Laura Menchini

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.

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.

Encephalocraniocutaneous lipomatosis (ECCL): Neuroradiological findings in three patients and a new association with fibrous dysplasia

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome characterized by involvement of tissues of ectodermal and mesodermal origin such as skin, eye, adipose tissue, and brain. Since 1970, when Haberland and Perou had described the first patient, 54 cases of ECCL have been reported in literature. We report on three new boys with ECCL. In addition to their typical dermal, ocular and central nervous system anomalies, one of them had a spheno‐ethmoidal osseous lesion. Histopathological evaluation confirmed the benign nature of the lesion and was consistent with fibrous dysplasia. The aim of our study is to review clinical records and brain imaging studies of these three new patients with ECCL and compare these findings with those reported in literature to better define the phenotypic spectrum and radiological findings in ECCL.

Parapharyngeal neuroglial heterotopia in Pierre Robin sequence: MR imaging findings

Heterotopic neuroglial tissue is a rare lesion, occurring more frequently in the nasal cavities. Other rare locations are the orbit, the scalp, the palate, the pharynx, the parapharyngeal space and the lungs. They are usually detected occasionally because they are often asymptomatic, but sometimes they might present with dyspnoea, feeding difficulty, snorting and nasal flaring. Respiratory symptoms occur when heterotopic neuroglial tissue is located in the parapharyngeal space. We report a case of an infant affected by Pierre Robin sequence (PRS) who was admitted to our Institution for a worsening respiratory distress that was not explainable only by PRS.

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.

Dynamic expiratory CT: An effective non‐invasive diagnostic exam for fragile children with suspected tracheo‐bronchomalacia

Tracheobronchomalacia, defined as variable collapse of the airways, has been recognized as an important cause of respiratory morbidity but still widely underdiagnosed. Bronchoscopy is still considered as the gold standard, but numerous limitations are known, especially for fragile sick children. Moreover, information on parenchymal lung disease cannot be described. There is a real need for a reliable, non‐invasive test to help detection of airway and parenchymal malformations in children, specifically when bronchoscopy cannot be performed.

Central nervous system tuberculosis in non-HIV-positive children: a single-center, 6 year experience

PurposeThe aim of this paper is to describe the imaging features of central nervous system (CNS) tuberculosis on computed tomography (CT) and magnetic resonance imaging (MRI) studies in non-HIV-positive children.Materials and methodsA retrospective descriptive evaluation was conducted on imaging studies obtained from ten children admitted to our hospital over a 6-year period who fulfilled criteria for a diagnosis of CNS tuberculosis. Data were collected with regard to patients’ clinical, laboratory and demographic characteristics, as well as results of radiological investigation.ResultsWe studied ten children, of whom five were boys and five were girls and whose mean age was 4 (range 7 months to16) years. Neuroradiological findings on the first imaging study were basal meningeal enhancement (100%), hydrocephalus (70%), infarcts (90%), tuberculomas (40%) and cranial nerve involvement (20%). Follow-up studies revealed basal meningeal enhancement, hydrocephalus, and infarcts in all patients, tuberculomas in 70% and cranial nerve involvement in 50%. Only one patient showed a pattern of miliary tuberculosis.ConclusionsCNS tuberculosis is still an important cause of childhood morbidity and mortality even in nonimmunosuppressed children. Because prompt diagnosis results in earlier treatment, it is crucial to be aware of tuberculous meningitis and its complications at imaging, especially because of the impact on patients’ prognosis.RiassuntoObiettivoScopo di questo studio è descrivere le caratteristiche della tubercolosi del sistema nervoso centrale alla tomografia computerizzata e alla risonanza magnetica, in un gruppo di bambini non positivi al virus dell’immunodeficienza umana acquisita (HIV).Materiali e metodiAbbiamo condotto una indagine retrospettiva descrittiva su 10 bambini con diagnosi di tubercolosi del sistema nervoso centrale, ricoverati nel nostro ospedale in un periodo di 6 anni. I dati dei pazienti riguardavano gli aspetti clinici, laboratoristici, demografici e neuroradiologici.RisultatiSono stati ammessi nello studio 10 pazienti, 5 maschi e 5 femmine. L’età media dei pazienti era di 4 anni (tra 7 mesi e 16 anni). I reperti neuroradiologici rilevati all’indagine iniziale sono stati impregnazione delle meningi della base cranica (100%), idrocefalo (70%), lesioni infartuali (90%), tubercolomi (40%) e interessamento dei nervi cranici (20%). Nel controllo successivo tutti i pazienti presentavano impregnazione delle meningi della base cranica, idrocefalo e infarti, il 70% presentava tubercolomi e il 50% interessamento dei nervi cranici. Solo in un paziente è stata evidenziata una forma miliare.ConclusioniLa infezione tubercolare del sistema nervoso centrale è ancora un’importante causa di morbilità e mortalità in bambini non immunodepressi. Poiché l’inizio precoce della terapia determina una prognosi migliore è importante effettuare una diagnosi neuroradiologica tempestiva.

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.

La tubercolosi del sistema nervoso centrale in bambini non-HIV positivi: l'esperienza di 6 anni di osservazione in un unico centro

PurposeThe aim of this paper is to describe the imaging features of central nervous system (CNS) tuberculosis on computed tomography (CT) and magnetic resonance imaging (MRI) studies in non-HIV-positive children.Materials and methodsA retrospective descriptive evaluation was conducted on imaging studies obtained from ten children admitted to our hospital over a 6-year period who fulfilled criteria for a diagnosis of CNS tuberculosis. Data were collected with regard to patients’ clinical, laboratory and demographic characteristics, as well as results of radiological investigation.ResultsWe studied ten children, of whom five were boys and five were girls and whose mean age was 4 (range 7 months to16) years. Neuroradiological findings on the first imaging study were basal meningeal enhancement (100%), hydrocephalus (70%), infarcts (90%), tuberculomas (40%) and cranial nerve involvement (20%). Follow-up studies revealed basal meningeal enhancement, hydrocephalus, and infarcts in all patients, tuberculomas in 70% and cranial nerve involvement in 50%. Only one patient showed a pattern of miliary tuberculosis.ConclusionsCNS tuberculosis is still an important cause of childhood morbidity and mortality even in nonimmunosuppressed children. Because prompt diagnosis results in earlier treatment, it is crucial to be aware of tuberculous meningitis and its complications at imaging, especially because of the impact on patients’ prognosis.RiassuntoObiettivoScopo di questo studio è descrivere le caratteristiche della tubercolosi del sistema nervoso centrale alla tomografia computerizzata e alla risonanza magnetica, in un gruppo di bambini non positivi al virus dell’immunodeficienza umana acquisita (HIV).Materiali e metodiAbbiamo condotto una indagine retrospettiva descrittiva su 10 bambini con diagnosi di tubercolosi del sistema nervoso centrale, ricoverati nel nostro ospedale in un periodo di 6 anni. I dati dei pazienti riguardavano gli aspetti clinici, laboratoristici, demografici e neuroradiologici.RisultatiSono stati ammessi nello studio 10 pazienti, 5 maschi e 5 femmine. L’età media dei pazienti era di 4 anni (tra 7 mesi e 16 anni). I reperti neuroradiologici rilevati all’indagine iniziale sono stati impregnazione delle meningi della base cranica (100%), idrocefalo (70%), lesioni infartuali (90%), tubercolomi (40%) e interessamento dei nervi cranici (20%). Nel controllo successivo tutti i pazienti presentavano impregnazione delle meningi della base cranica, idrocefalo e infarti, il 70% presentava tubercolomi e il 50% interessamento dei nervi cranici. Solo in un paziente è stata evidenziata una forma miliare.ConclusioniLa infezione tubercolare del sistema nervoso centrale è ancora un’importante causa di morbilità e mortalità in bambini non immunodepressi. Poiché l’inizio precoce della terapia determina una prognosi migliore è importante effettuare una diagnosi neuroradiologica tempestiva.