Dorothy I. Bulas

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

A recessive form of severe osteogenesis imperfecta that is not caused by mutations in type I collagen has long been suspected. Mutations in human CRTAP (cartilage-associated protein) causing recessive bone disease have been reported. CRTAP forms a complex with cyclophilin B and prolyl 3-hydroxylase 1, which is encoded by LEPRE1 and hydroxylates one residue in type I collagen, α1(I)Pro986. We present the first five cases of a new recessive bone disorder resulting from null LEPRE1 alleles; its phenotype overlaps with lethal/severe osteogenesis imperfecta but has distinctive features. Furthermore, a mutant allele from West Africa, also found in African Americans, occurs in four of five cases. All proband LEPRE1 mutations led to premature termination codons and minimal mRNA and protein. Proband collagen had minimal 3-hydroxylation of α1(I)Pro986 but excess lysyl hydroxylation and glycosylation along the collagen helix. Proband collagen secretion was moderately delayed, but total collagen secretion was increased. Prolyl 3-hydroxylase 1 is therefore crucial for bone development and collagen helix formation.

Image Gently: Ten Steps You Can Take to Optimize Image Quality and Lower CT Dose for Pediatric Patients

AJR:194, April 2010 This article suggests 10 steps that radiologists and radiologic technologists, with the assistance of their medical physicist, can take to obtain good quality CT images while properly managing radiation dose for children undergoing CT. The first six steps ideally should be completed before performing any CT on a pediatric patient. The final four steps address the unique consideration that should be given for each scanned patient.

Evaluating children with fractures for child physical abuse

Fractures are common injuries caused by child abuse. Although the consequences of failing to diagnose an abusive injury in a child can be grave, incorrectly diagnosing child abuse in a child whose fractures have another etiology can be distressing for a family. The aim of this report is to review recent advances in the understanding of fracture specificity, the mechanism of fractures, and other medical diseases that predispose to fractures in infants and children. This clinical report will aid physicians in developing an evidence-based differential diagnosis and performing the appropriate evaluation when assessing a child with fractures.

Color Doppler sonography and scintigraphy of the testis: a prospective, comparative analysis in children with acute scrotal pain.

Objective To compare testicular color Doppler sonography with testicular scintigraphy in differentiating between surgical and nonsurgical conditions of the pediatric testis, and to evaluate the role of testicular color Doppler sonography in the pediatric population. Materials and Methods Forty-six children (age range, 1 day to 18 years; median age, 11 years) with acute scrotal pain were evaluated with both scintigraphy and color Doppler sonography by two separate groups of radiologists who had no knowledge of the results of the other modality. The final radiologic diagnosis was classified as a surgical condition, nonsurgical condition, or indeterminate and was compared with the patient’s surgical diagnosis or clinical diagnosis, which was established by response to treatment and follow-up. Results Sonography correctly diagnosed 11 of 14 surgical conditions and 31 of 32 nonsurgical conditions. There was one indeterminate sonogram. There were no false-positive examinations, and there were three false-negative examinations (sensitivity = 78.6% [95% CI, 66.7–90.5%], specificity = 96.9% [95% CI, 94.3–99.5%], accuracy = 91.3%). Color flow was demonstrated in the asymptomatic testis in 34 of 44 boys. Scintigraphy correctly diagnosed 11 of 14 surgical conditions and 29 of 32 nonsurgical conditions. There were two indeterminate scintigrams. There were two false-positive examinations and two false-negative examinations (sensitivity = 78.6% [95% CI, 66.7%–90.5%], specificity = 90.6% [95%CI, 82.2%–99.0%], accuracy = 87.0%). Conclusions Color Doppler sonography and scintigraphy show similar sensitivity for the diagnosis of testicular torsion. A small number of false-negative cases can occur with either modality. The two studies may provide complementary information in indeterminate cases.

MRI imaging of fetal neck masses with airway compromise: utility in delivery planning

Abstract. We present two cases of fetal neck masses that were initially diagnosed by ultrasound and further evaluated with prenatal MRI. MRI findings aided in further delineating the neck masses, increasing confidence in the final diagnosis (cervical teratoma and cystic hygroma). With the fetal airway typically filled with fluid that is of high signal on T2-weighted sequences, MRI images in three planes could identify whether the fetal larynx and trachea were partially or completely compressed by the neck tumor. This information was particularly useful in determining if a controlled delivery such as ex utero intrapartum treatment (EXIT) was necessary and aided the surgeons in planning their approach to establishing airway control in the delivery room.

Benign bacteremia caused by Salmonella typhi and paratyphi in children younger than 2 years.

Blood cultures were systematically performed in children under 2 years of age with fever who were seen at 2 health centers in Santiago Chile during the peak months for typhoid fever to determine whether the very low reported incidence of typhoid fever in this age group reflects lack of consumption of the vehicles that transmit Salmonella typhi or whether infant hosts manifest an atypical response that goes unrecognized. S. typhi was isolated from 4 (2%) of the 197 blood cultures S. paratyphi B from 2 (1%) cultures and S. paratyphi A from 1 (0.5%) culture. The clinical syndrome in these infants was mild consisting of fever for 1-5 days and coughing. All infections resolved without complications even though the mothers spontaneously discontinued chloramphenicol therapy when the symptoms disappeared. The results of this study the 1st ot systematically examine the incidence of typhoid fever in children under 2 years indicate that infants become infected at a higher rate (3.6%) than is commonly assumed and manifest a very mild clinical illness.

Extracorporeal membrane oxygenation exposes infants to the plasticizer, di(2-ethylhexyl)phthalate.

OBJECTIVES To determine the exposure to, and evaluate the potential toxicity from, the plasticizer, di(2-ethylhexyl)phthalate (DEHP) during extracorporeal membrane oxygenation (ECMO) therapy. DESIGN Protocol 1 consisted of a prospective comparison of three ECMO circuit designs in vitro. Protocol 2 consisted of a prospective, comparative clinical study evaluating DEHP plasma concentrations in ECMO vs. non-ECMO patients with respiratory failure. SETTING Neonatal intensive care unit at The Childrens National Medical Center, Washington, DC. PATIENTS In protocol 2, 28 consecutive term infants were referred for ECMO therapy. Eighteen infants required ECMO; ten control patients received conventional ventilation and improved without ECMO. INTERVENTIONS In protocol 1, three ECMO circuit designs were primed in vitro with normal saline, albumin, and human blood, which was maintained at 37 degrees C and recirculated at 400 mL/min for 48 hrs. Plasma samples were obtained at time 0, 1 hr, and every 6 hrs. In protocol 2, ventilatory and cardiovascular management of the patients in the study was conducted by the attending physician. Patients were placed on ECMO when they met the institutional criteria for ECMO therapy. Daily plasma concentrations for DEHP were collected until 3 days after decannulation from bypass in the ECMO group. Control patients were sampled daily until extubation. Evidence of cardiac, liver, or lung toxicity was evaluated by Chest Radiographic Scores, liver function studies, and echocardiograms obtained on day 1, day 3, and the day of decannulation in the ECMO group, or at the time of extubation in the control group. Sedation, blood product transfusions as indicated, antibiotics, and hyperalimentation were administered to all patients. MEASUREMENTS AND MAIN RESULTS All DEHP plasma concentrations were measured by gas chromatography. In protocol 1, three circuits were studied: circuit A (small surface area); circuit B (larger surface area); and circuit C (surface area of A but with heparin-bonded tubing in the circuit). DEHP leached from circuit A at 0.32 +/- 0.12 microgram/ mL/hr, compared with 0.57 +/- 0.14 microgram/mL/hr from circuit B (p < .05). This amount of DEHP extrapolates in the ECMO patient to a potential exposure of 20 to 70 times that exposure from other medical devices or procedures, such as transfusions, dialysis, or short-term cardiopulmonary bypass. Circuit C showed almost no leaching from the circuit; DEHP concentrations decreased at a rate of 0.2 +/- 0.04 microgram/mL/ hr. In protocol 2, DEHP was undetected in the control patients. DEHP concentrations in ECMO patients were greater in the early course of ECMO. However, most patients cleared this compound from the plasma before decannulation. In contrast to the in vitro results in protocol 1, the average highest concentration at any time on bypass was 8.3 +/- 5.7 micrograms/mL or 2 mg/kg. CONCLUSIONS DEHP leaches from ECMO circuits, with potential exposure concentrations related to the surface area of the tubing in the ECMO circuit. Heparin bonding of the tubing eliminates this risk. Although significant concentrations of DEHP leach from the nonheparin-bonded circuits over time, our in vivo studies showed that the DEHP plasma concentrations were less than the previously reported values and do not correlate with any observable short-term toxicity. This compound may be either efficiently metabolized by the newborn, or redistributed into various tissues. Although signs of toxicity were not found in this study, long-term complications from chronic exposure to DEHP have not been determined.

Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks’ gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Transcranial Doppler (TCD) screening for stroke prevention in sickle cell anemia: pitfalls in technique variation

Background. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) identified children as being at high stroke risk if the time-averaged maximum mean velocity (TAMMV) of the middle cerebral or intracranial internal carotid arteries measured ≥ 200 cm/s. These values were obtained utilizing a 2-mHz dedicated nonimaging pulsed Doppler technique (TCD) and manual measurements. Questions have been raised as to the comparability of results obtained with different ultrasound machines and measurement techniques.¶Objective. The purpose of this study was to compare nonimaging (TCD) and transcranial duplex imaging (TCDI) findings in children potentially at risk for stroke with sickle cell disease.¶Materials and methods. Twenty-two children with sickle cell disease and no history of stroke were evaluated by both TCD and TCDI. Examinations were performed on the same day without knowledge of the other modality results and read independently using manually obtained measurements. Mean velocities, peak systolic velocities, and end diastolic velocities obtained by the two techniques were compared. In a subgroup, manual measurements were compared to electronically obtained measurements. ¶Results. TCDI values were lower than TCD measurements for all vessels. TCDI TAMMV values were most similar to the TCD values in the middle cerebral artery (–9.0 %) and distal internal cerebral artery (–10.8 %), with greater variability in the anterior cerebral artery (–19.3 %), bifurcation (–16.3 %), and basilar arteries (–23.1 %). Risk group placement based on middle cerebral artery TAMMV values did not change when comparing the two techniques. Measurements obtained electronically were lower than those obtained manually. ¶Conclusion. Velocities obtained by TCDI may be lower than TCD measurements, and these differences should be taken into consideration when performing screening for stroke risk and selection for prophylactic transfusion based on the STOP protocol.

Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS)

The practice of contrast-enhanced ultrasound in children is in the setting of off-label use or research. The widespread practice of pediatric contrast-enhanced US is primarily in Europe. There is ongoing effort by the Society for Pediatric Radiology (SPR) and International Contrast Ultrasound Society (ICUS) to push for pediatric contrast-enhanced US in the United States. With this in mind, the main objective of this review is to describe the status of US contrast agent safety in non-cardiac applications in children. The five published studies using pediatric intravenous contrast-enhanced US comprise 110 children. There is no mention of adverse events in these studies. From a European survey 948 children can be added. In that survey six minor adverse events were reported in five children. The intravesical administration of US contrast agents for diagnosis of vesicoureteric reflux entails the use of a bladder catheter. Fifteen studies encompassing 2,951 children have evaluated the safety of intravesical US contrast agents in children. A European survey adds 4,131 children to this group. No adverse events could be attributed to the contrast agent. They were most likely related to the bladder catheterization. The existing data on US contrast agent safety in children are encouraging in promoting the widespread use of contrast-enhanced US.