Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Necrotising pneumonia is an increasingly detected complication of pneumonia in children.

Necrotising pneumonia (NP) is a severe complication of community-acquired pneumonia characterised by liquefaction and cavitation of lung tissue. The present study describes the epidemiology, aetiology, management and outcomes of children hospitalised with NP over a 15-yr period. A retrospective observational study of NP cases was conducted from January 1990 to February 2005 analysing clinical presentation, laboratory data, hospital course and long-term follow-up. A total of 80 NP cases were identified, with the number of detected cases increasing from 12, in the period 1993-1996, to 40 in the period 2001-2004. In total, 69 (86%) cases had pleural effusion with a low pH (mean 7.08) and 38 (48%) patients had positive cultures, with Streptococcus pneumoniae as the predominant organism. Recently, other organisms, most notably methicillin-resistant Staphylococcus aureus, emerged. Patients had prolonged hospitalisations (median 12 days). A total of 69 patients required pleural interventions and those receiving chest drainage alone had similar outcomes to those managed surgically. All patients had full clinical resolution within 2 months of presentation. Necrotising pneumonia has increasingly been identified as a complication of paediatric pneumonia. Streptococcus pneumoniae remains the predominant organism, but since 2002, different bacteria have been isolated and the age range of cases has broadened. Despite the serious morbidity, massive parenchymal damage and prolonged hospitalisations, long-term outcome following necrotising pneumonia is excellent.

Thymic size on chest radiograph and rapid disease progression in human immunodeficiency virus 1-infected children.

BACKGROUND: Early infection of the thymus, an organ central to the ontogeny of the immune system, has been proposed as a cause of rapid progression in pediatric HIV disease. OBJECTIVE: To test the hypothesis that small thymic volume is associated with rapid disease progression in HIV-infected children. DESIGN: Three pediatric radiologists established criteria for rating the size of the thymic profile on chest radiographs. All available baseline chest radiographs were reviewed in a random sequence, with radiologists blinded to study subjects' clinical status. A consensus was reached on whether the thymus was normal or small for age. SETTING: A prospective multicenter study of the natural history of HIV-1 infection in children, the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Infection (P2C2) Study. PATIENTS: Fifty-eight HIV-infected children and 38 control children (uninfected but born to HIV-infected women) for whom chest radiographs in the first year of life were available. MAIN OUTCOME MEASURE: Rapid progression of HIV disease, defined as CDC Clinical Category C (severely symptomatic) or Immunologic Category 3 (severe immunosuppression) by 1 year of age. RESULTS: The mean age at the time of chest radiography was 3.5 months. Ten (17%) HIV-infected children had reduced thymic profile size, whereas no controls did (P = 0.006). Of the 58 (59%) HIV-infected children 34 were classified as rapid progressors, and 9 (26%) of them had reduced thymus size, compared with 1 (4%) of the non-rapid progressor children [odds ratio, 8.28; 95% confidence interval (CI), 1.0, 70.5; P = 0.035]. Baseline mean CD4+ count was 1642 (95% CI 1322 to 2009) cells/microl for those with normal thymus and 740 (95% CI 380 to 1275) cells/microl for those with reduced thymus (P = 0.007). CONCLUSION: Early thymic involution is associated with rapidly progressive disease in HIV-infected children.

Digit effects produced by prenatal exposure to antiepileptic drugs.

The hypothesis tested was that digit anomalies among individuals exposed in utero to antiepileptic drugs (AED) are best identified by a systematic search, including radiographs and dermatoglyphics, rather than relying only on visual inspection. A systematic search was made for five types of digit abnormalities in 46 AED-exposed individuals ages 5-29 years in comparison with controls: visible anomalies, size of fingernails, dermal ridge patterns, length of metacarpals and phalanges, and qualitative changes in the distal phalanges. Among the AED-exposed, nail size was not decreased. However, there was a 10.8% frequency of digit anomalies, a 12% frequency of three or more arch patterns, and significant shortening and qualitative changes in the distal phalanges, all of which are consistent with the fetal effects of AED. Among the 42 individuals who underwent all evaluations, 14.3% had two or more of these abnormalities, most of which would not be identified by clinical inspection. This frequency is much higher in these AED-exposed individuals than in the general population. Radiographs in 13 individuals over a period of several years showed that the changes in the phalanges and metacarpals persisted.

Cystic fibrosis: predictors of accelerated decline and distribution of disease in 230 patients.

OBJECTIVE: The purpose of this study was to determine predictors of accelerated deterioration in radiographic manifestations of cystic fibrosis. The incidence and distribution of focally accentuated disease were also studied. MATERIALS AND METHODS: From 230 patients, 3038 chest radiographs were scored using the Brasfield system. Scores were plotted against age, and a single age-based severity curve was created. Specific observations (at least one episode in the first 5 years of life of air trapping, linear markings, nodular cystic lesions, or large lesions) were assessed to determine predictors of accelerated decline in scores compared with the aggregate scores plotted in the age-based severity curve. Specific observations were noted as present or absent and graded as to severity. A specific observation was counted as present if seen on at least one occasion. (The number of occasions on which the observation was made did not affect statistical analysis.) We also evaluated the distribution of lung disease by assessing the severity and nature of disease through specific lobar distribution. RESULTS: Males showed a slightly greater rate of radiologic decline. Early development of air trapping or bronchiectasis was associated with an accelerated rate of decline over time. Lobe-dominant disease occurred in one third of all images and in two thirds of the patients. It varied with age in its incidence, location, and etiology. CONCLUSION: Hyperinflation or bronchiectasis that occurs before age 5 is associated with accelerated radiographic deterioration. The incidence and location of lobe-dominant disease varied with age in these patients.

Cystic fibrosis: a system for assessing and predicting progression.

OBJECTIVE: This study presents a radiography-based database scoring changes over time in a large population of patients with cystic fibrosis. The purpose of this database is to provide comparison for groups of patients undergoing experimental treatment to assess effect of the treatment. The data may also be used to compare individuals with their age-matched cohorts with cystic fibrosis. MATERIALS AND METHODS: From 230 patients, 3038 chest radiographs were scored using the Brasfield system. The scores from radiographs from all the patients were individually plotted for age, and a single age-based severity curve was created. The age-based severity curve was compared with similar curves derived from pulmonary function studies of a subset of the same patient population. RESULTS: We found high inter- and intraobserver reliability. The difference between the observers averaged 1.3 Brasfield points, the scale of which ranges up to 25 points. The age-based severity curve was presented as mean Brasfield scores versus age (birth to > 30 years) plotted with 95% confidence limits; the curve was also plotted in percentiles. The rate of decline of this curve was similar to the decline of pulmonary function studies in this patient population. CONCLUSION: The age-based curve, a structural anatomic parameter, differs from pulmonary function studies, which are functional. Thus the age-based severity curve provides an additional, independent basis for comparison between groups and individuals. It may be used for the initial assessment of lung disease and for gauging and predicting the rate of decline. The curve may be used as a long-range outcome criterion to evaluate new treatments in groups of patients with cystic fibrosis.

Chest radiographic data acquisition and quality assurance in multicenter studies.

BACKGROUND: Multicenter studies rely on data derived from different institutions. Forms can be designed to standardize the reporting process allowing reliable comparison of data. OBJECTIVE: The purpose of the report is to provide a standardized method, developed as a part of a multicenter study of vertically transmitted HIV, for assessing chest radiographic results. MATERIALS AND METHODS: Eight hundred and five infants and children were studied at five centers; 3057 chest radiographs were scored. Data were entered using a forced-choice, graded response for 12 findings. Quality assurance measures and inter-rater agreement statistics are reported. RESULTS: The form used for reporting chest radiographic results is presented. Inter-rater agreement was moderate to high for most findings, with the best correlation reported for the presence of bronchovascular markings and/or reticular densities addressed as a composite question (kappa = 0.71). The presence of nodular densities (kappa = 0.56) and parenchymal consolidation (kappa = 0.57) had moderate agreement. Agreement for lung volume was low. CONCLUSION: The current tool, developed for use in the pediatric population, is applicable to any study involving the assessment of pediatric chest radiographs for a large population, whether at one or many centers.

A study of level of lesion, associated malformations and sib occurrence risks in spina bifida.

Neural tube defects remain the most serious common birth defect and, despite considerable progress in understanding these malformations, the etiology of most cases remains unknown. It has been proposed that the cause may vary with the type and location of the malformation but, if these variables are to be studied, a rigorous classification of cases is required. This has become more important as birth prevalence has fallen, mainly due to prenatal diagnosis and elective termination of pregnancy, and future studies will increasingly require collaboration between centres. In this study we have combined data from Ottawa, Ontario, and Boston, Massachusetts, in an attempt to examine the effect of level of spina bifida on sib occurrence rates and the rates of associated malformations, and to compare the level of lesion when determined radiographically with that recorded on the clinical chart. Malformations appeared to be more frequent with thoracic spina bifida and were more often associated with additional vertebral anomalies. Significant differences were found between the upper level of lesion recorded in the clinical file and that visible radiographically. Sib recurrences were too few for statistical comparison, but the data suggest a higher rate among sibs and more distant relatives of propositi with upper level lesions. There was not evidence to support a greater than expected concordance for level of lesion between sibs.

Pseudomembranous colitis: CT findings in children.

A spectrum of nodular haustral thickening and an accordion pattern have been reported as specific features of pseudomembranous colitis (PMC) in adults. A retrospective review of nine patients with PMC was performed to assess whether this spectrum of CT findings also occurred in children. In four girls and five boys, CT scans were performed within 3 days of a positive stool toxin assay for Clostridium difficile. Documented CT abnormalities included nodular haustral thickening, the accordion pattern, colonic wall thickening, ascites, and pericolonic edema. These results were then correlated as to their impact on the clinical outcome. Circumferential colon wall thickening was identified in 7/9 (78 %) patients (mean thickening 14.5 mm). Nodular haustral thickening was identified in 4/9 (44 %) and the accordion pattern in 2/9 (22 %). Other findings included pericolonic edema in 3/9 (33 %) and ascites in 1/9 (11 %). Wall thickening was confined to the left colon and rectum in 2/9 (22 %), to the right colon in 2/9 (22 %), and involved the whole colon in 3/9 (33 %). Although CT findings associated with PMC in children may be suggestive for this diagnosis, CT is less specific than laboratory and clinical findings.

A radiologic update on medical diseases of the newborn chest.

This paper reviews the common spectrum of medical diseases of the neonatal chest. Emphasis is on radiographic changes that have been produced by the introduction of new therapeutic maneuvers, particularly the use of artificial surfactant in treating hyaline membrane disease and the survival of profoundly premature newborns (less than 650 g). A discussion of meconium aspiration syndrome, neonatal pneumonia, transient tachypnea of the newborn, congenital lymphangiectasia, and congenital heart disease is also included. The effects on the neonatal chest radiograph of extracorporeal membrane oxygenation and high-frequency ventilation are also mentioned.

Retained fetal lung liquid in congenital lobar emphysema: a possible predictor of polyalveolar lobe.

The purpose of this study was to determine whether retention of fetal lung liquid is more prevalent in polyalveolar congenital lobar emphysema than in conventional congenital lobar emphysema. Two patients with congenital lobar emphysema were prospectively identified in a 3-year period. Twenty-five such patients were identified in a retrospective study covering 39 years. Medical records were available for 22 patients who had 23 emphysematous lobes. Both babies from the prospective study and six subjects from the retrospective group had respiratory symptoms and underwent chest X-ray in the first day of life. Six of the eight babies with respiratory symptoms and chest imaging in the first day of life had retention of fetal lung liquid in an emphysematous lobe. All six of these lobes were polyalveolar. The lobe in one child was a polyalveolar lobe but without retained fetal lung liquid, and one child exhibited conventional lobar emphysema also without retained fetal lung liquid. One polyalveolar lobe caused no neonatal symptoms and was not imaged until the child was 3 months old. No baby with conventional lobar emphysema was shown to have retained fetal lung liquid. There seems to be a correlation between polyalveolar lobe and onset of respiratory symptoms in the first day of life. Retention of fetal lung liquid within the affected lobe was documented only in cases of polyalveolar lobe.

Voiding cystourethrography in children: value of digital fluoroscopy in reducing radiation dose.

Voiding cystourethrography is a commonly used fluoroscopic procedure in children that can directly irradiate the gonads. As a consequence, much attention has been given to reducing the dose of radiation received during the procedure. A digital fluoroscope, especially adapted for use in children, was evaluated for potential reduction of the dose of radiation during the procedure. Entrance and midplane doses were calculated on child-sized phantoms by using the digital fluoroscope, digital spot films, and 105-mm spot films. Subsequently, data were collected on 47 children, grouped by ages (neonate to 1 year, 1-5 years, and 5-7 years), in whom voiding cystourethrography was performed by using the same exposure factors as those for the phantoms. On the basis of the exposure doses for the phantoms and recorded clinical peak kilovoltages, milliamperes, milliseconds, and fluoroscopic time, average skin and ovarian doses were calculated for each group of children. These doses were compared with previously reported doses for fluoroscopic and radionuclide voiding cystourethrography. Results of line-pair resolution studies for the digital spot films and 105-mm spot films were similar. Images from the digital device and 105-mm images obtained on a conventional fluoroscope were considered equally adequate for clinical decision making. The average midplane and skin doses with digital spot films for children less than 5 years old were equal to or less than 0.66 and 2.37 mGy, respectively, as opposed to 1.37 and 5.32 mGy with the 105-mm spot films. Previously reported ovarian doses range from 2.52 to 10.0 mGy for fluoroscopic voiding cystourethrography and from 0.04 to 0.05 mGy for radionuclide voiding cystourethrography. The use of digital spot films reduced dose approximately 50% compared with 105-mm spot films; the ovarian dose was 0.62 mGy greater than that for radionuclide voiding cystourethrography.

Videofluoroscopic analysis of the infant swallow.

A better understanding of the abnormal infant swallowing mechanism requires better knowledge of the normal infant swallow. Twenty-one full-term infants under six months of age were examined using videofluoroscopy of the swallowing portion of upper gastrointestinal examinations. Components of the oral and pharyngeal stages of swallowing were evaluated. Results showed high reliability between two raters in obtaining measurement data. There was variability in suck and oral transit time, which was correlated to the number of sucks per swallow. All infants appeared to move their tongue in a "stripping" motion, and collected the material in various sites in the oral cavity or oropharynx before initiation of the swallow. The incidence of nasopharyngeal reflux was low (9.5%). The majority of infants demonstrated a slight residue in their valleculae and hesitation in the cervical esophagus. These findings indicate that videofluoroscopy provides an objective and systematic method for analyzing the infant swallowing mechanism.

Epiphyseal marrow in infancy: MR imaging.

Hypointense epiphyseal marrow on T1-weighted magnetic resonance images often suggests disease. To determine whether hypointense marrow sometimes represents normal red marrow in a recently ossified epiphyseal center, the authors studied 38 infants without known marrow disease. Patients with hypointense epiphyseal marrow on T1-weighted images were younger (3.9 months +/- 3.2) than those with hyperintense marrow (9.6 months +/- 3.9) (P less than .001). T1-weighted imaging and histologic correlation were also performed in animals. The signal was hypointense and the marrow was red in the epiphyseal centers of all newborn animals, while all 6-week-old animals had hyperintense signal and yellow marrow. The authors conclude that hypointense marrow on T1-weighted images represents normal red marrow in a recently formed ossification center in newborn rabbits and lambs, and the same is probably true in humans. Epiphyseal marrow becomes hyperintense within a few months of development of the secondary center of ossification.

Neonatal cranial ultrasonography.

We trace the evolution of pediatric cranial sonography from its inception to the present. Technical considerations and Doppler imaging are discussed. Scanning techniques and a review of the sonographic landmarks of normal anatomy are presented. Knowledge of these landmarks will facilitate screening examinations. We then present clinical and screening indications for cranial sonography in the neonate, emphasizing the pathogenesis and classification of intracranial hemorrhage and porencephaly. Finally a description of inflammatory lesions and their sonographic appearances and a review of cystic and solid lesions completes the discussion of cranial sonography in the neonate.

Coexisting nephrolithiasis and cholelithiasis in premature infants.

Though the coexistence of nephrolithiasis and cholelithiasis in premature infants is extremely rare, we report four patients seen in a two year period. All patients weighed less than 1100 grams at birth, developed severe bronchopulmonary dysplasia, and all had Grade III or IV bilateral intraventricular hemorrhages. All four infants received prolonged furosemide therapy lasting at least 28 consecutive days. The renal stones disappeared in all four upon cessation of therapy, while in none have the gallstones disappeared after a mean follow-up period of 13 months. Ultrasound was superior in identifying and monitoring these stones. Their presence resulted in manipulating diuretic therapy which then was shown to limit renal and possibly biliary complications.