Surfactant Protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation.

BACKGROUND: Monoallelic mutations of the Surfactant Protein C gene (SFTPC) are associated with Interstitial Lung Disease in children. I73T is the most common mutation, accounting for 30 % of all cases reported. CASE PRESENTATION: We describe three patients carrying the same I73T SPC mutation with very different phenotypes, clinical course (ranging from mild respiratory symptoms to death for respiratory failure) and outcome. CONCLUSIONS: The disease mechanisms associated with SP-C mutations suggest that the combination of individual genetic background and environmental factors contribute largely to the wide variability of clinical expression. Infants, children and adults with ILD of unknown etiology should be investigated for SP-C genetic abnormalities.

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations.

Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC - the gene encoding SP-C - SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.

Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene.

NK2 homeobox-1 (NKX2.1) gene encoding the thyroid transcription factor-1 (TTF-1) plays a critical role in lung, thyroid, and central nervous system morphogenesis and function; mutations cause a rare form of progressive respiratory failure associated with alterations of surfactant synthesis, composition, and homeostasis. Molecular mechanisms are heterogeneous and poorly explored. A 28 days old male, soon after birth, presented respiratory failure requiring oxygen treatment at FiO2 27%, prolonged for 2 weeks. Routine neonatal screenings detected a high thyroid stimulating hormone concentration. On day 27 congenital hypothyroidism was confirmed and substitutive treatment was begun. Since the persistence of respiratory symptoms sweat test, CFTR mutation, lymphocyte subpopulations, and sputum cultures were tested, resulting negative. Brain and cardiac defects were also ruled out. Bronchoscopy and BAL analysis were normal. Computed tomography showed bilateral multiple ground glass attenuation, consolidative areas and diffuse bronchial wall thickening. Based on the severity of symptoms, the exclusion of other causes of respiratory disease and the CT findings of interstitial lung disease, we investigated genes affecting the surfactant homeostasis. Sequencing analysis of the three exons of the TTF1 revealed a heterozygous mutation c.334G > T that results in the replacement of glycine in position 112 with a stop codon, generating a nonsense protein that lacks the correct transactivation domain in the C-terminal region. Genetic analysis of the family showed that the father, who was asymptomatic, carried the mutation. Screening for TTF-1 deletions or mutations should always be considered in children with congenital hypothyroidism and an unexplained neonatal respiratory distress or neurodevelopmental deficits.

Late diagnosis of double aortic arch: consequences on long-term follow-up.

Double aortic arch is the most common congenital anomaly of the aortic arch system, in which the trachea and esophagus are completely encircled by vascular segments of the aortic arch and its branches, often resulting in variable airway compression. One case of late diagnosis of this congenital malformation and long-term consequences of late surgical treatment with persistent tracheo-broncomalacia and dynamic airway obstruction is reported. This report emphasizes the importance of an early diagnosis to minimise the progressive airways damage and subsequent respiratory symptoms, that need an accurate medical follow-up.

Night-to-night consistency of at-home nocturnal pulse oximetry testing for obstructive sleep apnea in children.

RATIONALE: At-home nocturnal pulse oximetry has a high positive predictive value (PPV) for polysomnographically-diagnosed obstructive sleep apnea (OSA) but no studies have been published testing the night-to-night consistency of at-home nocturnal pulse oximetry for the evaluation of suspected OSA in children. We therefore determined the night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA in children. METHODS: We prospectively studied 148 children (96 male) aged 4.9 ± 2.4 (1.2-11.8) years, referred for suspected OSA. To evaluate night-to-night consistency, we compared an oximetry analysis method, the McGill Oximetry Score (MOS), from two consecutive at-home nocturnal pulse oximetry recordings. RESULTS: Pulse oximetry metrics were similar on the two nights. The MOS on the two nights showed excellent night-to-night consistency when analyzed as positive for OSA versus inconclusive, 143/148 (Spearman's correlation coefficient = 0.90). A more detailed analysis using four categories (MOS 1, 2, 3, and 4) of OSA severity showed very good night-to-night agreement, 133/148 (Spearman's correlation coefficient = 0.91). Variability was increased in children younger than 4 years of age compared to older children. CONCLUSIONS: Night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA showed excellent agreement. Night-to-night consistency of pulse oximetry, as analyzed by the MOS, for diagnosis and severity evaluation further validates this abbreviated testing method for pediatric OSA. Polysomnography (PSG) is required to rule in or rule out OSA in children if a single night oximetry testing is inconclusive.

Horseshoe lung associated with unique left pulmonary vein: an unreported association.

Horseshoe lung is a rare malformation that is often associated with lung hypoplasia and/or vascular anomalies. We describe a 10-year-old girl with horseshoe lung and unique left pulmonary vein. This is the first reported case with this vascular feature. The patient presented with signs and symptoms of severe pulmonary hypertension and was treated with sildenafil.

Usefulness of a program of hospital-supervised physical training in patients with cystic fibrosis.

Exercise is an important part of normal childhood, but the ability to exercise may be impaired in chronic lung diseases such as cystic fibrosis (CF). Improving exercise performance by training is very attractive. The aim of the present study was the evaluation of the effects of a physical aerobic training program, performed in the Children's Hospital and Research Institute "Bambino Gesù" (Rome, Italy) in outpatient CF children, supervised by a physician. Twelve patients (mean forced expiratory flow in 1 sec (FEV1), 71%), age range 12-24 years (16.7 +/- 4.4 years), were enrolled. They performed a maximal exercise stress test on the treadmill (modified Bruce protocol) with breath-by-breath determination of oxygen consumption (VO2) to maximum at end-exercise; we measured time of exercise (TE), maximal heart rate (Hrmax) in beats per minute (bpm), and maximal systolic blood pressure (SBPm) in mmHg. The program consisted of 12 weeks of training twice a week. Each training session consisted of walking or running on the treadmill for 30 min at the speed that allowed the child to attain 60% of the maximal heart rate obtained during a baseline stress test for 4 weeks, 70% in the following 4 weeks, and 80% in the last 4 weeks, under strict medical supervision. HR was continously monitored. There was no change in FEV1 and forced vital capacity after the treatment period. Hrmax and SBPm also remained the same (P = 0.37 and P = 0.25, respectively). There was a significant increase in TE (P < 0.002), VO2, VO2/kg, and pulmonary ventilation (VE) (P < 0.0001, P < 0.001, and P < 0.001, respectively). This pilot study showed that a simple training program improves short-term cardiopulmonary fitness in children with CF. Further studies with a larger sample and for a more prolonged time are necessary to assess if sport can have a long-term effect on lung function or survival in CF patients.