA were determined in healthy non-smoking adults and children. RMR (indirect calorimetry; 14 children, 16 adults), total energy expenditure (TEE; doubly labelled water technique; 4 children, 6 adults), and lean body mass (LBM; dual-energy X-ray absorptiometry; 14 children, 16 adults) were also measured. Degradation of t- and rRNA (micromol/d/kg LBM; 4 children, 6 adults) was highly correlated with RMR (kJ/d/kg LBM), r=0.867 (p<0.005) and 0.959 (p<0.001), respectively. Excretion of oxo(8)dG (pmol/d/kg LBM; 14 children, 16 adults) was not significantly correlated with RMR (p>0.05). Neither excretion of oxo(8)dG nor degradation of RNA was significantly correlated with TEE (kJ/d/ kg LBM) (p>0.05). In healthy subjects further factors, other than the metabolic rate, seem to influence the excretion rate of oxo(8)dG. The degradation rates of t- and rRNA seem to be appropriate indicators of the RMR.