Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA3: A case report.

Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C-terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C-terminal domain, which includes sequence motifs necessary for the function of human paralogs ABCA1, ABCA4, and the bacterial homolog DrrA. This observation suggests the C-terminal domain is also required for normal function of ABCA3.

Nous conceptes sobre la malaltia pulmonar difusa de la infància / Nuevos conceptos sobre la enfermedad pulmonar de la infancia / New concepts of diffuse lung disease in children

Fonament: la malaltia pulmonar intersticial de la infància és un terme poc acurat tenint en compte l'existència d'entitats pulmonars difuses sense afectació intersticial. Per aquest motiu, l'American Thoracic Society (ATS) pro-posa el terme de malaltia pulmonar difusa de la infància específica de pacients menors de dos anys. Objectiu: conèixer les característiques clíniques, radiològiques i histològiques d'aquest tipus de malalties. Mètode: revisió bibliogràfica dels últims deu anys mitjançant Pubmed i Uptodate. Resultats: les entitats que formen part de la malaltia pulmonar difusa de la infància tenen les característiques següents: són específiques de pacients menors de 2 anys, presenten alteracions genètiques i alteracions en el desenvolupament i el creixement pulmonar, i són diferents de la malaltia pulmonar intersticial de l'adult. Es manifesten amb clínica d'insuficiència respiratòria, més o menys greu, i presenten infiltrats difusos a la radiografia de tòrax. Aquestes entitats s'agrupen en quatre categories: les anomalies del desenvolupament difús del pulmó, les anomalies del creixement pulmonar, les condicions específiques de causa indeterminada i les malalties relacionades amb el dèficit de surfac-tant. El tractament amb corticoides i/o hidroxicloroquina sembla beneficiós en alguna. El trasplantament pulmonar és l'única opció en les entitats més greus, mentre que d'altres poden tenir un curs més benigne o cronificar-se. Conclusions: cal destacar la importància de tenir present aquestes malalties en el diagnòstic diferencial de pacients menors de 2 anys amb afectació pulmonar difusa i clínica d'insuficiència respiratòria persistent, per planificar-ne el maneig i establir un pronòstic a curt i llarg termini

Fundamento. La enfermedad pulmonar intersticial de la infancia es un término poco preciso dada la existencia de entidades pulmonares difusas sin afectación intersticial. Por este motivo, la American Thoracic Society (ATS) propone el término de enfermedad pulmonar difusa de la infancia específica de pacientes menores de dos años. Objetivo. Concocer las características clínicas, radiológicas e histológicas de este tipo de enfermedades. Método. Revisión bibliográfica de los últimos diez años mediante Pubmed y Uptodate. Resultados. Las entidades que forman parte de la enfermedad pulmonar difusa de la infancia tienen las siguientes características: son específicas de pacientes menores de 2 años, presentan alteraciones genéticas y alteraciones en el desarrollo y crecimiento pulmonar y son diferentes de la enfermedad pulmonar intersticial del adulto. Se manifiestan con clínica de insuficiencia respiratoria, más o menos grave, y presentan infiltrados difusos en la radiografía de tórax. Estas entidades se agrupan en cuatro categorías: las anomalías del desarrollo difuso del pulmón, las anomalías del crecimiento pulmonar, las condiciones específicas de causa indeterminada y las enfermedades relacionadas con el déficit de surfactante. El tratamiento con corticoides y/o hidroxicloroquina puede ser beneficioso en alguna de ellas. El trasplante pulmonar es la única opción en las entidades ás graves, mientras que otras pueden tener un curso más benigno o cronificarse. Conclusiones. Destacar la importancia de tener presente este tipo de enfermedades en el diagnóstico diferencial de pacientes con afectación pulmonar difusa y clínica de insuficiencia respiratoria persistente, para planificar su manejo y establecer un pronóstico a corto y largo plazo (AU)

Background. The term 'childhood interstitial lung disease' is not very accurate due to the many diffuse lung conditions without interstitial involvement. The American Thoracic Society (ATS) proposes instead the use of the term 'childhood diffuse lung disease' for patients less than two years of age. Objective. To describe the clinical, radiological, and histological features of this condition. Method. Review of published literature over the last 10 years, as reported in Pubmed and UpToDate. Results. All entities described as childhood diffuse lung disease share the following features: they are specific for patients under two years of age; they are associated with genetic abnormalities and lung growth development defects, and they differ from adult interstitial lung disease. Patients suffer from varying degrees of respiratory distress, and most often have diffuse opacities on chest radiography. Such entities are grouped around four categories, namely: pulmonary diffuse developmental disorders, anomalies in lung growth, diseases of unknown etiology, and surfactant dysfunction disorders. Corticosteroids and/or hydroxychloroquine treatment may improve respiratory symptoms for some patients. The only curative option for severe cases is lung transplantation, while mild cases may have a more benign or chronic course. Conclusion. It is important to consider these disorders in the differential diagnosis of persisting respiratory failure and diffuse lung disease, in order to manage them properly (AU)

Evaluation of specificity and sensitivity of gastric aspirate shake test to predict surfactant deficiency in Iranian premature infants.

INTRODUCTION: Respiratory failure secondary to pulmonary surfactant deficiency is an important cause of severe respiratory distress in term and preterm infants. The aim of this study was to evaluate the specificity and sensitivity of gastric aspirate shake test (GAST) to predict surfactant deficiency in newly born premature infants in Arash Hospital (Iran) during 2012-13. METHODS: In this case-control study, the case group comprised 69 premature infants (gestational age<37 weeks) who were admitted to the neonatal intensive care unit due to respiratory distress. The control group included 50 healthy infants .GAST test was done. The subjects were finally categorized as healthy or surfactant-deficient based on clinical and radiological assessments. RESULTS: Using statistical methods the sensitivity, specificity, and positive and negative predictive values of GAST were 60%, 75%, 15%, and 52%, respectively. There was a significant difference between respiratory distress syndrome (RDS) scores and receiving surfactant in neonates with gestational age below 34 weeks. Moreover, there were significant differences between GAST results and both radiological findings of RDS and receiving oxygen in premature infants (gestational age<34 weeks). Negative GAST results were more prevalent in neonates who were born to mothers with hypothyroidism, preeclampsia, diabetes mellitus, and premature rupture of membranes. However, this difference was not significant. CONCLUSION: According to our findings, the application of GAST on gastric aspirate secretions is not a useful method to predict surfactant deficiency. Therefore, decisions for RDS management must be made based on clinical and radiological findings.

Ultrastructural characterization of genetic diffuse lung diseases in infants and children: a cohort study and review.

Pediatric diffuse lung diseases are rare disorders with an onset in the neonatal period or in infancy, characterized by chronic respiratory symptoms and diffuse interstitial changes on imaging studies. Genetic disorders of surfactant homeostasis represent the main etiology. Surfactant protein B and ABCA3 deficiencies typically cause neonatal respiratory failure, which is often lethal within a few weeks or months. Although heterozygous ABCA3 mutation carriers are mostly asymptomatic, there is growing evidence that monoallelic mutations may affect surfactant homeostasis. Surfactant protein C mutations are dominant or sporadic disorders leading to a broad spectrum of manifestations from neonatal respiratory distress syndrome to adult pulmonary fibrosis. The authors performed pathology and ultrastructural studies in 12 infants who underwent clinical lung biopsy. One carried a heterozygous SP-B mutation, 3 carried SP-C mutations, and 7 carried ABCA3 mutations (5 biallelic and 2 monoallelic). Optical microscopy made it possible to distinguish between surfactant-related disorders and other forms. One of the ABCA3 monoallelic carriers had morphological features of alveolar capillary dysplasia, a genetic disorder of lung alveolar, and vascular development. One patient showed no surfactant-related anomalies but had pulmonary interstitial glycogenosis, a developmental disorder of unknown origin. Electron microscopy revealed specific lamellar bodies anomalies in all SP-B, SP-C, and ABCA3 deficiency cases. In addition, the authors showed that heterozygous ABCA3 mutation carriers have an intermediate ultrastructural phenotype between homozygous carriers and normal subjects. Lung biopsy is an essential diagnostic procedure in unexplained diffuse lung disorders, and electron microscopy should be performed systematically, since it may reveal specific alterations in genetic disorders of surfactant homeostasis.

Surfactant dysfunction.

Mutations in genes encoding proteins needed for normal surfactant function and metabolism cause acute lung disease in newborns and chronic lung disease in older children and adults. While rare these disorders are associated with considerable pulmonary morbidity and mortality. The identification of genes responsible for surfactant dysfunction provides clues for candidate genes contributing to more common respiratory conditions, including neonatal respiratory distress syndrome and lung diseases associated with aging or environmental insults. While clinical, imaging and histopathology features of these disorders overlap, certain features are distinctive for surfactant dysfunction. Natural histories differ depending upon the genes involved and a specific diagnosis is important to provide accurate information concerning prognosis and mode of inheritance. Diagnosis of surfactant dysfunction can be made by biopsy, but identification of the specific gene involved requires molecular genetic testing, which is non-invasive. Currently there are no effective medical treatments for surfactant dysfunction. Development of therapies is a priority for research, which may benefit patients with other lung diseases.

Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice.

ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3(Δ/Δ)) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3(Δ/Δ) mice survived after birth. Surviving Abca3(Δ/Δ) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3(Δ/Δ) mice. In adult Abca3(Δ/Δ) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells.

[Atelectasis in general anesthesia and alveolar recruitment strategies]. / Atelectasias en anestesia general y estrategias de reclutamiento alveolar.

Atelectasis occurs in most patients during general anesthesia and is the main cause of hypoxemia. The objective of this review is to examine the causes and diagnosis of atelectasis and the different strategies for reducing or preventing this complication and improving oxygenation. Pulmonary atelectasis is mainly caused by 3 factors: compression, gas absorption, and lack of surfactant. Compression and gas absorption are, however, the 2 most commonly implicated factors. Lung collapse is accentuated if pure oxygen is inhaled during induction or if the patient is morbidly obese. Laparoscopic, thoracic, and upper abdominal interventions also carry risk of lung collapse. Various techniques may be used to prevent atelectasis or to reopen collapsed lung tissue. These include using positive end-expiratory pressure or a high tidal volume-thus providing a higher airway pressure (vital capacity maneuver)-or both in combination. Alveolar recruitment strategies have been tried in bariatric surgery, single-lung ventilation, laparoscopy, and adult respiratory distress syndrome. Their application has reduced or prevented atelectasis, thereby reducing postoperative pulmonary complications.

[Lung diseases associated with inherited disorders of surfactant metabolism]. / Pathologies respiratoires associées à des anomalies héréditaires du métabolisme du surfactant.

Lung diseases associated with surfactant-metabolism disorders are a heterogeneous group of rare diseases. Intra-alveolar accumulation of protein related to surfactant dysfunction leads to cough, hypoxemia, and radiological-diffuse infiltration. Inherited deficiency of pulmonary surfactant protein B (SP-B) was initially described in infants who develop respiratory failure at birth. More recently, mutations in other constitutive surfactant proteins, such as surfactant protein C or implied in its metabolism, such as ATP-binding cassette, subfamily A, member 3 (ABCA3) and thyroid transcription factor 1 (TTF-1) were identified in newborns with respiratory distress as well as in children with chronic-infiltrative pneumonia. The aim of this review is therefore to summarize the current state of our knowledge in this area.

Heterozygous ABCA3 mutation associated with non-fatal evolution of respiratory distress.

A boy without symptoms up to 12 months of age started with persisting cough followed by respiratory failure at 18 months of age, resulting in mechanical ventilation because of alveolar proteinosis. Lung biopsy showed PAS-positive material. PCR was negative for CMV, Pneumocystis jiroveci and adenovirus. BALF showed mature SP-B. Analysis of the ATP-binding cassette transporter A3 (ABCA3; OMIM 601615) gene showed a compound heterozygous mutation from paternal W1148X and maternal T1114A. Alveolar lavage with 720 mg of bovine surfactant allowed weaning from ventilator support. Heterozygous mutation in the ABCA3 gene could be associated with a milder evolution as compared to the homozygous frequently lethal evolution.

Deficiencia genética de proteínas surfactantes y patologia pulmonar / Surfactant protein genetic deficiency and pulmonary disease

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Defects in surfactant synthesis: clinical implications.

Since the original description of deficiency of the pulmonary surfactant in premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most commonly been attributed to developmental immaturity of surfactant production. Studies of different ethnic groups, gender, targeted gene ablation in murine lineages, and recent clinical reports of monogenic causes of neonatal respiratory distress syndrome have demonstrated that genetic defects disrupt pulmonary surfactant metabolism and cause respiratory distress syndrome, especially in term or near-term infants and in older infants, children, and adults. In contrast to developmental causes of respiratory distress, which may improve as infants and children mature, genetic causes result in both acute and chronic (and potentially irreversible) respiratory failure.

The genetics of neonatal respiratory disease.

This chapter reviews some of the genetic predispositions that may govern the presence or severity of neonatal respiratory disorders. Respiratory disease is common in the neonatal period, and genetic factors have been implicated in some rare and common respiratory diseases. Among the most common respiratory diseases are respiratory distress syndrome of the newborn and transient tachypnoea of the newborn, whereas less common ones are cystic fibrosis, congenital alveolar proteinosis and primary ciliary dyskinesias. A common complication of neonatal respiratory distress syndrome is bronchopulmonary dysplasia or neonatal chronic lung disease. This review examines the evidence linking known genetic contributions to these diseases. The value and success of neonatal screening for cystic fibrosis is reviewed, and the recently characterised contribution of polymorphisms and mutations in the surfactant protein genes to neonatal respiratory disease is evaluated. The evidence that known variability in the expression of surfactant protein genes may contribute to the risk of development of neonatal chronic lung disease or bronchopulmonary dysplasia is examined.

Genetic disorders influencing lung formation and function at birth.

Adaptation to air breathing at birth is dependent on formation and function of the lung. Lung morphogenesis is a complex process dependent on precise temporal-spatial control of cell proliferation, differentiation and behavior mediated by autocrine-paracrine signaling that instructs transcriptional processes during organogenesis. Mutations in genes causing severe, and often lethal, lung malformations include those in the sonic hedgehog, fibroblast growth factor and thyroid transcription factor-1 pathways. Mutations in genes regulating surfactant homeostasis, necessary for reduction of surface tension in the alveoli, cause lethal respiratory distress at birth or interstitial lung disease in childhood. Inherited disorders of the surfactant system that affect neonatal respiratory adaptation at birth include hereditary surfactant protein B deficiency, mutations in surfactant protein C and the ABCA3 transporter.

Inherited disorders of neonatal lung diseases.

Although genetic factors are assumed to have a role in the etiology of respiratory distress syndrome (RDS), specific genes underlying this susceptibility are incompletely known. The most promising candidates are the genes coding for the lung-specific protein components of the surfactant. In congenital absence of surfactant protein A in mice, lung mechanics or surfactant homeostasis is normal. However, there is an increased susceptibility to infections. The major surfactant protein A alleles, 6A(2) and 1A(0), are the general high-risk RDS alleles, while the allele 6A(3) carries a decreased risk of RDS. The allele 6A(6) is also over-represented in infants with bronchopulmonary dysplasia. To date, no human infants who lack surfactant protein A have been identified, and the human respiratory phenotype associated with the 1A(0) allele has been demonstrated to be variable, therefore, surfactant protein A polymorphisms are not currently useful for estimation of individual risk of having an affected infant. Surfactant protein B (SP-B) plays an essential role in the structure of tubular myelin. Mutations resulting in an absence of surfactant protein B have been identified. They cause a recessively inherited, progressive respiratory disease. More than 27 loss of function mutations have been identified in the surfactant protein B gene that result in lethal neonatal respiratory failure. Of the several known common variants of the surfactant protein B gene, the most common mutation is 121ins22 that accounts for 60-70% of the mutant cases. Although the frequency of the 121ins2 mutation is rare, the consistent phenotype is exhibited by infants with a homozygous genotype. The clinical presentation in infants homozygous for the 121ins2 mutation is full-term infants who develop respiratory distress within the first 12-24 hours of life. Surfactant replacement therapy fails to reverse this outcome, and without lung transplantation, they expire within the first 1-6 months of life. Surfactant protein B gene mutations may also result in milder phenotypes. These mutations resulting in reduced synthesis of SP-B appear to be family-specific and result in respiratory distress, but sometimes with more gradually progressive or chronic respiratory failure. Surfactant protein C plays a role in the stabilization of surfactant and may also have a role in the intracellular processing of the surfactant complex. Surfactant protein B is important in the intracellular processing and production of surfactant protein C. Although surfactant protein C-deficient mice are viable and survive to adulthood without obvious pulmonary abnormalities, their lung have reduced viscoelasticty. Human respiratory disease in the neonatal period caused by loss-of-function mutations in the surfactant protein C gene has not been identified. However, an autosomal dominant inherited mutation at the surfactant protein C gene causes chronic interstitial lung disease. Surfactant protein D is a member of the collectin family like surfactant protein A, therefore it opsonizes pathogens and enhances their phagocytosis by alveolar macrophages and neutrophils. Unlike surfactant protein A, it does not contribute to lowering surface tension. Surfactant protein D-deficient mice have no respiratory abnormalities at birth, but it causes development of emphysema and predisposition to specific infections. No human infant or child with respiratory distress and mutation in the surfactant protein D gene has been identified.

Genetic mechanisms of surfactant deficiency.

The production of pulmonary surfactant is necessary to maintain alveolar stability and normal lung function. Mutations in three different genes important for surfactant production and function have now been recognized to result in surfactant deficiency and acute and/or chronic lung disease. The clinical and laboratory features associated with these genetic disorders, along with their implications for the understanding of normal surfactant metabolism, are reviewed.

ABCA3 gene mutations in newborns with fatal surfactant deficiency.

BACKGROUND: Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism. METHODS: We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy. RESULTS: Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations. CONCLUSIONS: Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.

Surfactant with SP-B and SP-C analogues improves lung function in surfactant-deficient rats.

The use of mammalian lung surfactant extracts has sharply reduced mortality and morbidity from respiratory distress syndrome in premature infants. Synthesis of surfactant protein B and C (SP-B and SP-C) analogues may lead the way to a synthetic surfactant preparation. Dimeric SP-B(1-25) (dSP-B(1-25)) is based on the N-terminal domain of human SP-B and SP-Cfc is a modified human SP-C in which a single phenylalanine is substituted for a palmitoylated cysteine residue in the N-terminal segment (Phe-4 > Cys-4 variant). We tested the effects of synthetic surfactants with 1 or 2% dSP-B(1-25) and 1% SP-Cfc on lung function in surfactant-deficient rats. Four experimental surfactant preparations were prepared by mixing 1% dSP-B(1-25), 2% dSP-B(1-25), 1% dSP-B(1-25) +1% SP-Cfc, and 2% dSP-B(1-25) +1% SP-Cfc with phospholipids (PL). PL and Survanta, a bovine lung extract, were controls. Groups of 8 rats were ventilated, lavaged until surfactant deficiency, and treated with 100 mg/kg surfactant. Arterial blood gas values and dynamic compliance were measured every 15 min and after 2 h of ventilation, the rats were killed and pressure-volume curves performed. Oxygenation improved quickly after instillation of surfactant with synthetic peptides and Survanta. Oxygenation and lung volumes were consistently higher in the 2% than in the 1% dSP-B(1-25) groups. Addition of 1% SP-Cfc to the synthetic surfactants further improved oxygenation and lung volume, but to a lesser extent than increasing the dSP-B(1-25) content from 1 to 2%. These data indicate that improvements in oxygenation and lung volume in lavaged rats are dependent on the concentration of dSP-B(1-25) in the surfactant preparation and that the presence of SP-Cfc has a relative minor effect on these parameters.

Surfactant proteins and genetic predisposition to respiratory distress syndrome.

Respiratory distress syndrome (RDS) is caused by surfactant deficiency at birth. The risk of RDS decreases from the gestational age of 24 weeks to full-term. Genetic and acquired factors additionally influence the risk of RDS. Surfactant deficiency in RDS is mainly caused by immaturity and a lack of differentiation of the alveolar epithelial cells involved in surfactant synthesis and secretion. A network of hormones and growth factors regulate perinatal development. Host-related factors, including the levels of expression of surfactant proteins (SP), modulate the responsiveness of growth factors. SP-A has roles in surface activity and regulatory roles particularly in innate immunity; SP-B is essential for the processing of surfactant and for the surface activity; SP-C has roles in surfactant metabolism and function; the regulatory roles of SP-D mainly pertain to innate immunity. The genetic variation of SP-A and SP-B genes and the risk of RDS have been studied. Both SP-A and SP-B associate with susceptibility to RDS. The association between the SP-A allele and genotypes and the risk of RDS is dependent on the SP-B genotype and significantly influenced by the degree of prematurity, antenatal glucocorticoid therapy, multiple birth, and birth order. The alleles/genotypes of SP-A, SP-C, or SP-D also associate with several other inflammatory lung and airway diseases. Rare mutations in SP-B or SP-C cause serious, often fatal lung diseases. Genetic and post-genomic research is likely to eventually result in new diagnostic applications and specific therapies for the prevention of respiratory failure and inflammatory lung diseases.