Oliver Rompel

TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects. DOI: http://dx.doi.org/10.7554/eLife.08077.001

Dual source computed tomography in patients with congenital heart disease.

OBJECTIVES The objective of this study was to review our early experience with the dual source computed tomography (DSCT), a recently available scanner technique equipped with two X-ray tubes and two detectors, in the context of congenital cardiac malformations. PATIENTS AND METHODS We reviewed 40 pediatric patients with congenital heart disease (CHD) who underwent DSCT between September 2009 and December 2011 as diagnostic imaging tool for surgical procedures. RESULTS The median age was 0.36 years (range: 3 days to 44 years). Great vessels (n = 13), cardiac anatomy (n = 13), trachea and vascular rings (n = 7), pulmonary veins (n = 4), and coronary arteries (n = 3) were focused on, which revealed important information for surgery. Scanning quality was affected in only two cases (metal artifacts and tachycardia). Overall median age-specific dose was 1.47 mSv. In patients younger than 1 year (n = 26), median dose was 1.28 mSv. CONCLUSION DSCT allows a very rapid scan speed, examinations are performed in spontaneously breathing patients, and the radiation exposure is relatively low. It is very valuable in the setting of complex surgery by revealing the position of anatomical structures in their relation to each other. Missing information can be acquired less invasively in addition to echocardiography and might replace cardiac catheterization for several morphological indications.

Contrast medium application in pediatric high-pitch cardiovascular CT angiography: Manual or power injection?

BACKGROUND Dual-source CT offers accurate depiction of cardiac structures in children with congenital heart disease. For cardiac CT, optimal enhancement of the cardiovascular structures is essential. There is considerable controversy about the administration of contrast medium (CM) in infants and small children, with either a power injector or a manual (hand) injection. OBJECTIVE The aim of this study was to compare image quality with power injection of CM (study group) and manual injection (control group). METHODS Thirty-four patients (study group, 6.8 ± 9.6 months and control group, 4.6 ± 8.9 months, nonrandomized) underwent dual-source CT angiography of the chest using a prospective electrocardiography-triggered high-pitch spiral mode (pitch, 3.4; 80 kV). In the study group (17 patients), a power injector was used, and in the control group (17 patients, historical group), manual CM injection had been performed. To assess image quality, both subjective and objective parameters were evaluated independently by 2 experienced radiologists. RESULTS Subjective overall image quality, signal-to-noise ratio, and contrast-to-noise ratio were significantly higher using power injection compared with manual injection (P < .05). However, depiction of cardiovascular structures did not differ significantly between both groups in all evaluated regions except the superior vena cava and the coronary arteries. CONCLUSION In infants and small children with congenital heart disease, both manual and power injector protocols allowed for diagnostic imaging of cardiac and extracardiac structures. However, image quality and vascular attenuation were superior using a power injector.

Diffuse Encephalopathy Associated with Isolated Cerebral Langerhans Cell Histiocytosis

BACKGROUND Langerhans cell histiocytosis is a rare disease of the monocyte-macrophage system. Abnormalities of the hypothalamic-pituitary region are common in individuals with central nervous system involvement. PATIENT DESCRIPTION This six-year-old boy developed rapidly progressive aggressive behavior, central diabetes insipidus, and repeated complex partial seizures. Magnetic resonance imaging revealed a diffuse leukoencephalopathy-like pattern and numerous infratentorial and supratentorial granulomatous nodules in the brain parenchyma along with infundibular and hypothalamic mass lesions. Stereotactic serial biopsies enabled histopathologic and immunohistochemical diagnosis of Langerhans cell histiocytosis. CONCLUSIONS Similar MRI findings have rarely been described in the literature. These findings represent part of the broad neuroradiological spectrum of Langerhans cell histiocytosis of the nervous system in children.

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding

RYR1 mutations, the most common cause of non-dystrophic neuromuscular disorders, are associated with the malignant hyperthermia susceptibility (MHS) trait as well as congenital myopathies with widely variable clinical and histopathological manifestations. Recently, bleeding anomalies have been reported in association with certain RYR1 mutations. Here we report a preterm infant born at 32 weeks gestation with arthrogryposis multiplex congenita due to compound heterozygous, previously MHS-associated RYR1 mutations, with additional signs of prenatal hemorrhage. The patient presented at birth with multiple joint contractures, scoliosis, severe thoracic rigidity and respiratory failure. He continued to depend on mechanical ventilation and tube feeding. Muscle histopathology showed a marked myopathic pattern with eccentric cores. Interestingly, the patient had additional unusual prenatal intraventricular hemorrhage, resulting in post-hemorrhagic hydrocephalus as well as epidural hemorrhage affecting the spinal cord. This report adds to the phenotypic variability associated with RYR1 mutations, and highlights possible bleeding complications in affected individuals.

Asymmetric Omphalopagus in a Triplet after In Vitro Fertilization: A Rare Case of Conjoined Twinning

Introduction Asymmetric omphalopagus is a rare situation of conjoined twinning, in which a grossly defective twin is attached to the thorax and upper abdomen of the main twin. We describe a case of an asymmetric omphalopagus accompanied by a normal triplet after assisted reproductive technology (ART) and tried to further characterize the all aspects of the conjoined twins. Case Presentation: Perioperative diagnostic imaging was carried out followed by an autopsy to evaluate all aspects of the parasite accompanied by histological, immunohistochemical, and molecular biological evaluation. The parasite had well-developed lower extremities as well as upper extremities with a cleft hand syndrome. The sex was nondeterminable, but DNA fingerprinting revealed that both parasite and autosite are monozygotic, so are females. There was no sign of any axial skeleton or central nervous system. We found a rudimentary rectum with a nonpervious anus, a kidney, ureter, urinary bladder, and a blind-ending urethra. The blood supply of the parasite was connected to the vessel system of the autosite. Conclusions To our knowledge, only two cases of parasitic omphalopagus after ART have been described to date. Altogether, 52 cases have been reported, and in most of them, the parasites were successfully separated.

Histopathological proof of the pathogenicity of a rare GFAP mutation in a patient with flaccid paraparesis

Infantile Alexander disease is a rare progressive leukodystrophy caused by autosomal dominant mutations in the (GFAP) gene typically presenting with psychomotor retardation, progressive macrocephaly and refractory epilepsy. Neuroradiological hallmarks are extensive white matter lesions with frontal preponderance as well as signal intensity changes of basal ganglia and medulla oblongata with variable contrast enhancement. Here, we report an atypical manifestation in a 21-month-old boy presenting with flaccid paraparesis and areflexia. Cognitive, visual as well as fine motor skills and muscular strength of the upper extremities were appropriate for age. Weight and height as well as head circumference were within normal range. Clinical or electroencephalographic signs of seizures were absent. Cranial MRI demonstrated bifrontal cystic tumorous lesions with partial contrast rims, as well as space-occupying focal lesions of the caudate nuclei. Spinal MRI revealed swelling of the lumbar and cervical spinal cord. CSF and blood chemistry showed normal results. Histopathology of a subcortical lesion showed large amounts of Rosenthal fibers and protein droplets characteristic of Alexander disease. Sequencing detected a heterozygous mutation of the GFAP gene (c.205G > A; p.(Glu69Lys)) that has been reported before as probably pathogenetic in another case of lower spinal involvement. This well documented case draws attention to atypical spinal manifestations of Alexander disease and gives histopathological proof of the pathogenetic role of a rare GFAP mutation with marked spinal involvement.

Cardiac MRI in Children and Adolescents Who Have Undergone Surgical Repair of Right-Sided Congenital Heart Disease: Automated Left Ventricular Volumes and Function Analysis and Effects of Different Manual Adjustments.

PURPOSE To evaluate automated segmentation and the effects of different manual adjustments regarding left ventricular parameter quantification in cardiac magnetic resonance (MR) data on children and adolescents who have undergone surgical repair of right-sided congenital heart disease (CHD). MATERIALS AND METHODS Dedicated software (syngo.via, Siemens AG) was used to automatically segment and/or manually adjust the end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), myocardial mass (MM) and ejection fraction (EF) before/after manual apex/base adjustment (ADJ-step 1) and after manual apex/base/myocardial contour adjustment (ADJ-step 2; reference standard). MR data of 40 patients (13.1 ± 3. y, 4 - 17 y) with repaired CHD with decreased pulmonary blood flow (CHD-DPBF) were evaluated. Intra- and inter-rater reliability was determined for 10 randomly selected patients. RESULTS The software correctly detected the left ventricle in 38/40 (95%) patients. EDV after automated segmentation: 119.1 ± 44.0 ml; after ADJ-step 1: 115.8 ± 9.5 ml; after ADJ-step 2: 116.2 ± 39.4 ml. The corresponding results for ESV were 52.0 ± 18.5/49.6 ± 6.9/49.7 ± 16.4 ml; for SV 67.1 ± 28.5/66.2 ± 25.4/66.5 ± 25. ml; for EF 55.5 ± 7.3/56.7 ± 6.6/56.7 ± 6.3%; for MM 83.7 ± 35.9/76.2 ± 8.3/74.6 ± 27.2 g. Significant differences were found for ESV/MM/EF comparing the automated segmentation results with these after ADJ-step 1 and ADJ-step 2. No significant differences were found when comparing all results of ADJ-step 1 and ADJ-step 2 or when comparing EDV/SV results. Intra- and inter-rater reliability was excellent. The mean time effort was 63.4 ± 6.9 s for the automated segmentation, 74.2 ± 8.9 s for ADJ-step 1 and 269.5 ± 39.4 s for ADJ-step 2. CONCLUSION Automated left ventricular volumes and function analysis in children and adolescents with surgically treated CHD proved to be feasible with excellent intra- and inter-rater reliability. Automated segmentation with manual apex/base adjustment provided clinically acceptable results. KEY POINTS Automated left ventricular volume and function analysis in children and adolescents with surgically treated right-sided heart disease is feasible with excellent intra- and inter-rater reliability. Automated segmentation with manual apex/base adjustment provides clinically acceptable results. Additional manual myocardial contour adjustment does not significantly improve the results.