Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.

Acute hemoptysis and pulmonary hemorrhage after judo as presentation of intralobar sequestration.

Intralobar sequestration (ILS) is a rare anomaly that is usually diagnosed with symptoms of cough, expectoration, or recurrent pneumonia in children. We experienced a case of an 11-year-old boy with massive hemoptysis after judo sports. He was admitted to hospital and intubated due to respiratory failure. His chest computed tomography (CT) scan which was performed without contrast agent revealed a large intrapulmonary hematoma or tumor, mimicking traumatic hemothorax. Due to blood loss and circulatory instability, emergency thoracotomy was performed and a massive intralobar hemorrhage due to a ruptured ILS artery was found. After lobectomy including resection of the ILS, the patient was stabilized and extubated. Aspergillus was detected in the resected lobe and postoperatively acute respiratory distress syndrome (ARDS) and invasive aspergillosis occurred and was treated specifically. However, the young patient was discharged home 3 weeks later. In young patients with hemoptysis and intrapulmonary hemorrhage after trauma, the possibility of ruptured ILS should be kept in mind. This report shows that ILS can have a dramatic course of disease, and for this reason a nonurgent resection should be considered in all patients when this diagnosis is made.

Case report: Idiopathic subglottic stenosis in a girl; successful treatment with macrolides.

An 8-year-old girl presented with treatment-refractory cough and inspiratory stridor. Bronchoscopies showed progressive scarring leading to narrowing of the proximal trachea (Myer-Cotton Grade 2) and epithelial metaplasia of the tracheal and bronchial mucosa. After excluding other causes of congenital and acquired tracheal stenosis, an idiopathic subglottic tracheal stenosis (iSGS) was diagnosed. Because of the patient's young age, a judicious therapeutic approach seemed appropriate. Therapy with azithromycin, followed by roxithromycin, was started. Symptoms almost completely subsided, spirometry normalized, and endoscopic and histologic findings improved considerably. Therapy has been continued for more than 3 years with normal lung function values, and no compromise on physical activities and development. In instances of iSGS, therapy with macrolides is worth considering before more invasive procedures such as dilatation, laser, intralesional injections, or surgical resection are performed.

Lung function tests in neonates and infants with chronic lung disease of infancy: functional residual capacity.

This is the second paper in a review series that will summarize available data and discuss the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses the expansive subject of measurements of lung volume using plethysmography and gas dilution/washout techniques. Following orientation of the reader to the subject area, we focus our comments on areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. Measurements of lung volume are important both for assessing growth and development of lungs in health and disease, and for interpreting volume-dependent lung function parameters such as respiratory compliance, resistance, forced expiratory flows, and indices of gas-mixing efficiency. Acute neonatal lung disease is characterized by severely reduced functional residual capacity (FRC), with treatments aimed at securing optimal lung recruitment. While FRC may remain reduced in established chronic lung disease of infancy, more commonly it becomes normalized or even elevated due to hyperinflation, with or without gas-trapping, secondary to airway obstruction. Ideally, accurate and reliable bedside measurements of FRC would be feasible from birth, throughout all phases of postnatal care (including assisted ventilation), and during subsequent long-term follow-up. Although lung volume measurements in extremely preterm infants were described in a research environment, resolution of several issues is required before such investigations can be translated into routine clinical monitoring.

Lung function tests in neonates and infants with chronic lung disease: forced expiratory maneuvers.

This fourth paper in a review series on the role of lung function testing in infants and young children with acute neonatal disorders and chronic lung disease of infancy (CLDI) addresses measurements of forced expiration using rapid thoraco-abdominal compression (RTC) techniques and the forced deflation technique. Following orientation of the reader to the subject area, we focus our comments on the areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. All studies on infants and young children with CLDI using forced expiratory or deflation maneuvers demonstrated that forced flows at low lung volume remain persistently low through the first 3 years of life. Measurement of maximal flow at functional residual capacity (V'maxFRC) is the most commonly used method for assessing airway function in infants, but is highly dependent on lung volume and airway tone. Recent studies suggested that the raised volume RTC technique, which assesses lung function over an extended volume range as in older children, may be a more sensitive means of discriminating changes in airway function in infants with respiratory disease. The forced deflation technique allows investigation of pulmonary function during the early development of CLDI in intubated subjects, but its invasive nature precludes its use in the routine setting. For all techniques, there is an urgent need to establish suitable reference data and evaluate within- and between-occasion repeatability, prior to establishing the clinical usefulness of these techniques in assessing baseline airway function and/or response to interventions in subjects with CLDI.

Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency.

Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.

Limitations of electronic compensation for measuring plethysmographic airway resistance in infants.

Electronic compensation to overcome thermal artifacts during plethysmographic estimations of airway resistance is now used routinely in adults and school-age children, and was shown to be a valuable means of discriminating airway function between preschool children with and without lung disease. A similar system is now commercially available for infants, which could increase the applicability of this technique. However, we noted marked discrepancies in electronically calculated values of airway resistance in this age group, both with respect to absolute values displayed and marked within-subject variability on a single test occasion. The aim of this technical report is to summarize our recent findings in order to alert other users to potential problems. Airway resistance (R(aw)) was measured in 62 infants (28 with cystic fibrosis (CF); 34 healthy). Three to five epochs of quiet regular tidal breathing were collected in each infant. Marked within-subject, within-test variability was observed, with the median coefficient of variation (CV) being 9.1% (range, 1.2-52.6%) within and 8.5% (0.1-112%) between epochs. Among healthy infants, R(aw) varied from 0.1-6.4 (kPa x liter(-1) x sec), with no relationship to either body or lung size and complete overlap of results with those from infants with CF, despite abnormal lung function in the latter when assessed by other means. The marked within- and between-subject variability in healthy infants, and lack of discriminative power of R(aw) when derived from electronically compensated values, currently preclude application in either clinical or research studies.

Raine syndrome: report of a family with three affected sibs and further delineation of the syndrome.

We describe three affected sibs with Raine syndrome born to a consanguineous Turkish couple. Clinical findings and post-mortem assessment are presented. We have added previously unreported meso and severe telebrachyphalangy and urogenital anomalies to the clinical spectrum. Appositional new bone formation may be mistaken for fractures and callus formation--both prenatally by ultrasound and postnatally in radiographs. Further research is required to detect the underlying metabolic and molecular defects of this autosomal recessive syndrome.

Potential misinterpretation of infant lung function unless prospective healthy controls are studied.

UNLABELLED: SUMMARY RATIONALE: Reliable interpretation of pulmonary function tests relies on appropriate reference data, which remain very limited for infants. OBJECTIVES: This study aimed to assess the validity of published reference equations for forced expiratory flow-volume (FEFV) data in infants when using current, commercially available equipment, and how this could impact on interpretation of results from infants with lung disease. METHODS: The Jaeger Masterscreen BabyBody (v4.67) equipment was used to perform partial and raised volume FEFV maneuvers in healthy infants and those with cystic fibrosis (CF). Results were initially expressed as Z-scores using published reference equations. Multilevel modeling was used to calculate differences, if any, from predicted scores in healthy infants. RESULTS: Data were available from 66 healthy full term infants on 89 test occasions; [median (range) postnatal age 49.4 (12-101) weeks. All FEFV outcomes were significantly lower than predicted, with mean (SD) Z-score differences of -0.4 (1.1) for FVC; -0.6 (1.0) for FEV(0.5); -1.0 (1.0) for FEF(25-75) and -1.4 (1.1) for V'(maxFRC). After adjustments using multilevel modeling, mean Z-scores were within 0.1 (SD approximately 1.0) predicted for all outcomes in healthy infants. Among 50 infants with CF, studied on 85 test occasions, results were "abnormal" (<-1.96 Z-scores) on 35 (41%) and 37 (45%) test occasions for FEV(0.5) and FEF(25-75), respectively, when using published equations. This fell to 24 (28%) and 20 (24%), respectively, after adjustment. CONCLUSIONS: Dependence on published equations for interpreting FEFV data in infants may lead to misinterpretation of lung function status, which could impact adversely both in the research setting and on clinical management. Use of a contemporary control group or establishment of equipment-specific reference data is essential for meaningful interpretation of infant lung function data.

Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests.

BACKGROUND: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. OBJECTIVES: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. METHODS: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. RESULTS: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV(0.5) and FEF(25-75 )) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to -0.3) for FEV(0.5) Z score; FEF(25-75): -1.2 (-2.2 to -0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. CONCLUSIONS: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.

Gastroschisis: a 15-year, single-center experience.

70 cases of gastroschisis (GS) were surgically treated at the Pediatric Surgical University Clinic, Münster, from 1984 through 1998. The defect occurred more frequently in males (44) than females (26). The average birth weight was 2,383 g and mean gestational age 36.8 weeks. 9 infants (12.9%) were delivered vaginally and the rest (87.1%) by cesarean section; 34 of the 61 (55.7%) cesarean sections were done solely for prenatal ultrasonic identification of the abdominal-wall defect. 10 infants (14.3%) underwent primary closure; in 19 (27.1%) primary closure of the skin was possible, however, a single solvent-dried dura (SDD) graft was required for fascial enlargement. The remaining 41 infants (58.6%) had extensive defects and required two grafts for optimal closure. 22 patients (31.4%) had associated anomalies, the most common being bowel atresias and undescended testis. 14 (20%) required secondary laparotomies because of bowel-associated complications and 1 (1.4%) for a urinary-bladder perforation. 11 patients (15.7%) had non-bowel-associated complications. The average postoperative tracheal intubation time was 3.9 days and the average hospital stay was 75.6 days. The overall mortality was 2.8%. No major complications associated with SDD implants were encountered; only 4 patients (5.7%) had minor complications such as local inflamation and infection and were managed conservatively. The present data support the employment of SDD implants as acceptable biomaterial for the repair of large GS defects.

Progressive decline in plethysmographic lung volumes in infants: physiology or technology?

During the last 30 years, there has been an unexplained trend toward declining values for plethysmographic assessments of lung volume at functional residual capacity (FRC) in infants. The aim of this study was to compare data collected from healthy infants using contemporary equipment with published reference data and to explore reasons for discrepancies. Lung volumes were measured in 32 healthy infants (age, 4-93 weeks; weight, 3.9-12.4 kg) using a new, commercially available infant plethysmograph. Mean (SD) FRC was 19.6 (3.4) ml/kg (within subject coefficient of variation 3.4 [2.3%]), which was on average 7.0 [3.5] ml/kg and 2.3 [1.2] SD (Z) scores lower than the recently collated reference data from an American Thoracic Society task force. A total of 66% of these healthy infants had a FRC that was below the predicted normal range. Comparison of equipment, software, and protocols with those from previous reports revealed the importance of minimization of dead space and of adequate subtraction of all compressible occluded volume when calculating FRC in infants. These findings emphasize the need to establish reference data for lung function tests in infants that are appropriate for the equipment and protocols in current use.

Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia.

UNLABELLED: Severely affected children with congenital disorder of glycosylation type Ia (CDG-Ia; MIM 212065) may develop hypertrophic cardiomyopathy. In this report we describe the near-death of a 10-month-old girl with CDG-Ia due to acute left-ventricular outlet obstruction caused by hypertrophic cardiomyopathy and acute dehydration. The girl had multi-organ failure and signs of severe myocardial damage mimicking myocardial infarction. CONCLUSION: hypertrophic cardiomyopathy contributes to the high mortality of young children with congenital disorder of glycosylation type Ia. Even if cardiomyopathy in this disease is non-obstructive, acute fluid-loss might cause left ventricular outflow tract obstruction and life-threatening myocardial ischaemia. Patients with congenital disorder of glycosylation type Ia are at risk for cardiac complications and should be monitored regularly by echocardiography.

Neuropathology of Raine syndrome.

We present three cases of Raine syndrome occurring in siblings of consanguineous parents. Raine syndrome is characterised by generalised osteosclerosis with craniofacial anomalies and intracranial calcifications. So far, only nine cases have been reported, and no evaluation of the distribution and extent of the cerebral mineralisations, as well as their impact on the surrounding tissue, has been undertaken yet. In our cases, calcifications were unevenly distributed throughout the central nervous system, not associated with neuronal loss or dystrophic events and appeared mostly as single calcospherites within the neuropil with occasional confluent deposits at advanced gestational age. There was intense perifocal microgliosis around single immature calcospherites, as well as mild astrogliosis around and within the confluent lesions, in which occasional macrophages could be found. Rarely, mineralisations occurred in blood-vessel walls, mainly affecting basal ganglia. Preferential sites of calcification were parietal and occipital periventricular white matter and corpus callosum, while frontal lobes were mildly affected. The cortex, temporal lobes as well as internal capsule, brain stem, cerebellum, leptomeninges, pituitary gland and choroid plexus were devoid of mineralisations. The subcortical grey matter was moderately involved in the putamen and pallidum, mildly in the caudate nucleus and subependymal germ cell matrix and not at all in the thalamus, Ammon's horn, amygdala and substantia nigra. The distribution of mineral deposits was thus inversely correlated to regional blood circulation and capillary density, with calcifications being concentrated in more sparsely perfused areas but lacking in highly vascularised tissue. This inverse relationship between mineralisation and regional blood flow was reflected in the varying distribution of calcospherites in grey and white matter as well as in the white matter of different lobes.