Teresa Salerno

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

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.

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. Pediatr Pulmonol. 2014; 49:E42–E44.

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.

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. Pediatr Pulmonol. 2014; 49:E75–E77.

Bronchiectasis and severe respiratory insufficiency associated with a new surfactant protein C mutation.

Surfactant Protein C (SP-C) mutations determine a wide range of clinical manifestations, from neonatal/infantile diffuse lung disease to adult pulmonary fibrosis (1). Mutations in SP-C gene cause diffuse lung disease in infants, older children and adults. The most common mutations are located in the BRICHOS domain, resulting in misfolding and cytosolic aggregation of the protein. Bronchiectasis has not been reported as a prominent feature in SP-C deficiency. We describe a case of bronchiectasis and severe respiratory insufficiency in a young adult with SP-C deficiency due to a novel mutation in BRICHOS domain. A 27-year-old female was referred for respiratory insufficiency after a severe pneumonia occurred 4 months before. She had suffered from recurrent pneumonia and productive cough since the first years of life. Family history was negative for respiratory disease. General conditions were poor, Body Mass Index 13.7, clubbing, reduced breath sounds in both lung fields. Chest radiograms showed tubular and varicose bronchiectasis and left lower lobe consolidation. High-resolution chest computed tomography (HRCT) confirmed cystic and varicose bronchiectasis predominant in upper lobes, and a left lower lobe consolidation (Fig. 1). Sputum culture was negative, spirometry consistent with marked bronchial obstruction (FEV1 26% of predicted). She was not able to perform a 6-min walking test. Cystic fibrosis (CF) was excluded by three consecutive negative sweat tests and negative CFTR mutations search; immune system deficiencies were ruled out; Primary Ciliary Dyskinesia was ruled out (normal ciliary beating pattern and frequency, normal nasal exhaled Nitric Oxide); no Allergic Bronchopulmonary Aspergillosis (ABPA) was detected; and gastroesophageal reflux disease was excluded by a negative 24-h pHmonitoring. Genetical analysis of SP-C genes revealed a novel BRICHOS nucleotide sequence variant in one allele: the c.463G>C transposition resulting in an amino acid substitution (p. Ala155Pro) in the apoprotein structure. Over 30 mutations were identified within the SP-C gene determining a wide range of clinical manifestations, from neonatal/infantile diffuse lung disease to adult familial and idiopathic pulmonary fibrosis (2). BRICHOS domain mutations, located in the C-terminus of proSP-C, are the most common type: they determine precursor protein misfolding, aberrant intracellular trafficking and cytotoxic protein aggregate storage and impaired proSP-C processing, resulting in altered stress tolerance and surfactant lipid composition. Mature protein mutations are infrequent and lead to SP-C haploinsufficiency, with a less characterized phenotype (3). In our patient, we found a novel BRICHOS nucleotide sequence variant in one allele: the c.463G>C transposition resulting in an amino acid substitution (p.Ala155Pro) in the apoprotein structure. This variation is believed to be pathogenetic because it has not been observed in 100 control chromosomes from our reference population; hence, it is to be considered a novel missense mutation. Unfortunately, the parents, clinically healthy, declined testing, so inheritance remained undetermined, but more than 50% SP-C mutations are known to be sporadic. All patients with proSP-C BRICHOS domain mutations are heterozygous, suggesting a dominant-negative effect of the mutant allele. In a previous study, also Guillot et al. (4) described new mutations in SP-C, linked to the phenotype of their patients: in three patients they were not able to specify if the mutation was familiar or de novo (two in BRICHOS domain): the mutation were considered pathogenic because they have not been found in control chromosomes of the same origin. The mechanisms bridging this SP-C mutation and bronchiectasis are speculative. Mutant SP-C isoforms destabilize endoplasmic reticulum (ER) quality control mechanisms, resulting in the intracellular accumulation of aggregating propeptide, activation of apoptotic pathway and induction of proinflammatory signalling pathway (5). Hence, chronic alveolar epithelial injury may have determined recurrent lower respiratory tract infections and airway damage resulting in bronchiectasis. Phenotype of SP-C deficiency, especially with BRICHOS domain mutations, is extremely variable and sometimes silent and includes apparently healthy subjects who do not have evidence for lung disease, including asymptomatic parents. Hence, DNA analysis of the nearest relatives would have been helpful. Tredano et al. (6) proposed environmental exposures or modifiers genes to play a role in the phenotype, although a rare polymorphism restricted to that population cannot be ruled out. These data indicate a crucial role of SP-C in lung innate immunity, which may explain recurrent infections and bronchiectasis in this patient; her symptoms of severe asthma and suppurative lung disease started in the paediatric age, and all the diagnostic tests performed were negative. SP-C deficiency should always be considered in the differential diagnosis of bronchiectasis, especially when other more frequent causes have already been excluded and in the presence of an unusually severe course. The link between the present phenotype and this new mutation must be confirmed by further molecular studies. Identifying new mutations may improve the diagnosis and our understanding of the pathophysiology of the disease and may allow the development of new therapeutical strategies.

Interstitial lung disease in a child heterozygous for the 1549C→GAA (121ins2) mutation of surfactant protein B

To the Editors: The SFTPB gene encodes the hydrophobic pulmonary surfactant protein (SP)-B, which is essential for the build-up of the surfactant layer and lowering of surface tension in the airways. SP-B deficiency was the first reported genetic cause of lethal respiratory distress syndrome (RDS) in infants in 1993 [1]. The phenotype of infants with hereditary SP-B deficiency is of a typically full-term neonate with respiratory failure in the first 24–48 h of life; diagnosis can be delayed, as affected infants may show initially mild symptoms and not require ventilation or further medical support for some time. Chest radiography shows a bilateral, wide ground-glass pattern consistent with a diagnosis of hyaline membrane disease. Typical histological findings are the presence of periodic acid–Schiff-positive eosinophilic material in the alveoli, epithelial cell desquamation, enlarged alveolar macrophages with lamellar inclusions and accumulation of SP-A [2]. Since SP-B was found to be essential for the proteolytic processing of pro-SP-C, newborns with hereditary SP-B deficiency show aberrantly processed SP-C in the intra-alveolar lumen. Lung disease is rapidly progressive and fatal respiratory failure finally sets in within 3–6 months; lung transplantation is suggested as the only effective treatment. To our knowledge, heterozygous mutation has not previously been reported to cause clinical symptoms. A 6-month-old male was admitted to the Bronchopneumology …

SP-C deficiency: Three different phenotypes for the same mutation

SP-C dysfunction is one of the most frequent causes of Interstitial Lung Disease (ILD). We describe three pts with the same SP-C mutation but different phenotypes. Case 1: TD, 3 yrs, persistent cough, dyspnoea, ground glass opacities and subpleural micronodules at CT. SP-C gene analysis positive for the mutation I73T. Hydroxychloroquine was started, 3 months later TD was asymptomatic, CT improved and normalised after 6 months. Case 2: UM, 4 yrs, healthy up to 6 months, when a RSV caused severe respiratory insufficiency. Normal bronchoscopy, CT with ILD. Referred at one yr, O2 and steroid dependent, CT with wide ground glass opacities and “honeycomb”. Despite systemic steroids CT worsened. Lung biopsy showed desquamative interstitial pneumonia (DIP), ultrastructure was consistent with surfactant deficiency. Genetical analysis showed the I73T mutation. After the 6th iv bolus of high dose steroids CT worsened, hydroxychloroquine was started with a reduction of O2 and steroid needs. The last CT is stable, O2 discontinued. Case 3: CR, recurrent pneumonia in the first year, admitted at 15 months (Naples) for acute respiratory distress. Chest Xray with wide opacities and interstitial thickening, CT scan increased parenchymal density and multiple consolidation. Because of prolonged VM tracheostomy was performed. A lung biopsy, examinated in our Hospital, showed ILD with DIP/alveolar proteinosis. Ultrastructurel was consistent with congenital abnormalities of surfactant proteins. Molecular analysis showed the presence of the mutation I73T. Hydroxychloroquine started after the biopsy, the patient died after 2 weeks Conclusion: This study confrims the eterogeneity of SP-C deficiency despite same genetic mutations.

CONTINUOUS POSITIVE PRESSURE NON-INVASIVE VENTILATION FOR THE MANAGEMENT OF OBSTRUCTIVE SLEEP APNOEA IN A 15-YEAR-OLD GIRL WITH POLYCYSTIC OVARY SYNDROME

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age (4–12%). There may be a strong association between Obstructive Sleep Apnoeas (OSA) and the metabolic derangements of PCOS (insulin resistance in particular). Management of PCOS should consist of appropriate investigations, including assessment of potential OSA, with first line treatments being lifestyle intervention and pharmacological therapies. AG, 15 years, was referred for obesity (BMI 35 kg/m), hypertension, hirsutism, and menstrual irregularity. Normal insulin, glucose and lipid profile, blood pressure, electrocardiography, chest X-ray and lung function, echocardiography. Hormones assay and pelvic ultrasound indicated PCOS. Caloric restriction, exercise program and hormonal treatment were prescribed. Polysomnography (PSG) was consistent with severe OSA. On observation, tonsils occupied less than 25% of the oropharynx and no indication for tonsillectomy was given. Nasal Continuous Positive Airway Pressure (nCPAP) ventilation (10 cmH2O) was provided. She showed optimal compliance to treatment obtaining significant weight loss, improvement of hyperandrogenism, normalization of pelvic ultrasound and OSA resolution. On day 240 of treatment (BMI 24.7 kg/m2), PSG was normal, nCPAP and hormone treatment were discontinued. On day 540, PSG confirmed the absence of OSA (Table 1). OSA are highly prevalent in PCOS, reported in more than 50% PCOS women compared to 19% of controls. Androgen excess, abnormal estrogens and visceral adiposity could be involved. De Sousa reported that weight status, hyperandrogenism, insulin resistance and metabolic syndrome do not seem to have significant effects on Respiratory Polysomnographic Variables (RPV) in adolescents with PCOS, suggesting that the pathomechanisms leading to OSA in PCOS patients develop in the later course of the disease. In PCOS adolescents RPV do not differ from healthy controls; however, there seem to be differences concerning sleep architecture. Adenotonsillectomy represents the first line treatment in the management of paediatric OSA. Non-Invasive Ventilation (NIV) is an additional treatment option for subjects who do not respond to adenotonsillectomy, or in whom it is contraindicated or delayed. No data are reported regarding NIV in adolescent PCOS with OSA. Hoppin et al. described a 15-year-old obese girl with OSA, PCOS and non-alcoholic fatty liver disease who refused NIV was described. In conclusion, adolescents with PCOS are also at risk of OSA. In our patient nCPAP, in combination with lifestyle intervention and pharmacological treatment, resulted in the resolution of OSA, normalization of the weight and significant improvement of clinical and biochemical hyperandrogenism.

Where has the air gone

Pneumorrhachis (air within the spinal canal) is rare and usually associated with other air leaks. Diagnosis is usually by high resolution CT scan. A 9-year-old boy had a 10-day history of persistent cough despite treatment with inhaled bronchodilators, systemic steroids and antibiotics before coming to hospital. Physical examination demonstrated good general condition, cervical subcutaneous emphysema and reduced breath sounds with widespread crackles and …