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The article presents a modern understanding of the components of the surfactant, the functions of non-serum proteins SP-A, SP-B, SP-C and SP-D. The history of the discovery of protein deficiencies SP-B, SP-C and ABCA3 is described. The authors had analyzed modern epidemiology, clinical and histological features of various deficiencies of surfactant proteins. Va­rious variants of SFTPC, SFTPB and ABCA3 mutations and their influence on the course, clinical manifestations and outcome of interstitial lung disease in children are demonstrated.

BACKGROUND: The majority of unexplained respiratory distress syndrome (URDS) cases in late preterm and term infants are caused by genetic abnormalities, with the most common of these being ABCA3 gene mutation. At present, it is unclear to neonatologists whether URDS patients with ABCA3 mutation have similar or more challenging clinical profiles to those without any defined genetic abnormalities. Our study aimed to answer this question by comparing the clinical characteristics of severe URDS patients with homozygous or compound heterozygous ABCA3 mutations, a single ABCA3 mutation, or no defined genetic abnormalities. METHODS: This retrospective cohort study involved 39 late preterm and term infants with URDS underwent a clinical exome sequencing at a tertiary neonatal intensive care unit between January 2013 and December 2019. Based on the sequencing result, the study subjects were classified into the homozygous or compound heterozygous mutations, single ABCA3 mutation, or no defined genetic abnormalities groups. The major outcomes, including mortality, the age of symptom onset and development of severe RDS, and the radiological score, were compared between the groups. RESULTS: A novel splicing site (c.3862+1G>C) was identified in one twin with homozygous expression. Patients with homozygous or compound heterozygous ABCA3 mutations exhibited symptom onset and development of severe respiratory distress syndrome (RDS) earlier than those with a single mutation or no genetic abnormalities (P

Reverse Potts shunt is a palliative procedure aimed at decompressing the pressure-overloaded right ventricle in severe pulmonary hypertension (PH). We, herein, report the first case of an interventional creation of an “endogenous” reverse Potts shunt by stenting a pre-existing small but patent ductus arteriosus (PDA) in a 2 months old female infant with severe, supra-systemic PH, associated with a novel combination of a compound heterozygous ABCA3 mutation and additional heterozygous genetic variants of surfactant protein B (SFTPB) and C (SFTPC). The aforementioned combination of human genetic mutations has not been described before in viable infants, children or adults. The catheter intervention was performed via percutaneous femoral arterial access and was well-tolerated. Subsequently, the infant improved by means of clinical status, echocardiographic systolic right ventricular (RV) function, and serum NT-proBNP levels as biomarker of right atrial and RV pressure load. In conclusion, this single case report suggests that interventional stenting of a pre-existing PDA to create an “endogenous” reverse Potts shunt is feasible and efficacious in infants less than 3 months old with severe PH and impending RV failure associated with developmental lung disease.

Rare or private, biallelic variants in the ABCA3 (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lun...

Purpose of review The current review aims to recognize the variability in clinical presentation of adult patients with bi-allelic ABCA3 mutations, create more depth in ABCA3 mutations reported and highlight the influence of environmental factors on disease course. Recent findings Mutations in ABCA3 are predominantly linked to neonatal and pediatric interstitial lung disease (ILD) with a minority surviving beyond puberty. Here, we present three patients with ABCA3 mutations who present with disease at the age of 19, 61 and 77. Moreover, we identified c.4451G>C (p.R1484P), c.1675G>A (p.G559R) and c.4745C>G (p.T1582S) as three novel ABCA3 mutations. In addition, we identified six additional patients with ABCA3 mutations in literature who reached an age above 18. Furthermore, we discuss the influence of infections, drugs and smoking on disease course. Summary Although extremely rare, patients with bi-allelic mutations in ABCA3 may present at adulthood. Late onset of disease may be influenced by type of mutation or environmental factors.

Pulmonary surfactant is a heterogeneous combination of lipids and proteins, which prevents alveolar collapse at the end of expiration cycle by decreasing the alveolar surface tension at the air-liquid interface. At birth, the expression of surfactant is very important for normal lung function and it is strictly correlated to gestational age. The best known genetic mutations associated with the onset of respiratory distress in preterm and full-term newborns and with interstitial lung disease later in childhood are those involving the phospholipid transporter (ABCA3) or surfactant proteins C and B (SP-C and SP-B) genes. In particular, mutations in the SP-B gene induce respiratory distress in neonatal period, while alterations on gene encoding for SP-C are commonly associated with diffuse lung disease in children or in adults. Both clinical phenotypes are present, if genetic mutations interest even the phospholipid transporter ABCA3 ambiguity in the sentence. Interstitial lung disease in children (chILD) is defined as a mixed category of mainly chronic and rare respiratory disorders with increased mortality and morbidity. Although genetic alterations are mainly responsible for the onset of these diseases, however, there are also other pathogenic factors that contribute to increase the severity of clinical presentation. In this review, we analyze all clinical features of these rare pulmonary diseases in neonatal and in pediatric age.

Background The relationship between clinical outcomes and gene mutations in Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension (PAH) is unclear. Methods We retrospectively studied the clinical characteristics and outcomes of pediatric patients who visited Beijing Anzhen Hospital from September 2008 to December 2018. Results Eighty-two pediatric patients were included. Forty-two gene mutations were identified in 41 patients (50%), including 25 mutations in BMPR2, 5 mutations in ACVRL1, 3 mutations each in ABCA3 and NOTCH3, 2 mutations each in KCNK3 and HTR2B, 1 mutation in ENG, and 1 mutation in EIF2AK4. The mean age at diagnosis of PAH was 86.4 ± 55.1 months. Forty-eight patients (twenty-eight mutation carriers) underwent cardiac catheterization examinations, with acute vasodilator testing performed simultaneously. Results showed that mutation carriers demonstrated a higher pulmonary vascular resistance index (P = 0.037). Patients with gene mutations responded poorly to vasodilators (P = 0.001). The 1-, 2-, and 3-year survival rates of mutation noncarriers were 95.1%, 87.8%, and 82.5% respectively; while for mutation carriers, the proportions were 86.6% (P = 0.216), 63.8% (P = 0.021), and 52.2% (P = 0.010), respectively. Cardiac index was an independent predictor of death (P = 0.005; odds ratio [OR] 2.16, 95% confidence interval [CI] 1.258-3.704), as well as RAP (P = 0.01; OR 1.26, 95% CI 1.056-1.503). Conclusions In our cohort of Chinese pediatric patients, those with an identified gene mutation demonstrated worse clinical outcomes. Therefore, early gene screening for pediatric patients with idiopathic and heritable PAH is recommended, and more aggressive treatment for mutation carriers may be advisable.

The adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3) is a transmembrane glycoprotein that uses energy of ATP hydrolysis to transport phospholipids into the lamellar bodies of type 2 alveolar epithelial cells (AEC) and regulates lung surfactant homeostasis. More than 200 mutations have already been described in ABCA3, located on chromosome 16 [1, 2]. Patients present with a great heterogeneity of phenotypes, from lethal neonatal respiratory distress syndrome (RDS) to childhood and rarely adult interstitial lung disease (ILD) [3, 4]. ABCA3 mutations-related lung disease inheritance is autosomal recessive, as it requires two disease-causing (bi-allelic) mutations, one from each parent., Children with ABCA3 mutations may survive beyond infancy and reach adulthood. Genetic mechanisms should always be examined in adult patients with childhood onset ILD and molecular analysis should be performed accordingly in specialised referral centres. http://bit.ly/2LzMNOE

Background Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES. Methods The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed. Results The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function. Conclusions Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.

Surfactant, which was first identified in the 1920s, is pivotal to lower the surface tension in alveoli of the lungs and helps to lower the work of breathing and prevents atelectasis. Surfactant proteins, such as surfactant protein B and surfactant protein C, contribute to function and stability of surfactant film. Additionally, adenosine triphosphate binding cassette 3 and thyroid transcription factor-1 are also integral for the normal structure and functioning of pulmonary surfactant. Through the study and improved understanding of surfactant over the decades, there is increasing interest into the study of childhood interstitial lung diseases (chILD) in the context of surfactant protein disorders. Surfactant protein deficiency syndrome (SPDS) is a group of rare diseases within the chILD group that is caused by genetic mutations of SFTPB, SFTPC, ABCA3 and TTF1 genes.Conclusion: This review article seeks to provide an overview of surfactant protein disorders in the context of chILD. What is Known: • Surfactant protein disorders are an extremely rare group of disorders caused by genetic mutations of SFTPB, SPTPC, ABCA3 and TTF1 genes. • Given its rarity, research is only beginning to unmask the pathophysiology, inheritance, spectrum of disease and its manifestations. What is New: • Diagnostic and treatment options continue to be explored and evolve in these conditions. • It is, therefore, imperative that we as paediatricians are abreast with current development in this field.

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy (‘lung disease in utero’). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.

Background Pulmonary surfactant is a complex mixture of lipids and specific proteins that stabilizes the alveoli at the end of expiration. Mutations in the gene coding for the triphosphate binding cassette transporter A3 (ABCA3), which facilitates the transfer of lipids to lamellar bodies, constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome and chronic interstitial lung disease in children. Hydroxychloroquine can be used as an effective treatment for this rare severe condition. Case presentation We report a late preterm Bosnian baby boy (36 weeks) who suffered from a severe form of respiratory distress syndrome with poor response to intensive conventional management and whole exome sequencing revealed homozygous ABCA3 mis-sense mutation. The baby showed remarkable improvement of the respiratory condition after the initiation of Hydroxychloroquine, Azithromycin and Corticosteroids with the continuation of Hydroxychloroquine as a monotherapy till after discharge from the hospital. Conclusion Outcome in patients with ABCA3 mutations is variable ranging from severe irreversible respiratory failure in early infancy to chronic interstitial lung disease in childhood (ChILD) usually with the need for lung transplantation in many patients surviving this rare disorder. Hydroxychloroquine through its anti-inflammatory effects or alteration of intra-cellular metabolism may have an effect in treating cases of ABCA3 gene mutations.

Familial pulmonary fibrosis (FPF) is defined as interstitial lung involvement in at least two members of the same biological family. Pathogenesis of FPF involves background of genetic risk factors further modified by environmental exposures and aging. Manifesta tion of FPF mirrors manifestation of interstitial lung diseases generally. Patients may present also with involvement of other organs, as seen usually in those affected by complex syndromes or telomeropaties. Described mutations concern telomeres homeostasis genes (TERT, TERC, RTEL1, PARN, DKC1, TINF, NAF1), surfactant genes (SFTPC, ABCA3, NFKX21) or genes associated with complex syndromes (COPA, TMEM173, HPS18, NF1, FAM111B, NDUFAF6, GATA 2). Genetic tests are indicated by specialist in clinical genetics, optimaly after consultation with respiratory specialist involved in interstitial lung diseases. Treatment of FPF is currently unknown. In patients with multiorgan involvement growing number of organs may be affected in time and sometimes dysfunction of mostly severe affected organ may manifest before interstitial lung involvement.

Background Inflammatory processes are key drivers of bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants. In a large sample, we verify previously reported associations of genetic variants of immunology-related genes with BPD. Methods Preterm infants with a gestational age ≤32 weeks from PROGRESS and the German Neonatal Network (GNN) were included. Through a consensus case/control definition, 278 BPD cases and 670 controls were identified. We identified 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously associated with BPD through a comprehensive literature survey. Additionally, a quantitative genetic association analysis regarding oxygen supplements, mechanical ventilation, and continuous positive air pressure (CPAP) was performed. Results Five candidate SNPs were nominally associated with BPD-related phenotypes with effect directions not conflicting the original studies: rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, and rs4148913-CHST3. Four of these genes are involved in cell adhesion. Extending our analysis to all well-imputed SNPs of all candidate genes, the strongest association was rs45538638-ABCA3 with CPAP (p = 4.9 × 10−7, FDR = 0.004), an ABC transporter involved in surfactant formation. Conclusions Most of the previously reported associations could not be replicated. We found additional support for SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3. Larger studies and meta-analyses are required to corroborate these findings. Impact Larger cohort for improved statistical power to detect genetic associations with bronchopulmonary dysplasia (BPD). Most of the previously reported genetic associations with BPD could not be replicated in this larger study. Among investigated immunological relevant candidate genes, additional support was found for variants in genes CRP, NUAK1, SELL, VNN2, and CHST3, four of them related to cell adhesion. rs45538638 is a novel candidate SNP in reported candidate gene ABC-transporter ABCA3. Results help to prioritize molecular candidate pathomechanisms in follow-up studies.

Surfactant, which was first identified in the 1920s is pivotal to lower the surface tension in alveoli of the lungs and helps to lower the work of breathing and prevents atelectasis. Surfactant proteins, such as surfactant protein B and surfactant protein C contribute to normal functioning of surfactant. Additionally, Adenosine Triphosphate Binding Cassette 3 and Thyroid Transcription Factor-1 are also integral for the normal structure and functioning of pulmonary surfactant. Through the study and improved understanding of surfactant over the decades, there is increasing interest into the study of childhood interstitial lung diseases (chILD) in the context of surfactant protein deficiencies. Surfactant protein deficiency syndrome (SPDS) is a group of rare diseases within the chILD group that is caused by genetic mutations of SFTPB, SPTPC, ABCA3 and TTF1 genes. This review article seeks to provide an overview of surfactant protein deficiencies in the context of chILD.

Respiratory distress syndrome caused by a secondary surfactant deficiency is one of the most common diagnoses requiring admission to the Neonatal Intensive Care Unit. We illustrate the case of a term female newborn without prenatal and peripartal risks. There had been significant signs of respiratory distress 4 h after delivery. The condition gradually worsened to the point of needing oscillatory ventilation. The most common infectious and non-infectious causes were excluded. Considering the course of illness, a congenital surfactant deficiency was suspected. There nevertheless was no significant improvement after administration of surfactant. Following a short period of palliative care, the child died at 34 days of age due to respiratory failure. DNA diagnostics revealed compound heterozygosity of ABCA3 functional mutations leading to the p.Pro147Leu and p.Pro246Leu exchanges. The second identified mutation of ABCA3 c.737C>T had not to date been described in connection with primary surfactant deficiency.

Introduction: Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM:601615) gene was the commonest genetic cause for severe neonatal respiratory distress syndrome (RDS) and childhood interstitial lung disease (chILD). Most literature review has been from patients of Caucasian heritage. Case Description: We report a case of a term male newborn of South East Asian heritage that developed severe respiratory distress soon after birth, and diagnosis was made on clinical, radiological and genetic basis without lung biopsy. He was found to have compound heterozygous variants for the adenosine triphosphate-binding cassette transporter A3 (ABCA3) gene: a novel c.3364G>A (p.Glu1122Lys) variant and previously reported pathogenic c. 737C>T (p.Pro246Leu). The variant c.3364G>A (rs1233043384) was not previously identified in clinical/disease databases such as ClinVar and The Human Gene Mutation Database. Further analysis and bioinformatics study indicated this variant was likely pathogenic. Parental genetic studies revealed parents had one mutation each. Conclusion: Newborns with unexplained respiratory distress syndrome (RDS) and pulmonary surfactant deficiency should have genetic sequencing study. This will be vital for early diagnosis, disease prognostication, treatment planning such lung transplantation, genetic counseling and provide the molecular basis for prenatal diagnosis and pre-implantation genetic diagnosis. It is important to raise awareness of this condition in the Southeast Asia region. Further larger population-based studies are required to determine the frequency of this mutation in our population. ABCA3 deficiency should be considered in term babies who develop severe respiratory distress syndrome in this region.

Paediatric disorders of pulmonary surfactant may occur due to mutations involving surfactant proteins B and C, and ATP‐binding cassette subfamily A member 3 (ABCA3) genes. Recessive frameshift or nonsense ABCA3 mutations are associated with respiratory failure and neonatal death but milder phenotypes of ABCA3 deficiency due to missense, splice site, and insertion/deletions may result in survival beyond infancy. To date, only one case report describes the clinical course from birth to age 21 years and there are less than 10 adult cases. No guidelines exist for medical therapy due to the rarity of this condition. We describe the clinical course of a patient over 39 years and her younger brother who were both diagnosed at birth with an unspecified paediatric interstitial lung disease (ILD) and were eventually diagnosed with ABCA3 mutation in their adulthood. Our report highlights the minimal progression of the ABCA3‐related ILD without long‐term medications, but the development of dyspnoea due to progressive pulmonary hypertension and airflow obstruction., We describe the clinical progress of siblings who initially presented with an undifferentiated paediatric interstitial lung disease at birth which was eventually diagnosed in adulthood as pulmonary surfactant dysfunction due to ATP‐binding cassette subfamily A member 3 (ABCA3) mutations. Clinical deterioration was due to progressive pulmonary hypertension and a moderate decline in forced expiratory volume in 1 sec (FEV1), rather than progression of the interstitial lung disease.

Respiratory distress syndrome (RDS) is one of the most common neonatal diseases causing early life morbidity and mortality. We present a case of a full-term baby born to consanguineous parents who died due to severe progressive respiratory failure (PRF). Whole exome sequencing (WES) identified a homozygous disease-causing variant in the ABCA3 gene. Histopathological and electron microscopic examination of postmortem lung tissue revealed characteristic findings consistent with congenital surfactant deficiency along with the ultrastructural evidence of ‘fried-egg’ like inclusions. Our study provides thorough clinical, radiological, and ultrastructural analysis of the variant’s clinical impact and elucidates WES’s valuable role in the molecular diagnosis of (PRF).

Background This study intended to determine important genes related to the prognosis and recurrence of breast cancer. Methods Gene expression data of breast cancer patients were downloaded from TCGA database. Breast cancer samples with recurrence and death were defined as poor disease-free survival (DFS) group, while samples without recurrence and survival beyond 5 years were defined as better DFS group. Another gene expression profile dataset (GSE45725) of breast cancer was downloaded as the validation data. Differentially expressed genes (DEGs) were screened between better and poor DFS groups, which were then performed function enrichment analysis. The DEGs that were enriched in the GO function and KEGG signaling pathway were selected for cox regression analysis and Logit regression (LR) model analysis. Finally, correlation analysis between LR model classification and survival prognosis was analyzed. Results Based on the breast cancer gene expression profile data in TCGA, 540 DEGs were screened between better DFS and poor DFS groups, including 177 downregulated and 363 upregulated DEGs. A total of 283 DEGs were involved in all GO functions and KEGG signaling pathways. Through LR model screening, 10 important feature DEGs were identified and validated, among which, ABCA3, CCL22, FOXJ1, IL1RN, KCNIP3, MAP2K6, and MRPL13, were significantly expressed in both groups in the two data sets. ABCA3, CCL22, FOXJ1, IL1RN, and MAP2K6 were good prognostic factors, while KCNIP3 and MRPL13 were poor prognostic factors. Conclusion ABCA3, CCL22, FOXJ1, IL1RN, and MAP2K6 may serve as good prognostic factors, while KCNIP3 and MRPL13 may be poor prognostic factors for the prognosis of breast cancer.

The mutations in the ABCA3 (ATP-binding cassette transporter subfamily A member 3) gene could result in lethal respiratory distress syndrome (RDS) in neonates and interstitial lung disease (ILD) in infants and children. Here we describe a full-term newborn who manifested respiratory distress 20 minutes after birth and then gradually developed hypoxemic respiratory failure and died on 53 days of life. A homozygous missense mutation (c.746C >T) was identified in exon 8 of ABCA3 gene in the neonate by next generation sequencing, and the mutations were inherited from parents respectively. This homozygous mutation is firstly reported up to date.

Chronic pneumonitis of infancy (CPI) is a rare interstitial lung disease (ILD) that can be fatal in some cases. It occurs in infants who initially appear well and then develop respiratory symptoms with hypoxemia and diffuse interstitial infiltrates (1). Recently, the development of molecular genetic techniques has been rapidly increasing the understanding of the cause of CPI, and mutations in related genes encoding proteins such as surfactant protein (SP)-B, SP-C and ATP-binding cassette protein family A3 (ABCA3) have been identified as a representative cause (2).

Multidrug resistance (MDR) is considered as the major obstacle for treating pediatric acute lymphoblastic leukemia (ALL). MicroRNAs (miRNAs) are small non coding RNAs which may potentially regulate response to chemotherapy. In this study, total RNA was isolated from bone marrow samples of 46 children with de novo ALL and 16 controls. Quantitative reverse transcriptase polymerase chain reaction was used to investigate the expression profile of the predicted miRNAs; miR-326 and miR-200c, and their predicted targets ABCA2, and ABCA3 transporters. The presence of minimal residual disease was studied using PCR-SSCP (single-strand conformation polymorphism) 1 year after treatment. The association between the miRNA expression and drug resistance was analyzed statistically. Results showed a significant down-regulation of both miR-326 and miR-200c expressions in ALL patients compared with non-cancer controls (P = 0.0002, AUC = 0.813 and P = 0.035, AUC = 0.79, respectively). A considerable negative association between miR-326 expression and MDR was identified which could raise the risk of chemoresistance by 4.8- fold. The expression profiles of miR-326 and ABCA2 transporter were inversely correlated. Data revealed, a novel diagnostic role for miR-326 and miR-200c as potential biomarkers of pediatric ALL. Down-regulation of miR-326 was introduced, for the first time, as a prognostic factor for drug resistance in childhood ALL. To the best of our knowledge, this is the first time that ABCA2 transporter is proposed as a target gene for miR-326, through which it can exert its impact on drug resistance. These data may provide novel approaches to new therapeutics and diagnostics.

ATP-binding cassette A3 (ABCA3) is a phospholipid carrier that is mainly expressed in the alveolar epithelium. Biallelic mutations of ABCA3 has been associated with fatal respiratory distress syndrome and interstitial lung disease (ILD) in children. However, whether variations in ABCA3 have a role in the development of adult ILD, including idiopathic pulmonary fibrosis (IPF), remains to be addressed. In this study, we screened for germline variants of ABCA3 by exons-sequencing in 30 patients with sporadic IPF and in 30 matched healthy controls. Eleven missense variants, predominantly in heterozygous, were found in 13 of these patients, but only two missenses in 2 healthy controls. We then selected four of the detected missense variants (p.L39V, p.S828F, p.V968M and p.G1205R) to performed cohort analysis in 1,024 ILD patients, containing 250 IPF and 774 connective tissue disease-ILD (CTD-ILD) patients, and 1,054 healthy individuals. Our results showed that the allele frequency of p.G1205R, but not p.L39V, was significantly higher in ILD patients than in healthy controls. However, no additional subject carrying the variant p.S828F or p.V968M was detected in the cohort analysis. These results indicate that the heterozygous ABCA3 gene variants may contribute to susceptibility to diseases in the Chinese population.

Background Knowledge about the clinical spectrum of lung disease caused by variations in the ATP binding cassette subfamily A member 3 (ABCA3) gene is limited. Here we describe genotype-phenotype correlations in a European cohort. Methods We retrospectively analysed baseline and outcome characteristics of 40 patients with two disease-causing ABCA3 mutations collected between 2001 and 2015. Results Of 22 homozygous (15 male) and 18 compound heterozygous patients (3 male), 37 presented with neonatal respiratory distress syndrome as term babies. At follow-up, two major phenotypes are documented: patients with (1) early lethal mutations subdivided into (1a) dying within the first 6 months or (1b) before the age of 5 years, and (2) patients with prolonged survival into childhood, adolescence or adulthood. Patients with null/null mutations predicting complete ABCA3 deficiency died within the 1st weeks to months of life, while those with null/other or other/other mutations had a more variable presentation and outcome. Treatment with exogenous surfactant, systemic steroids, hydroxychloroquine and whole lung lavages had apparent but many times transient effects in individual subjects. Conclusions Overall long-term (>5 years) survival of subjects with two disease-causing ABCA3 mutations was

ResumenIntroducciónEl déficit congénito de surfactante es una entidad de diagnóstico inhabitual en recién nacidos. Se reporta un caso clínico de déficit de proteína B del surfactante, se revisa el estudio, tratamiento y diagnóstico diferencial de los déficit de proteínas del surfactante y enfermedad crónica intersticial de la infancia.Caso clínicoRecién nacido de término que cursa dificultad respiratoria, con velamiento pulmonar recurrente y respuesta transitoria a administración de surfactante. El estudio inmunohistoquímico y genético confirmaron diagnóstico de déficit de proteína B de surfactante.ConclusionesLa enfermedad pulmonar congénita requiere un alto índice de sospecha. El déficit de proteína B de surfactante genera un cuadro clínico progresivo y mortal en la mayoría de los casos, al igual que el déficit de transportador ATP binding cassette, sub-family A member 3 (ABCA3). El déficit de proteína C es insidioso y puede presentarse con un patrón radiológico pulmonar intersticial. Debido a la similitud en el patrón histológico, el estudio genético permite una mayor certeza en el pronóstico y la posibilidad de entregar un adecuado consejo genético.AbstractIntroductionCongenital surfactant deficiency is a condition infrequently diagnosed in newborns. A clinical case is presented of surfactant protein B deficiency. A review is performed on the study, treatment and differential diagnosis of surfactant protein deficiencies and infant chronic interstitial lung disease.Case reportThe case is presented of a term newborn that developed respiratory distress, recurrent pulmonary opacification, and a transient response to the administration of surfactant. Immunohistochemical and genetic studies confirmed the diagnosis of surfactant protein B deficiency.ConclusionsPulmonary congenital anomalies require a high index of suspicion. Surfactant protein B deficiency is clinically progressive and fatal in the majority of the cases, similar to that of ATP binding cassette subfamily A member 3 (ABCA3) deficiency. Protein C deficiency is insidious and may present with a radiological pulmonary interstitial pattern. Due to the similarity in the histological pattern, genetic studies help to achieve greater certainty in the prognosis and the possibility of providing adequate genetic counselling.

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.

Chronic obstructive pulmonary disease (COPD) is one of the most socially significant respiratory diseases. The development and progression of COPD is mainly associated with smoking, which leads to chronic inflammation of the respiratory tract, including both cellular and humoral immunological processes. Contribution in immune defense of the lungs of ATP-transporters (ABC) is of great interest. Three lipid transporters ABCA1, ABCG1 and ABCA3 are expressed in lung cells. The first two contribute to reverse cholesterol transport, ABCA3 is involved in surfactant formation. Objective: study the expression of ABCA1, ABCG1 and ABCA3 genes in smoking and COPD. Methods: the analysis was carried out on previously studied data sets (gene sets) obtained from the expression of Omnibus (GEO) genes. Results: gene expression in alveolar macrophages in smokers (set GSE2125) showed a significant decrease of gene expression of ABCA1, ABCG1, apolipoprotein L1, L3, L4. Gene expression in airway epithelium in smokers (sets GSE4498, GSE3320, GSE11906), showed no significant changes of gene expression ABCA1, ABCA3, ABCG1, apolipoprotein L3 and L6. Gene expression in alveolar epithelial type II cells in patients with COPD showed a significant decrease in the expression of genes ABCA1, ABCA3, ABCG1, apolipoprotein L1, L3, L6, increased expression of TLR3, TLR4 compared with healthy individuals (set GSE29133). Conclusion: smoking disrupts the reverse transport of cholesterol in macrophages and alveolar epithelium, which probably serves as a mechanism of inflammation progression, reduces the expression of apolipoprotein L, whose function is not well known, but is considered to be involved in immune processes.

Background and aims Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is firstly described in 2014 as a type I interferonopathy that resulting from heterozygous mutations of TMEM173. This gene encodes the STING adaptor protein, and mutations lead to a gain of function on STING and overproduction of interferon beta. SAVI is characterized by neonatal-onset systemic inflammation, a severe cutaneous vasculopathy and interstitial lung disease. JAK inhibitors are considered as an effective therapeutic strategy. We sought to describe two missed diagnosed patients with SAVI (P1 and P2) in order to draw attention to this illness. Methods The clinical data were collected and Sanger sequencing of the gene TMEM173 was performed. An introspection of missed diagnosis and differential diagnosis was discussed. Results The two boys shared similar manifestations including recurrent skin abscess in winter with skin lesions and recurrent respiratory tract infections since their births. It occurred to us neutrophil defects like CGD but NBT test and DHR123 were normal for both of them in 2011. Peroxidase staining was positive and no mutations in MYD88 (P1). Computed tomography of the chest revealed pulmonary fibrosis yet no relevant genes (including ABCA3, SFTPC) mutations were found. Joint pain was significant for P2 but Naproxen was ineffective. Treatments with antibiotics turned out little improvement and wouldn’t prevent the progression. Finally, both of them died of respiratory and circulatory failure in 2012 and 2016 respectively. Recently, genetic mutations (c.463 G>A and c.461 A>G) in exon5 of TMEM173 were discovered, confirming the diagnosis of SAVI. Conclusions Owing to unfamiliarity with this disease, some cases would have been misdiagnosed or missed diagnosed. Thus, we propose that SAVI should be taken into consideration for children with chilblain skin lesions and pulmonary fibrosis after ruling out other related genes mutations.

Objective To investigate the prevalence of surfactant dysfunction (SD) and the genotype distribution in Chinese childhood interstitial lung disease (chILD). Methods From December 2013 to December 2016, whole exons and splicing regions of surfactant protein (SP)-B, SP-C, and adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3) were sequenced in chILD with unknown etiology in five children's medical centers of China. The sequencing was performed by Next-generation sequencing technique in a molecular genetics laboratory. The clinical and genetic data were reviewed retrospectively. Results In total, 136 patients of age 3 months to 13 years (mean 12.5 ± 9.4 months) were recruited, among which 76 were males. Of the 136 cases of chILD, 13.2% (18 of 136) were diagnosed with SD. In these 18 SD cases, 15 had heterozygous SP-C deficiencies, two cases had compound heterozygous ABCA3 deficiencies, and no SP-B deficiency was identified. In SP-C deficiencies, there were six cases with p.I73T, 2 with p.I73N, 5 with p.V39L, 1 with c.417delA, and 1 case with IVS4, +1G>C. Two cases of ABCA3 mutation were heterozygous with c.1755delC and c.2890G>A; c.3913T>C (R1305W) and exon 13 to 18 deletion. One was negative by sequencing while diagnosed positive by pathology. Conclusion The proportion of genetic mutation of SD in chILD is 13.2% in China, of which SP-C deficiency is predominant. The mutation, SP-C p.V39L, was found to be relatively prevalent in China and warrants further investigation.

Background Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. Methods Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. Results The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). Conclusions As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.

Vestibular schwannoma (VS) is a common disease in the region of the cerebellopontine angle in the posterior cranial fossa. Large VS and its surgical management usually lead to severe cranial nerve dysfunction and affect the patient’s quality of life. We aimed to find some possible progression markers of VS. Here, we sought to characterize the cerebrospinal fluid (CSF) proteome of patients with different VS grades and recurrence to identify biomarkers predictive of VS growth or recurrence. CSF was collected intraoperatively prior to removal of untreated VS, including grade I–V and recurrence. Isobaric tags for relative and absolute quantitation–based proteomic analysis of CSF from 43 VS patients and 3 control patients was used to identify candidate proteins. Ninety-three overlapping proteins were found to display differential expression in grade I, II, III, IV, and V VS patients compared with the control group. Nine proteins were chosen for validation with enzyme-linked immunosorbent assay. VS was distinguished from control patients based on the expression patterns of six proteins (ATP-binding cassette subfamily A member 3 [ABCA3], secretogranin-1 [SCG1], Krueppel-like factor 11 [KLF11], voltage-dependent calcium channel subunit alpha-2/delta-1 [CA2D1], brain acid soluble protein 1 [BASP1], and peroxiredoxin-2 [PRDX2]. ABCA3 and KLF11 were positively correlated with the size of early-phase of VS, while BASP1 and PRDX2 showed a negative correlation. ABCA3, CA2D1, and KLF11 were upregulated, while BASP1 and PRDX2 were downregulated in the CSF from VS recurrence. But SCG1 was increased only at early-phase. These data suggest that increased ABCA3 and KLF11 and decreased BASP1 and PRDX2 in CSF are associated with VS growth at the early phase or recurrence.

Respiratory distress is one of the most common clinical presentations in newborns requiring admission to a Neonatal Intensive Care Unit (NICU). Many of these infants develop respiratory distress secondary to surfactant deficiency, which causes an interstitial lung disease that can occur in both preterm and term infants. Pulmonary surfactant is a protein and lipid mixture made by type II alveolar cells, which reduces alveolar surface tension and prevents atelectasis. : The etiology of surfactant deficiency in preterm infants is pulmonary immaturity and inadequate production. Term infants may develop respiratory insufficiency secondary to inadequate surfactant, either from exposure to factors that delay surfactant synthesis (such as maternal diabetes) or from dysfunctional surfactant arising from a genetic mutation. : The genetics of surfactant deficiencies are very complex. Some mutations are lethal in the neonatal period, while others cause a wide range of illness severity from infancy to adulthood. Genes that have been implicated in surfactant deficiency include SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD (which encode for surfactant proteins A, B, C, and D, respectively); ABCA3 (crucial for surfactant packaging and secretion); and NKX2 (a transcription factor that regulates the expression of the surfactant proteins in lung tissue). : This article discusses the interplay between the genotypes and phenotypes of newborns with surfactant deficiency to assist clinicians in determining which patients warrant a genetic evaluation.

ABCA3 deficiency is a rare cause of neonatal respiratory failure. Bi-allelic complete loss of function variants lead to neonatal demise without lung transplantation, but children with partial function variants have variable outcomes. The favorable clinical course of three such infants presenting with respiratory distress at birth is described.

About 10% of term neonates present with respiratory distress at birth. The most common aetiologies include transient tachypnoea of the newborn, pneumonia and meconium aspiration syndrome (MAS). Hyaline membrane disease (HMD) in a term infant occurs either as primary HMD, secondary surfactant deficiency or congenital surfactant dysfunction. A detailed history supported with appropriate radiological and laboratory investigations can help a clinician reach a diagnosis. We report a case of surfactant dysfunction disorder which presented as severe MAS and persistent pulmonary hypertension of the newborn. In the infant described, the significant history of a sibling death with severe neonatal respiratory disease led us to think of diffuse developmental lung diseases especially surfactant dysfunction syndromes. Exome sequencing detected a heterozygous missense variation in exon 21 of the ATP binding cassette protein member 3 (ABCA3) gene. Based on the clinical picture supported with the exome sequencing, a diagnosis of surfactant dysfunction disorder (ABCA3 deficiency) was confirmed.

BACKGROUND Adenosine triphosphate-binding cassette subfamily A member 3 (ABCA3) gene variants, which cause severe respiratory distress syndrome (RDS) in term newborns, can cause death, especially due to the lack of congenital surfactant protein. The relationship between the types, pathophysiology and effects of ABCA3 gene variants on surfactant metabolism and the clinical phenotype have not yet been fully clarified, but the ABCA3 genotype is known to affect clinical severity. CASE In our study, in a term newborn with a diagnosis of RDS resulting in death, we detected the c.3677 T > C (p.Leu1226Pro) variant homozygous variant in the ABCA3 gene according to the NM_001089.3 transcript, which, to our knowledge, was identified for the first time in the literature. CONCLUSIONS We consider that this case report contributes to the literature on RDS by showing the presence of c.3677 T > C (p.Leu1226Pro), a new homozygous variant of ABCA3 in our patient.

The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children’s interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume.

Background: Idiopathic interstitial pneumonia (IIP) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality. They have been associated with an increased frequency of lung cancer. A genetic cause is identified in up to 20% of familial cases, telomerase and surfactant genes (SFTPA2, SFTPB, SFTPC, ABCA3) mutations being the first etiologies. Objectives:This study investigates the implication of SFTPA1 (NM_005411) in 12 families affected by IPF and lung cancer. Methods:SFTPA1 was sequenced by Sanger method in 12 unrelated index cases. An informed signed consent was obtained for each patient. New SFTPA1 variations were studied with functional experimentations. Results: A heterozygous missense disease-causing mutation (p.Trp211Arg, W211R), in SFTPA1, that encodes the Surfactant Protein (SP)-A1, was identified in a large family. The affected members, aged 7 months to 59 years, presented with various forms of IIP, and adenocarcinoma. The W211R mutation segregated in a dominant pathway with the disease. The mutation involved an amino-acid that is located in the carbohydrate recognition domain (CRD) of SP-A1 and involved a residue invariant throughout evolution in SP-A1, but also in SP-A2 and in other CRD-containing proteins. The W211R mutation impaired SP-A1 secretion, and an abnormal expression pattern of SP-A was found in the alveolar epithelium of lung tissue from a patient carrying the SFTPA1 mutation. Conclusion: This first report of the involvement of SFTPA1 in a Mendelian disorder unveils the key role of SP-A1 in the pathophysiology of IIP from infancy to elderly, and open up a new field of research on the mechanisms involved in IIP and lung cancer.

Rare mutations in surfactant-associated genes contribute to neonatal respiratory distress syndrome. The frequency of mutations in these genes in the Chinese population is unknown. We obtained blood spots from the Guangxi Neonatal Screening Center in Nanning, China that included Han (n=443) and Zhuang (n=313) ethnic groups. We resequenced all exons of the surfactant proteins-B (SFTPB), -C (SFTPC), and the ATP-binding cassette member A3 (ABCA3) genes and compared the frequencies of 5 common and all rare variants. We found minor differences in the frequencies of the common variants in the Han and Zhuang cohorts. We did not find any rare mutations in SFTPB or SFTPC, but we found three ABCA3 mutations in the Han [minor allele frequency (MAF)=0.003] and 7 in the Zhuang (MAF=0.011) cohorts (P=0.10). The ABCA3 mutations were unique to each cohort; five were novel. The collapsed carrier rate of rare ABCA3 mutations in the Han and Zhuang populations combined was 1.3%, which is significantly lower than that in the United States (P

The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membrane disease (HMD). Baby was ventilated and treated with surfactant. Because of the persistence of high ventilation needs with X-ray pictures consistent with HMD with a transient response to surfactant every time, the possibility of an inherited disorder of surfactant metabolism was kept. Whole-exome sequencing revealed a novel homozygous missense mutation in the gene for ATP binding cassette transporter protein A3. The baby died after 100 days of ventilation.

The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in ABCA3 result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant. This patient was found to have a maternally inherited frameshift loss-of-function ABCA3 mutation and a paternally inherited synonymous variant in ABCA3 predicted to create a cryptic splice site. Additional studies showed reduced ABCA3 expression in hyperplastic alveolar epithelial type II cells and lamellar body alterations characteristic of ABCA3 deficiency, leading to a diagnosis of autosomal recessive ABCA3-related pulmonary surfactant dysfunction. This case highlights the need for an integrated, comprehensive approach for the diagnosis of inherited diseases when in silico modeling is utilized in the interpretation of key novel genetic mutations.

We report a case of an 18-month-old boy with severe respiratory failure. At 16 months of age he was hospitalised for acute respiratory distress. Chest X-ray showed a large bilateral parenchymal opacities, while the chest CT scan showed a bilateral picture of ground-glass opacification. Due the difficulty of oxygen weaning and considering the poor nutritional condition, the baby was transferred to our hospital. The chest CT scan images and the clinical course were suggestive interstitial lung disease1. The cytological analysis performed on bronchoalveolar lavage showed abundant periodic acid-Schiff staining material. Repeated sessions of whole lung lavage were performed, and exogenous surfactant and pulse steroid were administered, with no benefit. The anti-GM- CSF antibodies (auto-antibodies against granulocyte-macrophage colony stimulating factor) were negative (excluding the possible diagnosis of autoimmune pulmonary alveolar proteinosis, PAP), whereas the exome analysis showed a variant in homozygosity in exon 22 of the ABCA3 transporter gene2. This variant, although not described in literature so far, has been suggested as pathogenic and correlated with a picture of pulmonary alveolar proteinosis with an autosomal recessive transmission. Considering the progressive worsening of the respiratory failure and the poor nutritional conditions, the hypothesis of a possible lung transplant was evaluated. However, the patient died at the age of 21 months. 1. Hartl D, et al. Interstitial lung disease in children - genetic background and associated phenotypes. Respir Res 2005; 6:32–47. 2. Kroner C, at al. Lung disease caused by ABCA3 mutations. Thorax 2017; 72:213-220.

Objective: Genetic surfactant dysfunction causes respiratory failure in term and near-term newborn infants, but little is known of such condition in prematures. We evaluated genetic surfactant dysfunction in premature newborn infants with severe RDS. Patients and methods: A total of 68 preterm newborn infants with gestational age ≤32 weeks affected by unusually severe RDS were analysed for mutations in SFTPB, SFTPC and ABCA3. Therapies included oxygen supplementation, nasal CPAP, different modalities of ventilatory support, administration of exogenous surfactant, inhaled nitric oxide and steroids. Molecular analyses were performed on genomic DNA extracted from peripheral blood and Sanger sequencing of whole gene coding regions and intron junctions. In one case histology and electron microscopy on lung tissue was performed. Results: Heterozygous previously described rare or novel variants in surfactant proteins genes ABCA3, SFTPB and SFTPC were identified in 24 newborn infants. In total, 11 infants died at age of 2 to 6 months. Ultrastructural analysis of lung tissue of one infant showed features suggesting ABCA3 dysfunction. Discussion: Rare or novel genetic variants in genes encoding surfactant proteins were identified in a large proportion (35%) of premature newborn infants with particularly severe RDS. We speculate that interaction of developmental immaturity of surfactant production in association with abnormalities of surfactant metabolism of genetic origin may have a synergic worsening phenotypic effect.