Leguin, M.

ACTA2 Mutation With Childhood Cardiovascular, Autonomic and Brain Anomalies and Severe Outcome (Article)

2013-04-30T00:00:00Z

Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFβ-receptor 1- and -2 genes, the SMAD3 and TGFβ2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.

RTTN mutations link primary cilia function to organization of the human cerebral cortex (Article)

2012-09-07T00:00:00Z

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.

Single-balloon enteroscopy, magnetic resonance enterography, and abdominal US useful for evaluation of small-bowel disease in children with (suspected) Crohn's disease (Article)

2012-01-01T00:00:00Z

The usefulness of single-balloon enteroscopy (SBE) has not been evaluated in children with known or suspected Crohn's disease (CD). The objectives of this study are to evaluate the diagnostic yield of SBE for pediatric CD by comparing it with US and magnetic resonance enterography (MRE). Single-center prospective study. Tertiary-care referral hospital. Between February 2009 and April 2010, 20 pediatric patients (ages 8-18 years) with suspected inflammatory bowel disease (IBD) or with a previous diagnosis of CD with suspected persistent small-bowel disease were enrolled. All patients underwent proximal and distal SBE, 17 patients also underwent US combined with Doppler flow measurements, and 18 underwent MRE. The findings of US with Doppler flow measurements and MRE were compared with those with SBE. The mean patient age was 15.0 years (range 11.3-18 years, 70% male). Of 14 patients with suspected IBD, 8 had a diagnosis of CD made after SBE. Activity in the small bowel was found in 14 patients (70%) with both suspected and previously diagnosed CD. Twelve patients (60%) had small-bowel disease that was out of reach of conventional endoscopy. Three patients (15%) had small-bowel activity solely in the jejunum, which was not detected by either MRE or US. Single-center study with small sample size. SBE can be used in children to accurately assess small-bowel disease and CD. Small-bowel activity may be identified by SBE in some patients in whom it may not be apparent despite use of conventional upper endoscopy, ileocolonoscopy, US with Doppler flow measurements, or MRE.

Brain and ventricular volume in patients with syndromic and complex craniosynostosis (Article)

2012-01-01T00:00:00Z

Purpose: Brain abnormalities in patients with syndromic craniosynostosis can either be a direct result of the genetic defect or develop secondary to compression due to craniosynostosis, raised ICP or hydrocephalus. Today it is unknown whether children with syndromic craniosynostosis have normal brain volumes. The purpose of this study was to evaluate brain and ventricular volume measurements in patients with syndromic and complex craniosynostosis. This knowledge will improve our understanding of brain development and the origin of raised intracranial pressure in syndromic craniosynostosis. Methods: Brain and ventricular volumes were calculated from MRI scans of patients with craniosynostosis, 0.3 to 18.3 years of age. Brain volume was compared to age matched controls from the literature. All patient charts were reviewed to look for possible predictors of brain and ventricular volume. Results: Total brain volume in syndromic craniosynostosis equals that of normal controls, in the age range of 1 to 12 years. Brain growth occurred particularly in the first 5 years of age, after which it stabilized. Within the studied population, ventricular volume was significantly larger in Apert syndrome compared to all other syndromes and in patients with a Chiari I malformation. Conclusions: Patients with syndromic craniosynostosis have a normal total brain volume compared to normal controls. Increased ventricular volume is associated with Apert syndrome and Chiari I malformations, which is most commonly found in Crouzon syndrome. We advice screening of all patients with Apert and Crouzon syndrome for the development of enlarged ventricle volume and the presence of a Chiari I malformation.

Assessment of white matter microstructural integrity in children with syndromic craniosynostosis: A diffusion-tensor imaging study (Article)

2011-11-01T00:00:00Z

Purpose: To assess whether architectural alterations exist in the white matter of patients with syndromic and complex craniosynostosis. Materials and Methods: The medical ethics committee approved this study. Written informed consent was obtained from parents or guardians before imaging. A prospective study was performed in children with syndromic and complex craniosynostosis aged 6-14 years. Forty-five patients were included: four had Apert syndrome, 14 had Crouzon-Pfeiffer syndrome , eight had Muenke syndrome, 11 had Saethre-Chotzen syndrome, and eight had complex craniosynostosis. In addition, seven control subjects were evaluated. For diffusiontensor imaging, an echo-planar sequence was used with a diffusion gradient(b = 1000 sec/mm2) applied in 25 noncollinear directions. Regions of interest (ROIs) were placed in the following white matter structures: pontine crossing tract, corticospinal tracts, medial cerebral peduncles, uncinate fasciculus (measured bilaterally), anterior commissure, frontal and occipital white matter (measured bilaterally), fornix, corpus callosum (measured in the genu and splenium), and corpus cingulum (measured bilaterally). Eigenvalues were measured in all ROIs and fractional anisotropy (FA) was calculated. Results: Across all measured ROIs, FA values were generally lower in all patients combined than in the control subjects(P < .001). There were no significant differences among subgroups of patients. Conclusion: Diffusion-tensor imaging measurements of white matter tracts reveal significant white matter integrity differences between children with craniosynostosis and healthy control subjects. This could imply that the developmental delays seen in these patients could be caused by the presence of a primary disorder of the white matter microarchitecture.

Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia (Article)

2011-11-01T00:00:00Z

Purpose: We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). Patients and Methods: Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. Results: Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. Conclusion: Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

DTI reveals network injury in perinatal stroke (Article)

2011-10-20T00:00:00Z

Background: Previous research showed acute diffusion-weighted imaging changes in pulvinar after extensive cortical injury from neonatal stroke. The authors used diffusion tensor imaging (DTI) to see how separate regions of ipsilateral thalamus are directly affected after a primary hit to their connected cortex in neonatal stroke. Methods: The authors analysed DTI images of three term infants with acute unilateral cortical arterial ischaemic stroke. Probabilistic tractography was used to define separate thalamic regions of interests (ROIs). The authors evaluated the three eigenvalues (EV) and apparent diffusion coefficient (ADC) values in the ROIs. Results: The ADC and EV in voxels of ROIs placed within the nuclei corresponding to ischaemic cortex were significantly lower than those in the unaffected contralesional thalamic nuclei. Conclusions: Our findings support the concept of acute network injury in neonatal stroke. ADC and EV were altered in specific thalamic regions that corresponded to the specific cortical areas affected by the primary ischaemic injury. Copyright Article author (or their employer) 2011.

Are ultrasonography measurements of optic nerve sheath diameter an alternative to funduscopy in children with syndromic craniosynostosis? Clinical article (Article)

2011-09-01T00:00:00Z

Object. Children with syndromic or complex craniosynostosis are evaluated for increased intracranial pressure (ICP) using funduscopy to detect papilledema. However, papilledema is a late sign of increased ICP. Because papilledema might be preceded by an increase in optic nerve sheath (ONS) diameter, the authors conducted a prospective study to establish the validity and applicability of measuring the ONS using ultrasonography. Methods. From January 2007 to December 2009, 175 bilateral ultrasonography ONS measurements were performed in 128 patients with syndromic or complex craniosynostosis during the daytime. The measurements were correlated with ONS diameter assessed on CT and simultaneous funduscopy, when available. Furthermore, results were compared by using thresholds for ONS diameters on ultrasonography that are available in the literature. Results. The mean ONS diameter on ultrasonography was 3.1 &πλυσμν; 0.5 mm. The CT measurement was significantly correlated with the ultrasonography measurement (r = 0.41, p < 0.001). The mean ONS diameter in 38 eyes with papilledema was 3.3 &πλυσμν; 0.5 mm, compared with 3.1 &πλυσμν; 0.5 mm in the eyes of patients without papilledema (p = 0.039). Relative to the age-related thresholds, the ONS diameter was too large in 11 eyes (3%), particularly in patients with Crouzon syndrome. Compared with funduscopy, ultrasonography sensitivity was 11%, specificity was 97%, and positive and negative predictive values were 40% and 86%, respectively. Conclusions. Ultrasonography is a valid and easy way of quantifying the ONS. Although the ONS diameter is larger in children with papilledema, it cannot be used as a daytime screening tool instead of funduscopy. The ONS diameter is possibly a more real-time indicator of ICP.

Lumbar puncture in paediatric stroke (Article)

2011-08-27T00:00:00Z

Beare-Stevenson syndrome: Two Dutch patients with cerebral abnormalities (Article)

2011-04-01T00:00:00Z

Beare-Stevenson syndrome (BSS) is a rare autosomal-dominant condition characterized by cutis gyrata, craniosynostosis, acanthosis nigricans, anogenital anomalies, and a prominent umbilical stump. In 1996, two mutations in the fibroblast growth factor receptor 2 gene were found to cause this syndrome, thereby including BSS in the fibroblast growth factor receptor gene-related craniosynostosis spectrum. Until now, 12 patients with fibroblast growth factor receptor 2 gene-related BSS have been described. We report what is to our knowledge the first 2 Dutch patients with this syndrome, both caused by the mutation Tyr375Cys in the fibroblast growth factor receptor 2 gene. The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging. We discuss the clinical and radiologic findings in fibroblast growth factor receptor 2 gene-related BSS.

Vertical position of the orbits in nonsyndromic plagiocephaly in childhood and its relation to vertical strabismus (Article)

2011-01-01T00:00:00Z

Purpose: To determine the existence of a correlation between the vertical angle of strabismus and the vertical angle between the orbital axes in nonsyndromic plagiocephaly in childhood. Methods: Patients were included when diagnosed with plagiocephaly. Orthoptic measurements showed a vertical strabismus and three-dimensional computed tomographic (CT) imaging of the skull was available. Patients were excluded if plagiocephaly was part of a syndrome or if any surgical intervention had taken place before our measurements. Three-dimensional CT imaging was used to calculate the vertical angle between the orbital axes in 3 reference planes (VAO) perpendicular to a line of reference through the lower borders of the maxilla (VAOmax), both auditory canals (VAOaud), and the lower points of the external occipital protuberances (VAOocc). Results: Fourteen patients were included (mean age, 14 mo). Three-dimensional CT measurements showed a mean (SD) VAOmax of 1.70 (2.31) degrees, VAOaud of -1.54 (1.46) degrees, and VAOocc of -2.06 (4.29) degrees (a negative value indicates that the eye on the affected side was situated lower in the head). The mean vertical angle of strabismus was -2.39 (4.69) degrees in gaze toward the affected side, 3.66 (3.77) degrees in gaze ahead, and 8.14 (5.63) degrees in gaze toward the nonaffected side. The Pearson test showed no significant correlations. Conclusions: The clinical observation that vertical strabismus in adult plagiocephaly is correlated with the vertical angle of the orbital axes could not be confirmed in young children. Copyright

Comparable low-level mosaicism in affected and non affected tissue of a complex CDH patient (Article)

2010-12-01T00:00:00Z

In this paper we present the detailed clinical and cytogenetic analysis of a prenatally detected complex Congenital Diaphragmatic Hernia (CDH) patient with a mosaic unbalanced translocation (5;12). High-resolution whole genome SNP array confirmed a low-level mosaicism (20%) in uncultured cells, underlining the value of array technology for identification studies. Subsequently, targeted Fluorescence In-Situ Hybridization in postmortem collected tissues demonstrated a similar low-level mosaicism, independently of the affected status of the tissue. Thus, a higher incidence of the genetic aberration in affected organs as lung and diaphragm cannot explain the severe phenotype of this complex CDH patient. Comparison with other described chromosome 5p and 12p anomalies indicated that half of the features presented in our patient (including the diaphragm defect) could be attributed to both chromosomal areas. In contrast, a few features such as the palpebral downslant, the broad nasal bridge, the micrognathia, microcephaly, abnormal dermatoglyphics and IUGR better fitted the 5p associated syndromes only. This study underlines the fact that low-level mosaicism can be associated with severe birth defects including CDH. The contribution of mosaicism to human diseases and specifically to congenital anomalies and spontaneous abortions becomes more and more accepted, although its phenotypic consequences are poorly described phenomena leading to counseling issues. Therefore, thorough follow-up of mosaic aberrations such as presented here is indicated in order to provide genetic counselors a more evidence based prediction of fetal prognosis in the future.

The clinical presentation of preterm cerebellar haemorrhage (Article)

2010-10-01T00:00:00Z

The objective of this study was to evaluate clinical symptoms and findings on cranial ultrasound (CUS) in preterm infants with cerebellar haemorrhage through retrospective analysis of all preterm infants with a postnatal CUS or MRI diagnosis of cerebellar haemorrhage admitted in a tertiary care centre between January 2002 and June 2009. Fifteen infants were identified; median gestational age was 25 2/7 weeks and median birth weight 730 g. We discerned six types of haemorrhage: subarachnoid (n=3), folial (n=1), lobar (n=9, of which 4 bilateral), giant lobar (n=1, including vermis) and contusional (n=1). Especially in infants with lobar cerebellar haemorrhage, CUS showed preceding or concurrent lateral ventricle dilatation, mostly without intraventricular haemorrhage (IVH). Thirteen infants suffered from notable, otherwise unexplained motor agitation in the days preceding the diagnosis. In conclusion, motor agitation may be a presenting symptom of cerebellar haemorrhage in preterm infants. Unexplained ventriculomegaly can be a first sign of cerebellar haemorrhage and should instigate sonographic exploration of the cerebellum.

Long-term functional outcome in 167 patients with syndromic craniosynostosis; Defining a syndrome-specific risk profile (Article)

2010-10-01T00:00:00Z

Objective: Little is known about the long-term prevalence of elevated intracranial pressure (ICP), obstructive sleep apnoea (OSA), level of education, language and motor skills, impaired sight and hearing in craniosynostosis syndromes. The objective of this study was to define the prevalence per syndrome of elevated ICP, OSA, impaired sight and impaired hearing. Methods: A retrospective study was undertaken on 167 consecutive patients diagnosed with Apert, Crouzon, Pfeiffer, Muenke or Saethre-Chotzen syndrome, aged 1-25 years and treated between 1983 and 2008. The mean age at time of referral and review was 1 years and 2 months and 10 years and 3 months, respectively. Results: Patients with Apert and Crouzon/Pfeiffer syndromes had the highest prevalence of elevated ICP (33% and 53%, respectively) and OSA (31% and 27%, respectively), while Saethre-Chotzen syndrome was also associated with a fair risk for elevated ICP (21%). The prevalence of impaired sight (61%) and hearing (56%) was high in all syndromes. Conclusion: Based on these data, a syndrome-specific risk profile with suggestions for screening and treatment is presented.

Self-Limiting Sternal Tumors of Childhood (SELSTOC) (Article)

2010-07-15T00:00:00Z

Background. Because a sternal mass is often alarming, it is important to identify the clinical features of benign processes. Procedure. Data on clinical presentation, diagnostics, treatment and outcome of pediatric patients presenting with a sternal tumor between 2001 and 2009 were collected from medical records. Results. Among the 1,700 children who were referred to our pediatric-oncology center, 14 presented with a rapidly growing sternal mass. All patients (10 males) were Caucasian and median age was 16 (range: 7-50) months. Reported symptoms were local pain (n=7) and/or raised body temperature (n=5). No major preceding traumas were reported. Physical examination revealed solid tumors with a median diameter of 3 (range: 1-4.5)cm in a pre-sternal/parasternal location. Half of the patients showed red/blue discoloration of the skin. On radiology, dumbbell-shaped lesions extended to the area behind the sternal bone, involving the cartilage, leading to increased distance between ossification centers. Histopathology at diagnosis was available from five patients and showed aspecific chronic or acute inflammation (n=4) and a reactive osteochondromatous lesion (n=1). Laboratory infection parameters were not/only slightly raised and microbiologic cultures were negative in all patients. All tumors decreased in size within 1 month, in both patients with and without antibiotics. On physical examination the tumors disappeared within 6 months. Conclusions. This study reports 14 young children with a rapidly growing sternal mass due to aseptic inflammation, that we named self-limiting sternal tumor of childhood (SELSTOC). To prevent invasive diagnostic interventions and unnecessary treatment, we advocate a wait-and-see approach with close follow-up in the first weeks. Pediatr Blood Cancer 2010;55:81-84.

KBG syndrome associated with periventricular nodular heterotopia (Article)

2010-07-01T00:00:00Z

Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (Article)

2010-06-01T00:00:00Z

The combination of megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (MPPH) is a rare syndrome of unknown cause. We observed two first cousins affected by an MPPH-like phenotype with a submicroscopic chromosome 5q35 deletion as a result of an unbalanced der(5)t(5;20)(q35.2;q13.3) translocation, including the NSD1 Sotos syndrome locus. We describe the phenotype and the deletion breakpoints of the two MPPH-like patients and compare these with five unrelated MPPH and Sotos patients harboring a 5q35 microdeletion. Mapping of the breakpoints in the two cousins was performed by MLPA, FISH, high density SNP-arrays and Q-PCR for the 5q35 deletion and 20q13 duplication. The 5q35 deletion area of the two cousins almost completely overlaps with earlier described patients with an atypical Sotos microdeletion, except for the DRD1 gene. The five unrelated MPPH patients neither showed submicroscopic chromosomal aberrations nor DRD1 mutations. We reviewed the brain MRI of 10 Sotos patients and did not detect polymicrogyria in any of them. In our two cousins, the MPPH-like phenotype is probably caused by the contribution of genes on both chromosome 5q35 and 20q13. Some patients with MPPH may harbor a submicroscopic chromosomal aberration and therefore high-resolution array analysis should be part of the diagnostic workup.

Periventricular nodular heterotopia and distal limb deficiency: A recurrent association (Article)

2010-04-01T00:00:00Z

Malformations of cerebral cortical development, in particular periventricular nodular heterotopia(PNH), and distal transverse limb deficiency have been reported as associated congenital anomalies. Patients with PNH and transverse limb deficiency can be classified as having amniotic band sequence or Adams - Oliver syndrome (AOS). Controversy exists whether these should be considered separate entities. In some AOS patients, autosomal recessive inheritance has been shown, but in most patients causes are unknown, and both environmental and genetic factors have been implicated. We present three patients with PNH and distal transverse limb deficiency to support the hypothesis that these should be considered part of one group of disorders, and highlight the variable severity of the clinical and neuroradiological phenotype. Chromosome abnormalities were excluded by copy number analysis on 250K SNP microarray data.Research done on limb deficiency as on PNH caused by mutations in known genes, suggests the involvement of vascular developmental pathways. The combination of limb deficiency and PNH may have a common causative mechanism. Recognition and grouping of patients with this combination of abnormalities will help elucidating the cause.

Internal carotid dissection after Le Fort III distraction in Apert syndrome: A case report (Article)

2010-03-18T00:00:00Z

A 10-year-old girl with Apert syndrome underwent a Le Fort III osteotomy with the positioning of internal and external distraction devices. The operation was straightforward with no intraoperative complications. Very soon after completion of surgery an anisocoria (unilateral dilation of a pupil) was noticed. This was followed by intracranial oedema which was fatal. The aetiology was dissection of the right internal carotid artery is reported. The complications of Le Fort osteotomies are discussed regarding patients with complex syndromal craniosynostosis and midface hypoplasia, such as Apert syndrome.

Kidney growth curves in healthy children from the third trimester of pregnancy until the age of two years. The Generation R Study (Article)

2010-02-01T00:00:00Z

Information about growth of kidney structures in early life is limited. In a population-based prospective cohort study, from foetal life onwards, we constructed reference curves for kidney growth from the third trimester of pregnancy until early childhood, using data from 1,158 healthy children. Kidney size, defined as length, width, depth and volume, was measured in the third trimester of pregnancy and at the postnatal ages of 6 months and 24 months. Analyses were based on more than 2,500 kidney measurements. In the third trimester of pregnancy and at 6 months of age all kidney measurements were larger in boys than in girls. At 24 months of age, these gender differences were only significant for left kidney structures and right kidney length. Both groups showed trends towards smaller left kidney measurements than right kidney measurements at all ages. Gender-specific reference curves based on post-conceptional and postnatal ages were constructed for left and right kidney length, width, depth and volume. We concluded that kidney size is influenced by age and gender. Left kidney size tended to be smaller than right kidney size, except for kidney length. The reference curves can be used for assessing kidney structures by ultrasound in foetal life and early childhood.

Abdominal Fat in Children Measured by Ultrasound and Computed Tomography (Article)

2009-12-01T00:00:00Z

The prevalence of childhood obesity is increasing rapidly. Visceral fat plays an important role in the pathogenesis of metabolic and cardiovascular diseases. Currently, computed tomography (CT) is broadly seen as the most accurate method of determining the amount of visceral fat. The main objective was to examine whether measures of abdominal visceral fat can be determined by ultrasound in children and whether CT can be replaced by ultrasound for this purpose. To assess whether preperitoneal fat thickness and area are good approximations of visceral fat at the umbilical level, we first retrospectively examined 47 CT scans of nonobese children (body mass index <30 kg/m2; median age 7.9 y [95% range 1.2 to 16.2]). Correlation coefficients between visceral and preperitoneal fat thickness and area were 0.58 (p < 0.001) and 0.76 (p < 0.001), respectively. Then, to assess how preperitoneal and subcutaneous fat thicknesses and areas measured by ultrasound compare with these parameters in CT, we examined 34 nonobese children (median age 9.5 [95% range 0.3 to 17.0]) by ultrasound and CT. Ultrasound measurements of preperitoneal and subcutaneous fat were correlated with CT measurements, with correlation coefficients ranging from 0.75-0.97 (all p < 0.001). Systematic differences of up to 24.0 cm2for preperitoneal fat area (95% confidence interval -29.9 to 77.9 cm2) were observed when analyzing the results described by the Bland-Altman method. Our findings suggest that preperitoneal fat can be used as an approximation for visceral fat in children and that measuring abdominal fat with ultrasound in children is a valid method for epidemiological and clinical studies. However, the exact agreement between the ultrasound and CT scan was limited, which indicates that ultrasound should be used carefully for obtaining exact fat distribution measurements in individual children. (E-mail: v.jaddoe@erasmusmc.nl).

Diagnosis of perinatal stroke II: Mechanisms and clinical phenotypes (Article)

2009-11-04T00:00:00Z

Introduction: Here (and in an accompanying article dealing with definitions, differential diagnosis and registration), a structured sequential diagnostic flow is proposed to discern clinical phenotypes for perinatal stroke, including arterial ischaemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) and haemorrhagic stroke. Material and results: For neonatal AIS, the diagnostic sequence is infection, trauma, embolism, arteriopathy, other, primary thrombosis and unclassifiable; for neonatal CSVT, the sequence is infection, trauma, venopathy, other, primary thrombosis and unclassifiable. The proposed hierarchical diagnostic flows are an initial step towards a standard for registration of the causes of neonatal stroke. Such standardization should guide attempts at prevention and intervention. An extensive literature search and study of a retrospective cohort of 134 newborn infants with stroke suggest that embolism is the most common identifiable cause for stroke in general (25%), preceding trauma (10%) and infection (8%). Other causes, such as asphyxia, acute blood loss, extracorporeal membrane oxygenation, genetic disorders or prothrombotic conditions, are seen in <5% of cases. For neonatal AIS, the presence of an embolic phenotype is 33% in this cohort. The designation unclassifiable scored 34% for the entire stroke group and 25% for neonatal AIS. Complex arterial stroke with multiple arteries involved is often seen when the underlying cause is infection, cranial trauma or embolism. One important conclusion is that a means of prevention is avoidance of embolism from thrombosis outside the brain. Conclusion: To prevent the occurrence and recurrence of neonatal ischaemic stroke, clinicians must develop a standardized diagnostic approach that results in characterization of the clinical phenotype.

Magnetic resonance imaging in neonatal stroke (Article)

2009-10-01T00:00:00Z

Neonatal stroke occurs in 1 in 2300-5000 live births, the incidence of which is lower than that in adults, but still higher than that in childhood. The higher incidence of perinatal stroke in preterm and term infants compared to stroke in childhood may be partly explained by higher detection rates using routine fetal ultrasound and postnatal cranial sonography. In addition, there is greater availability of magnetic resonance imaging (MRI) for neuroimaging in preterm and full-term infants, which is due in part to the availability of MR-compatible incubators and MR systems at or near the neonatal intensive care unit. In addition, the wide range of MR techniques, such as T2-, diffusion- and susceptibility-weighted imaging allows improved visualization and quantification of neonatal stroke or hypoxic-ischemic injury. This chapter reviews the MR neuroimaging modalities that actually assist the clinician in the detection of neonatal stroke.

The spectrum of structural abnormalities on CT scans from patients with CF with severe advanced lung disease (Article)

2009-10-01T00:00:00Z

Rationale: In cystic fibrosis (CF), lung disease is the predominant cause of morbidity and mortality. Little is known about the spectrum of structural abnormalities on. CT scans from patients with CF with severe advanced lung disease (SALD). No specific CT scoring system for SALD is available. Objectives: To design a quantitative CT scoring system for SALD, to determine the spectrum of structural abnormalities in patients with SALD and to correlate the SALD system with an existing scoring system for mild CF lung disease and pulmonary function tests (PFTs). Methods: 57 patients with CF contributed one CT made during screening for lung transplantation. For the SALD system, lung tissue was divided into four components: infection/inflammation (including bronchiectasis, airway wall thickening, mucus and consolidations), air trapping/ hypoperfusion, bulla/cysts and normal/hyperperfused tissue. The volume proportion of the components was estimated on a 0-100% scale; mean volumes for the whole lung were computed. Scores were correlated with Brody-II scores and PFTs. Results: The SALD system identified a wide spectrum of structural abnormalities ranging from predominantly infection/inflammation to predominantly air trapping/ hypoperfusion. SALD infection/inflammation scores correlated with Brody-II scores (rs = 0.36-0.64) and SALD normal/hyperperfusion scores correlated with forced expiratory volume in 1 s (FEV1; rs = 0.37). Reproducibility for both systems was good. Conclusions: A CT scoring system was developed to characterise the structural abnormalities in patients with SALD. A wide spectrum was observed in SALD, ranging from predominantly air trapping to predominantly infection/ inflammation-related changes. This spectrum may have clinical implications for patients with SALD.

Herpes Simplex Virus Type-1 Encephalitis and Occipital Ischemic Stroke (Article)

2009-10-01T00:00:00Z

Childhood ischemic stroke is a rare complication of herpes simplex virus type-1 encephalitis. We describe a previously healthy 3-year-old girl who presented with bilateral occipital ischemic stroke, attributable to herpes simplex virus type-1 encephalitis, highlighting the importance of viral diagnostics in cerebrospinal fluid.

First locus for primary pulmonary vein stenosis maps to chromosome 2q (Article)

2009-10-01T00:00:00Z

AimsPrimary pulmonary vein stenosis (PVS) is a rare cardiac abnormality that exhibits a high morbidity and mortality rate. The disease is characterized by obstruction of the pulmonary venous blood flow owing to congenital hypoplasia of individual extra-pulmonary veins. We describe a consanguineous Turkish family with four affected siblings with primary PVS in association with prenatal lymphatic abnormalities. We aimed to map the first gene for primary PVS.Methods and resultsPatients had extensive cardiological examinations including electrocardiograms, echocardiograms, ventilation-perfusion scans, and cardiac catheterizations. All patients died before the age of 16 months because of severe progressive primary PVS. Chromosomal analysis revealed normal karyotypes. We performed a genome-wide linkage analysis using 250 K single nucleotide polymorphism arrays and found the first locus for primary PVS on chromosome 2q35-2q36.1 [multipoint logarithms (base 10) of odds (LOD) scores 3.6]. By fine-mapping with microsatellite markers, we confirmed the homozygous region that extended 6.6 Mb (D2S164-D2S133). Sequencing 12 (188 exons) of the 88 genes from the region revealed no disease-causing sequence variations.ConclusionOur findings open perspectives for the identification of the genetic cause(s) leading to PVS, which might contribute to elucidate the pathological mechanisms involved in this disorder.

Cystic fibrosis: Are volumetric ultra-low-dose expiratory CT scans sufficient for monitoring related lung disease? (Article)

2009-10-01T00:00:00Z

Purpose: To assess whether chest computed tomography (CT) scores from ultra-low-dose end-expiratory scans alone could suffice for assessment of all cystic fibrosis (CF)-related structural lung abnormalities. Materials and Methods: In this institutional review board-approved study, 20 patients with CF aged 6-20 years (eight males, 12 females) underwent low-dose end-inspiratory CT and ultra-lowdose end-expiratory CT. Informed consent was obtained. Scans were randomized and scored by using the Brody-II CT scoring system to assess bronchiectasis, airway wall thickening, mucus plugging, and opacities. Scoring was performed by two observers who were blinded to patient identity and clinical information. Mean scores were used for all analyses. Statistical analysis included assessment of intra- and interobserver variability, calculation of intraclass correlation coefficients (ICCs), and Bland-Altman plots. Results: Median age was 12.6 years (range, 6.3-20.3 years), median forced expiratory volume in 1 second was 100% (range, 46%-127%) of the predicted value, and median forced vital capacity was 99% (range, 61%-123%) of the predicted value. Very good agreement was observed between end-inspiratory and end-expiratory CT scores for Brody-II total score (ICC = 0.96), bronchiectasis (ICC = 0.98), airway wall thickening (ICC = 0.94), mucus plugging (ICC = 0.96), and opacities (ICC = 0.90). Intra- and interobserver agreement were good to very good (ICC range, 0.70-0.98). Bland-Altman plots showed that differences in scores were independent of score magnitude. Conclusion: In this pilot study, CT scores from end-expiratory and end-inspiratory CT match closely, suggesting that ultralow-dose end-expiratory CT alone may be sufficient for monitoring CF-related lung disease. This would help reduce radiation dose for a single investigation by up to 75%.

Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood (Article)

2009-07-20T00:00:00Z

Purpose: To prospectively study cognitive deficits and predictors 3 years after diagnosis in a large series of pediatric patients treated for pilocytic astrocytoma (PA). Patients and Methods: Sixty-one of 67 children were grouped according to infratentorial, supratentorial midline, and supratentorial hemispheric site. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Included predictors were sex, age, relapse, diagnosis-assessment interval, hydrocephalus, kind of treatment, and tumor variables. Results: All children with PA had problems with sustained attention and speed. In the infratentorial group, there also were deficits in verbal intelligence, visual-spatial memory, executive functioning, and naming. Verbal intelligence and verbal memory problems occurred in the brainstem tumor group. The supratentorial hemispheric tumor group had additional problems with selective attention and executive functioning, and the supratentorial midline tumor group displayed no extra impairments. More specifically, the dorsal supratentorial midline tumor group displayed problems with language and verbal memory. Predictors for lower cognitive functioning were hydrocephalus, radiotherapy, residual tumor size, and age; predictors for better functioning were chemotherapy or treatment of hydrocephalus. Almost 60% of children had problems with academic achievement, for which risk factors were relapse and younger age at diagnosis. Conclusion: Despite normal intelligence at long-term follow-up, children treated for PA display invalidating cognitive impairments. Adequate treatment of hydrocephalus is important for a more favorable long-term cognitive outcome. Even children without initial severe deficits may develop cognitive impairments years after diagnosis, partly because of the phenomenon of growing into deficit, which has devastating implications for academic achievement and quality of life (QOL).

Mutation in the AP4M1 Gene Provides a Model for Neuroaxonal Injury in Cerebral Palsy (Article)

2009-07-10T00:00:00Z

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G→T), was identified. AP4M1, encoding for the μ subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRδ2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

Apnoea in relation to neonatal temporal lobe haemorrhage (Article)

2009-07-01T00:00:00Z

Background: Six term newborns presented with apnoea and temporal lobe haemorrhage. Aim: In this observational study, we described involvement of the limbic system in apnoeic term newborns with temporal lobe injury. Methods: Six term newborns presented to the neonatal care unit with apnoea within the first 2 days of life. Ultrasound (US) and MRI of the brain were obtained in the first week of life. Results: Apnoea was related to temporal lobe haemorrhage in all. During apnoeic periods four had focal epileptic activity on EEG. All lesions were detected first with US. On MRI, haemorrhages were located in the parenchyma, the subdural and/or subarachnoid space. Three haemorrhages were surrounded by infarction in the temporal lobe. In three infants hippocampus and mesial temporal cortex were affected. In two basal temporal cortex only was involved. Vascular anomalies were excluded by MRA, serial MRI or serial US with Doppler imaging. Conclusion: Term infants with seizure associated apnoea may present with haemorrhage and/or infarction to hippocampus, mesial and basal temporal cortex. This study supports the existence and possible disruption of descending influences from the temporal cortex and/or amygdala on brainstem breathing centres in the term newborn.

Automatic determination of Greulich and Pyle bone age in healthy Dutch children (Article)

2009-06-01T00:00:00Z

Background: Bone age (BA) assessment is a routine procedure in paediatric radiology, for which the Greulich and Pyle (GP) atlas is mostly used. There is rater variability, but the advent of automatic BA determination eliminates this. Objective: To validate the BoneXpert method for automatic determination of skeletal maturity of healthy children against manual GP BA ratings. Materials and methods: Two observers determined GP BA with knowledge of the chronological age (CA). A total of 226 boys with a BA of 3-17 years and 179 girls with a BA of 3-15 years were included in the study. BoneXpert's estimate of GP BA was calibrated to agree on average with the manual ratings based on several studies, including the present study. Results: Seven subjects showed a deviation between manual and automatic BA in excess of 1.9 years. They were re-rated blindly by two raters. After correcting these seven ratings, the root mean square error between manual and automatic rating in the 405 subjects was 0.71 years (range 0.66-0.76 years, 95% CI). BoneXpert's GP BA is on average 0.28 and 0.20 years behind the CA for boys and girls, respectively. Conclusion: BoneXpert is a robust method for automatic determination of BA.

Segmentation of White Matter Flaring Areas in Ultrasound Images of Very-Low-Birth-Weight Preterm Infants (Article)

2009-06-01T00:00:00Z

In this article, we present an interactive algorithm segmenting white brain matter, visible as hyperechoic flaring areas in ultrasound (US) images of preterm infants with periventricular leukomalacia (PVL). The algorithm combines both the textural properties of pathological brain tissue and mathematical morphology operations. An initial flaring area estimate is derived from a multifeature multiclassifier tissue texture classifier. This area is refined based on the structural properties of the choroid plexus, a brain feature known to have characteristics similar to flaring. Subsequently, a combination of a morphological closing, gradient and opening by reconstruction operation determines the final flaring area boundaries. Experimental results are compared with a gold standard constructed from manual flaring area delineations of 12 medical experts. In addition, we compared our algorithm to an existing active contour method. The results show our technique agrees to the gold standard with statistical significance and outperforms the existing method in accuracy. Finally, using the flaring area as a criterion we improve the sensitivity of PVL detection up to 98% as compared with the state of the art. (E-mail: ervsteen@telin.ugent.be).

Fatal aspergillus rhinosinusitis during induction chemotherapy in a child with acute lymphoblastic leukemia (Article)

2009-05-01T00:00:00Z

Invasive fungal infections are a major problem in patients treated for hematologic malignancies. We report a 3-year-old girl who suffered from febrile neutropenia during induction therapy for acute lymphoblastic leukemia. Initial chest computed tomography revealed no evidence of intrapulmonary fungal lesions, however, plasma galactomannan ratio was positive. Aspergillus flavus was cultured from nasal swab and endoscopic biopsy confirmed Aspergillus rhinosinusitis. After an initially good response to voriconazole and extensive debridement, she developed late intracranial hemorrhage and infarction with fatal outcome. This case stresses the importance of early suspicion and aggressive treatment of Aspergillus rhinosinusitis in patients with febrile neutropenia.

Movement disorder and neuronal migration disorder due to ARFGEF2 mutation (Article)

2009-04-22T00:00:00Z

We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the basal ganglia, specifically to the putamen, may be caused by an increased sensitivity to degeneration, a dynamic dysfunction due to neurotransmitter receptor mislocalization or a combination of both.

Top of the basilar artery embolic stroke and neonatal myoclonus (Article)

2009-03-31T00:00:00Z

Cerebellar stroke has been virtually unreported in the living newborn infant. A term newborn male weighing 3380 g at birth suffered myoclonic seizures within 24 hours of birth by spontaneous vaginal delivery. Apgar scores were 3 and 4 at 1 and 5 minutes. Myoclonus persisted for 9 days, responding poorly to step-up anticonvulsant treatment including lidocaine, midazolam, and clonazepam. Imaging documented arterial ischaemic stroke within the left posterior cerebral and both superior cerebellar arteries, compatible with top of the basilar artery stroke. There was no electrographic correlate for the seizures. Disturbed oscillation within the dentato-rubro-olivary circuitry was the likely mechanism. The probable cause was embolism from an in-utero-onset inferior caval vein thrombosis. At 22 months the child was sitting unsupported. Scores on the Bayley Scales of Infant Development II were equivalent to those of a 12-month-year-old. He showed ataxic motor behaviour. Embolism can cause neonatal top of the basilar artery stroke, which may present with myoclonus due to cerebellar injury.

Reliability of renal ultrasound measurements in children (Article)

2009-03-12T00:00:00Z

The aim of the investigation reported here was to assess the intraobserver and interobserver variability of renal measurements in children. The study comprised 56 paired measurements in 28 children (median age 7.5 years, range 3.0-15.0 years) without renal or ureterovesical anomalies. Intraobserver and interobserver reproducibility was assessed by repeated measurements of the left and right renal length, width, and thickness. Intraclass correlation coefficients (ICCs) with the corresponding 95% confidence interval (CI) were calculated. Bland and Altman plots were computed to assess the agreement of the measurements. Limits of agreement ± 2 standard deviations (SD) for the mean differences in renal measurements were derived. Intraobserver ICCs ranged from 0.93 (left and right renal width and right renal thickness) to 0.99 (left renal length), and interobserver ICCs ranged from 0.64 (right renal thickness) to 0.90 (right renal length). Limits of agreement in the Bland and Altman plots ranged from -8.0 to 9.2% (intraobserver left renal width) to the widest limit from -18.0 to 19.2% (interobserver left renal length). Overall, this study demonstrated the good reproducibility and agreement of most renal dimensions in children measured by ultrasound (US). Based on these results, we conclude that US is an appropriate measure to assess renal dimensions in both clinical and epidemiological studies.

Imaging patterns of brain injury in term-birth asphyxia (Article)

2009-03-01T00:00:00Z

Aim: To develop an extended asphyxia-score based on cerebral ultrasound (US) and MRI in order to gain further insight into the pathophysiology of asphyxia. Patients and Methods: First week cerebral US and MRI of 80 asphyxiated term infants were scored according to a new scoring system based on separate grading of injury to deep grey matter and to (sub)cortical/white matter. Our findings were compared with published scoring systems. Results: Six patterns of brain injury were derived: deep grey matter injury with either limited or extensive cortical involvement, damage to deep grey matter with watershed injury, isolated watershed injury, isolated white matter injury (leukomalacia) and isolated cortical necrosis. The mortality rate was considerable in patterns with extensive cortical injury. Conclusion: Six patterns of brain injury, following term-birth asphyxia were found using a new imaging score.

Tracking and Determinants of Kidney Size From Fetal Life Until the Age of 2 Years: The Generation R Study (Article)

2009-02-01T00:00:00Z

Background: An adverse fetal environment may lead to smaller kidneys and subsequently kidney disease and hypertension in adulthood. The aims of this study are to examine whether kidney size tracks from fetal life to childhood and whether maternal and fetal characteristics are associated with kidney size at the age of 2 years. Study Design: Prospective cohort study from fetal life onward. Setting & Participants: The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity. Predictors: The maternal characteristics age, height, and prepregnancy weight were measured in early pregnancy. Fetal growth, head circumference, abdominal circumference, femur length and estimated fetal weight, and placental characteristics were assessed in the second and third trimesters. Outcomes & Measurements: Kidney size, defined as length, width, depth, and volume, was measured in the third trimester of pregnancy and at postnatal ages 6 and 24 months. Results: Overall median gestational age was 40.3 weeks (95% range, 36.0 to 42.3 weeks), and mean birth weight was 3,536 ± 524 (SD) g. Children tended to remain in the lowest and highest quartiles of kidney volume from the third trimester to the age of 2 years (odds ratio, 2.05; 95% confidence interval, 1.38 to 3.06; odds ratio, 3.29; 95% confidence interval, 2.22 to 4.87, respectively). Maternal height and prepregnancy weight were associated positively with kidney volume at the age of 2 years. Third-trimester fetal head circumference, abdominal circumference, and estimated weight and postnatal length were associated positively with kidney volume at the age of 2 years. Preferential fetal blood flow to the brain was associated with smaller kidneys. Limitations: Kidney measurements successfully performed in only 86% of children. Conclusions: Small kidney size in fetal life tends to persist in early childhood. Maternal anthropometrics and fetal biometrics and blood flow patterns are associated with kidney size in childhood. Follow-up studies are needed to examine whether these variations in kidney size are related to kidney function and blood pressure in later life.

Puberty induction in Turner syndrome: Results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels (Article)

2009-02-01T00:00:00Z

Background: Besides short stature, gonadal dysgenesis leading to a lack of oestrogen is one of the main characteristics of Turner syndrome (TS). In most TS girls, puberty is induced with exogenous oestrogens. Objective: To describe the pubertal development and uterine dimensions achieved by low-dose 17β-oestradiol (17β-E2) orally started at an appropriate age. Additionally, to determine whether serum hormone levels aid evaluation of pubertal progression. Design: In 56 TS girls, we prospectively studied pubertal stage, serum E2, LH, FSH, SHBG and oestrone (E1), starting oestrogen treatment with a low-dose 17β-E2 (5 μg/kg/day) during GH treatment at mean (SD) age 12.7 (0.7) years. Hormone levels were measured at start, 3 months after start and after increasing 17β-E2 dosage. Uterine dimensions were measured in 39 TS women at age 19.9 (2.2) years. Results: Although breast and pubic hair development were similar to that in normal Dutch girls up to Tanner stage B5 and P5, respectively, breast development was 2 years later. Before oestrogen therapy, E2 levels were comparable to those in prepubertal girls. With a 17β-E2 dose of 5 μg/kg/day, these levels increased significantly, becoming comparable to normal late pubertal or adult concentrations, whereas SHBG levels were unchanged. At the adult 17β-E2 dose, SHBG had increased significantly. Uterus shape was juvenile in four (10.2%), cylindrical in four and mature-adult shaped in 31 (79.5%) of TS patients. Conclusions: During GH treatment in TS girls, normal breast development up to B5 can be mimicked, with just a 2-year delay. In a clinical setting, serum hormone levels provide no additional information for evaluating pubertal progression. After age-appropriate pubertal induction, uterine dimensions in women aged nearly 20 years were subnormal. It remains unclear whether this was related to E2 dosage, timing or duration, or factors related to TS.

Lung morphology assessment using MRI: A robust ultra-short TR/TE 2D steady state free precession sequence used in cystic fibrosis patients (Article)

2009-02-01T00:00:00Z

To evaluate feasibility and diagnostic quality of ultra-short TR/TE two-dimensional (2D) steady state free precession (SSFP) MRI for cystic fibrosis (CF) patients. We performed lung MRI at 1.5 Tesla in 20 CF-patients (6-17 years, 12 males). Axial, coronal, and sagittal sections were acquired in inspiration and expiration with maximum breath-hold time 10 s. MR and CT images were scored using a modified Brody scoring system to assess bronchiectasis, mucous plugging, atelectasis/consoli-dations, and air trapping. All images were scored by two experienced observers. A complete MR investigation took maximally 15 min. Maximal breath-holds were only 10 s and well tolerated. MRI identified major bronchiectasis, mucous plugging and at-electasis. End-expiratory scans showed patches of parenchyma with reduced signal intensity that may corresponded to areas of trapped air on expiratory CT scans. This MRI protocol based on ultra-short TR/TE 2D SSFP is quick and well tolerated and provides highly relevant imaging features as seen on CT in CF patients. Most importantly, the SNR of the expiratory scans enables to visualize air trapping. The preliminary results of this study suggest MRI as a noteworthy additional imaging tool for routine monitoring of CF patients.

Cystic nephroma, cystic partially differentiated nephroblastoma and cystic Wilms' tumor in children: A spectrum with therapeutic dilemmas (Article)

2009-01-01T00:00:00Z

Background: Cystic renal tumors are a diagnostic and therapeutic challenge. Cystic nephroma (CN), cystic partially differentiated nephroblastoma (CPDN) and cystic Wilms' tumor (CWT) are a spectrum with CN at the benign end, CWT at the malignant end and CPDN in the intermediate position. CN and stage 1 CPDN are often treated with surgery alone. International Society of Pediatric Oncology (SIOP) protocols for Wilms' tumor (WT) advocate preoperative chemotherapy, which may be unnecessary and potentially harmful in CN and in stage 1 CPDN. There are difficulties in differentiating the three types using imaging techniques. Therefore, controversies exist regarding the optimal treatment. Methods: We describe 6 children, who each had a postoperative diagnosis of CN, CPDN or CWT, and we retrospectively evaluate the treatment strategies. Results: The three types cannot be differentiated using imaging techniques, although the presence of solid components in the tumor is indicative of WT. Conclusions: Surgery as first-line therapy should be seriously considered in children who have a cystic renal tumor, but further collaborative studies are needed since the distinction line between CPDN and CWT is not always clear. Copyright

Yield from Flexible Bronchoscopy in Pediatric Cystic Fibrosis Patients (Article)

2008-10-01T00:00:00Z

BACKGROUND : Recent data on the yield of bronchoscopy in pediatric cystic fibrosis (CF) patients are lacking. Therapeutic bronchoscopic lavage with the mucolytic recombinant human deoxyribonuclease (rhDNase) has been used during CF bronchoscopies, but efficacy data are scarce. METHODS: A retrospective review of all bronchoscopies performed in pediatric CF patients in our hospital in the past 15 years. AIMS OF THE STUDY: To evaluate indications for and safety of bronchoscopy in pediatric CF patients, to describe the findings of bronchoscopy and the contribution of these findings to clinical management, and to evaluate the application of bronchoscopic lavage with rhDNase. RESULTS: Between 1992 and 2007, 66 bronchoscopies were performed in 48 CF patients (25 males) at a median (range) age of 8.3 (0.1 to 20.4) years. Indications for bronchoscopy were persistent atelectasis (42%), refractory symptoms (29%), need for microbiologic culture (11%), suspected anatomic abnormality (11%), and bronchial toilet (7%). Relevant new information with therapeutic consequences was obtained in 28 (42%) bronchoscopies, including a first Pseudomonas aeruginosa infection (n≤3), infection with atypical mycobacteria (n≤3), or Aspergillus fumigatus (n≤5), and severe tracheo(broncho)malacia (n≤4). In patients with atelectasis, rhDNase lavage was associated with improved chest radiograph scores and a transient decline in forced vital capacity. In 7 of 11 patients with refractory symptoms, lung function tended to improve after rhDNase lavage. No serious complications were observed after bronchoscopy and rhDNase lavage. CONCLUSIONS: Bronchoscopy provides clinically relevant information in about 40% of these pediatric CF patients. Lavage with rhDNase seemed safe, and was associated with improved chest radiographs in patients with therapy resistant atelectasis. Copyright

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: A randomized controlled trial (Article)

2008-07-16T00:00:00Z

Context: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. Objective: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention: Simvastatin or placebo treatment once daily for 12 weeks. Main Outcome Measures: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. Results: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β=0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (β=-0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio=2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β=0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β=0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. Conclusion: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration: isrctn.org Identifier: ISRCTN14965707

Extensive cerebral infarction in the newborn due to incontinentia pigmenti (Article)

2008-07-01T00:00:00Z

Introduction: Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal multisystem disorder characterized by skin lesions following Blaschko lines. In almost all patients the skin is involved and in 30-50% the central nervous system (CNS) is. Vascular occlusive phenomena probably play a role in CNS involvement. Whether these vascular changes are based on macro- or microvascular disease in the neonatal presentation is not fully understood. Patients and methods: We describe two patients with IP with neonatal seizures related to cerebral infarction. In comparison, we reviewed reports of ischaemic cerebrovascular injury in neonatal IP. Results: No descriptions of documented large artery occlusion in neonatal IP was found in the literature. One of our patients showed striatal arteriopathy, never described before in IP. Extensive injury in one of our cases was heterogeneous, mixing healthy with diseased areas within large arterial fields. Conclusions: We postulate that neonatal cerebral infarction in IP is a macrovascular disorder of medium sized or small arteries. The pattern of arterial involvement might follow hypothetical brain Blaschko lines. The extent of cerebral involvement probably results from genetic mosaicism in which Lyonisation leads to endothelial apoptosis, similar to the process in the skin.

Estimation of the radiation dose from CT in cystic fibrosis (Article)

2008-05-01T00:00:00Z

Venous subtypes of preterm periventricular haemorrhagic infarction (Article)

2008-05-01T00:00:00Z

Background: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth that may lead to impairment and disability. Early diagnosis is possible by cranial ultrasonography (CUS). Extensive PVHI lesions can be graded using a scoring system that relates to outcome, based on CUS characteristics. Data on more subtle unilateral forms of PVHI are lacking. Objective: To refine the PVHI classification by relating subtypes to affected veins and to evaluate the effects of these anatomical subtypes on neurological outcome. Methods: Retrospective analysis of images and neurological outcome of 20 preterm infants with unilateral PVHI. Based on affected veins, PVHI was classified into six subtypes. Sonographic templates of infarct types are provided in the coronal and parasagittal planes. Standardised neurological examinations were done (according to Amiel-Tison and Touwen examinations) and children were classified as: normal, mildly or definitely abnormal. The outcome was based on the most recent neurological examination, at a corrected age of 1 (n = 7), 2 (n = 5), 3 (n = 5) or 5 (n = 3) years. Results: PVHI classification of the 20 patients was as follows: temporal (n = 3), pure caudate (n = 3), anterior terminal (n = 6), complete terminal (n = 3), extensive (n = 4), other (n = 1). With one exception, only PVHI patients showing the latter three subtypes had developed severe spastic contralesional hemiplegia. Conclusions: The classification was developed for PVHI correlates with neurological outcome. This refined classification can help clinicians in predicting neurological outcome at an early stage, with a subsequent targeted rehabilitation schedule instituted early in life.

Quantitative differentiation between healthy and disordered brain matter in patients with neurofibromatosis type I using diffusion tensor imaging (Article)

2008-04-01T00:00:00Z

BACKGROUND AND PURPOSE: Hyperintensities on T2-weighted images are seen in the brains of most patients with neurofibromatosis type I (NF-1), but the origin of these unidentified bright objects (UBOs) remains obscure. In the current study, we examined the diffusion characteristics of brain tissue in children with NF-1 to test the hypothesis that a microstructural abnormality is present in NF-1. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) was performed in 50 children with NF-1 and 8 controls. Circular regions of interest were manually placed in 7 standardized locations in both hemispheres, including UBO sites. Apparent diffusion coefficients (ADC), fractional anisotropy (FA), and axial anisotropy (Am) were used to differentiate quantitatively between healthy and disordered brain matter. Differences in eigenvalues (λ1, λ2, λ3) were determined to examine parenchymal integrity. RESULTS: We found higher ADC values for UBOs than for normal-appearing sites (P < .01) and higher ADC values for normal-appearing sites than for controls (P < .04 in 5 of 7 regions). In most regions, we found no differences in FA or Am. Eigenvalues λ2and λ3were higher at UBO sites than in normal-appearing sites (P < .04). CONCLUSION: With ADC, it was possible to differentiate quantitatively between normal- and abnormal-appearing brain matter in NF-1 and also between normal-appearing brain matter in NF-1 and healthy brain matter in controls, indicating subtle pathologic damage disrupting the tissue microstructure in the NF-1 brain. Higher diffusivity for λ1, λ2, and λ3indicates that this disturbance of microstructure is caused by accumulation of fluid or vacuolation.

The frontosphenoidal suture: Fetal development and phenotype of its synostosis (Article)

2008-04-01T00:00:00Z

Background: Isolated synostosis of the frontosphenoidal suture is very rare and difficult to diagnose. Little has been reported on the clinical presentation and fetal development of this suture. Objective: To understand the development of the frontosphenoidal suture and the outcome of its synostosis. Materials and methods: We studied the normal fetal development of the frontosphenoidal suture in dry human skulls and the clinical features of four patients with isolated synostosis of the frontosphenoidal suture. Results: The frontosphenoidal suture develops relatively late during the second trimester of pregnancy, which explains the mild phenotype when there is synostosis. This rare craniosynostosis results in a deformity that causes recession of the lateral part of the frontal bone and supraorbital rim, with minimal facial asymmetry. Three-dimensional CT is the best examination to confirm the diagnosis. Conclusion: Isolated frontosphenoidal synostosis should be considered in patients with unilateral flattening of the forehead at birth that does not improve within the first few months of life.

Cortical brain malformations: Effect of clinical, neuroradiological, and modern genetic classification (Article)

2008-03-01T00:00:00Z

Background: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear. Objective: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification. Design: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006. Setting: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center. Patients: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. Results: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients). Conclusions: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.

Foetal growth determines cerebral ventricular volume in infants. The Generation R Study (Article)

2008-02-15T00:00:00Z

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (β = 0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.

Fractional anisotropy in white matter tracts of very-low-birth-weight infants (Article)

2007-12-01T00:00:00Z

Background: Advances in neonatal intensive care have not yet reduced the high incidence of neurodevelopmental disability among very-low-birth-weight (VLBW) infants. As neurological deficits are related to white-matter injury, early detection is important. Diffusion tensor imaging (DTI) could be an excellent tool for assessment of white-matter injury. Objective: To provide DTI fractional anisotropy (FA) reference values for white-matter tracts of VLBW infants for clinical use. Materials and methods: We retrospectively analysed DTI images of 28 VLBW infants (26-32 weeks gestational age) without evidence of white-matter abnormalities on conventional MRI sequences, and normal developmental outcome (assessed at age 1-3 years). For DTI an echoplanar sequence with diffusion gradient (b = 1,000 s/mm2) applied in 25 non-collinear directions was used. We measured FA and apparent diffusion coefficient (ADC) of different white-matter tracts in the first 4 days of life. Results: A statistically significant correlation was found between gestational age and FA of the posterior limb of the internal capsule in VLBW infants (r = 0.495, P<0.01). Conclusion: Values of FA and ADC were measured in white-matter tracts of VLBW infants. FA of the pyramidal tracts measured in the first few days after birth is related to gestational age.

Renal Function and Size at Young Adult Age After Intrauterine Growth Restriction and Very Premature Birth (Article)

2007-10-01T00:00:00Z

Background: Premature birth and intrauterine growth restriction may increase the risk of developing renal disease at adult age. Renal function may already be impaired at young adult age. Study Design: Cross-sectional study. Setting & Participants: Very premature individuals (gestational age < 32 weeks) recruited from Project on Premature and Small for Gestational Age Infants and full-term-born controls (37 to 42 weeks) recruited from a children's hospital in Rotterdam, The Netherlands. All individuals were 20 years of age at the time of study. Predictors: Gestational age and birth weight: premature and small for gestational age (SGA; n = 23), premature and appropriate for gestational age (n = 29), and controls (n = 30). Outcomes & Measurements: Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction before and after renal stimulation with low-dose dopamine infusion and oral amino-acid intake. Urine albumin and renal ultrasound. Results: Height, weight, kidney length and volume, GFR, and ERPF were significantly lower in the SGA group than in controls. After adjustment for body surface area, GFR did not differ significantly among groups. Mean ERPF was 71 mL/min/1.73 m2(95% confidence interval [CI], 3 to 139) less, but filtration fraction was only 1.3% (95% CI, -0.3 to 3.0) greater, in the SGA group than controls. Renal stimulation significantly increased GFR and ERPF and decreased filtration fraction in all groups. After renal stimulation, ERPF was 130 mL/min/1.73 m2(95% CI, 21 to 238) greater in the SGA group than controls, but GFR and filtration fraction did not differ significantly among groups. Microalbuminuria was present in 2 patients (8.7%) in the SGA group, but none in the appropriate-for-gestational-age group or controls. Renal function correlated with renal size. Limitations: Small sample size. Conclusions: Our findings do not fully support the hypothesis that preterm birth in combination with intrauterine growth restriction contributes to renal function alterations at young adult age. Larger studies are needed to evaluate this hypothesis.

Nonpalpable testes: Is there a relationship between ultrasonographic and operative findings? (Article)

2007-04-01T00:00:00Z

Background: Ultrasonography (US) as a diagnostic tool in the work-up of boys with nonpalpable testes (NPT) is still controversial. Objective: To evaluate the relation between US and operative findings in boys with NPT. Materials and methods: During a 7-year period we saw 135 boys with 152 NPT. All were examined by the referring physician or a paediatric surgeon, underwent US examination, and were then re-examined afterwards by a specialist. Finally, all boys were surgically explored for testicular position. Results: US located 103 NPT (68%), 16 within the abdomen and 87 in the inguinal canal. With knowledge of the US result, 37 testes were palpable on re-examination. The sensitivity of US was 97% for inguinal and 48% for abdominal viable testes. Of the 49 testes (32%) missed by US, 16 were viable in either the abdominal (n=14) or the inguinal (n=2) position. Conclusion: All boys with presumed NPT should be referred to a specialist. US is useful to determine localization of NPT, which facilitates planning the surgical procedure. An inguinal exploration is called for when US identifies the testis in the inguinal canal. Because the sensitivity of US for viable abdominal testes is only 48%, we now always perform laparoscopic exploration when US is negative.

The clinical value of follow-up examinations in childhood T-cell acute lymphoblastic leukemia and T-cell non-Hodgkin lymphoma (Article)

2007-04-01T00:00:00Z

Background. The aim of this study was to evaluate the value of follow-up investigations of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell non-Hodgkin's lymphoma (T-NHL), including cerebrospinal fluid (CSF) examination, bone marrow (BM) aspiration, peripheral blood (PB) count, serum lactate dehydrogenase (LDH) and chest X-rays in patients with an initial mediastinal enlargement. Procedure. We reviewed clinical records of all T-ALL patients from 1987 to 2002 and all T-NHL patients from 1977 to 2002, seen at a single institution. Results. Of 48 T-ALL patients, 15 suffered from a relapse, 6 (40%) were asymptomatic at the time of relapse. T-ALL (13/30) with mediastinal enlargement at first diagnosis relapsed versus 2/16 of those without mediastinal enlargement. However, at relapse, only one patient had a mediastinal mass, which in addition was symptomatic. Of 39 T-NHL patients, 6 patients relapsed. Forty percent of relapsed T-ALL and 17% of relapsed T-NHL were asymptomatic. The seven asymptomatic relapses were detected by CSF (n = 4), BM (n = 2) or blood count (n = 1) examinations. All T-ALL and T-NHL patients with a mediastinal relapse were symptomatic. Conclusions. This study suggests that routine CSF examinations during treatment can detect relapses of T-ALL and T-NHL before onset of symptoms, which might be of clinical value. Relapses are rarely detected by BM or blood examinations and whether this translates in a clinical benefit is unlikely. Routine chest X-rays are not useful.