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1.
Hum Mutat ; 41(7): 1298-1307, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32196812

RESUMO

ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase-mediated phospholipid transport into the lamellar bodies (type II mutant). We qualitatively compared wild-type (WT-ABCA3) with four uncharacterized ABCA3 variants (c.418A>C;p.Asn140His, c.3609_3611delCTT;p.Phe1203del, c.3784A>G;p.Ser1262Gly, and c.4195G>A;p.Val1399Met) in A549 cells using protein processing, colocalization with intracellular organelles, lamellar body ultrastructure, and ATPase activity. We quantitatively measured lamellar body-like vesicle diameter and intracellular ABCA3 trafficking using fluorescence-based colocalization. Three ABCA3 variants (p.Asn140His, p.Ser1262Gly, and p.Val1399Met) were processed and trafficked normally and demonstrated well-organized lamellar body-like vesicles, but had reduced ATPase activity consistent with type II mutants. P.Phe1203del was processed normally, had reduced ATPase activity, and well-organized lamellar body-like vesicles, but quantitatively colocalized with both endoplasmic reticulum and lysosomal markers, an intermediate phenotype suggesting disruption of both intracellular trafficking and phospholipid transport. All ABCA3 mutants demonstrated mean vesicle diameters smaller than WT-ABCA3. Qualitative and quantitative functional characterization of ABCA3 variants informs mechanisms of pathogenicity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Células A549 , Vesículas Citoplasmáticas , Humanos , Doenças Pulmonares Intersticiais/genética , Mutação de Sentido Incorreto , Alvéolos Pulmonares , Surfactantes Pulmonares
2.
Eur J Radiol ; 165: 110886, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37267893

RESUMO

PURPOSE: Childhood interstitial lung disease (chILD) is an umbrella concept covering a wide range of rare lung diseases, many of which are unique to childhood. The diagnosis is based on clinical presentation, multidetector computed tomography (MDCT), genetic testing, lung-function testing, and lung biopsy. Because knowledge of the usefulness of MDCT pattern recognition in ChILD is at present limited, we examined the occurrence of MDCT patterns in children with histologically confirmed interstitial lung disease. METHOD: We searched the biopsy, MDCT, and clinical information database of a single national paediatric referral hospital for 2004-2020. Data were from affected children under age 18. MDCT images we reanalysed while blinded to the identity and referral information. RESULTS: We included 90 patients, of whom 63 (70 %) were male. The median age at biopsy was 1.3 years (interquartile range 0.1-16.8). Biopsy findings fell into 26 histological classes covering all nine chILD classification categories. We recognized six distinct MDCT patterns: neuroendocrine cell hyperplasia of infancy (23), organizing pneumonia (5), non-specific interstitial pneumonia (4), bronchiolitis obliterans (3), pulmonary alveolar proteinosis (2), and bronchopulmonary dysplasia (n = 2). Of the total 90, in 51 (57 %) children, none of these six MDCT patterns appeared. Of those 39 children with a recognizable MDCT pattern, in 34 (87 %), that pattern predicted their final diagnosis. CONCLUSIONS: Among cases of chILD, we identified a specific predefined MDCT pattern in only 43 %. However, when such a recognizable pattern occurred, it was predictive of the final chILD diagnosis.


Assuntos
Bronquiolite Obliterante , Doenças Pulmonares Intersticiais , Pneumonia , Recém-Nascido , Criança , Humanos , Masculino , Lactente , Adolescente , Feminino , Tomografia Computadorizada Multidetectores , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Bronquiolite Obliterante/patologia , Pneumonia/patologia
3.
Radiol Clin North Am ; 60(1): 83-111, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34836568

RESUMO

Childhood interstitial lung disease (ChILD) is an umbrella term encompassing a diverse group of diffuse lung diseases affecting infants and children. Although the timely and accurate diagnosis of ChILD is often challenging, it is optimally achieved through the multidisciplinary integration of imaging findings with clinical data, genetics, and potentially lung biopsy. This article reviews the definition and classification of ChILD; the role of imaging, pathology, and genetics in ChILD diagnosis; treatment options; and future goals. In addition, a practical approach to ChILD imaging based on the latest available research and the characteristic imaging appearance of ChILD entities are presented.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Pulmão/diagnóstico por imagem , Masculino , Guias de Prática Clínica como Assunto
4.
Pediatr Pulmonol ; 57(5): 1325-1330, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35170262

RESUMO

ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allele-specific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsense-mediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exon-intron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.


Assuntos
Epigênese Genética , Síndrome do Desconforto Respiratório do Recém-Nascido , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Criança , DNA/metabolismo , DNA Complementar/metabolismo , Humanos , Recém-Nascido , Pulmão/patologia , Mutação , Nucleotídeos/metabolismo , RNA/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismo
5.
Clin Respir J ; 14(2): 102-108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31724297

RESUMO

INTRODUCTION: Childhood diffuse parenchymal lung diseases (DPLD) are a heterogeneous group of respiratory disorders of both known and unknown causes that share common histological features. To date, there is not an exact consensus about the terminology, classification, therapy and follow up of this disease because of its rarity and wide clinical spectrum. OBJECTIVES: In this study, we tried to classify our DPLD patients according to the last classification scheme (chILD Network Classification). METHODS: The files of the children diagnosed with DPLD at our university hospital between 1974 and 2012 were retrospectively investigated. Clinical features, laboratory, radiological and histopathological findings, therapy and follow-up outcomes of these patients were recorded and evaluated according to the actual information and definitions. RESULTS: We described 130 DPLD patients, the largest childhood DPLD series from a single center, classified in 16 distinct groups according to their diagnosis. Our largest group in this serie is pulmonary hemosiderosis (28.5%); idiopathic interstitial pneumonias, pulmonary hemosiderosis, sarcoidosis and lipid storage diseases with lung involvement represent the 70% of the diagnoses. When we classified our patients according to the chILD Network Classification; patients with idiopathic interstitial pneumonia older than 2 years, idiopathic pulmonary hemosiderosis, pulmonary alveolar microlithiasis and diffuse chondroid malformation of the lung stayed out of this classification. CONCLUSION: To ensure a consensus about the therapy and follow up, we have to make revisions and reorganisations on the DPLD classification which was proposed in 2007. We need a new childhood DPLD classification that will cover all these disease groups.


Assuntos
Doenças Pulmonares Intersticiais/classificação , Pulmão/diagnóstico por imagem , Adolescente , Biópsia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
6.
Radiol Clin North Am ; 58(3): 487-502, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32276699

RESUMO

Childhood interstitial lung disease (chILD) in children, teenagers, and young adults presents a challenge to the clinicians and radiologist, given its rarity, diverse imaging manifestations, and often nonspecific clinical examination findings. This article discusses the utility of available imaging techniques and associated characteristic imaging findings, and reviews the 2015 chILD classification scheme, with clinical examples highlighting the imaging features to help the radiologist aid in an efficient and accurate multidisciplinary diagnosis of chILD.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Pulmão/diagnóstico por imagem , Adulto Jovem
7.
Cureus ; 11(9): e5766, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31723525

RESUMO

Neuroendocrine cell hyperplasia of infancy (NEHI) is a recently reported condition and commonly missed. A general pediatrician who encounters an infant with an insidious onset of breathlessness, hypoxemia, and failure to thrive should think through a diagnosis of NEHI when common respiratory diseases are excluded. Lung biopsy is regarded as the diagnostic gold standard for NEHI and typically demonstrates increased numbers of neuroendocrine cells (NECs) in otherwise near-normal lung tissues. However, classic high-resolution computed tomography (HRCT) findings can enable to establish the diagnosis without the need for a biopsy. This case shows typical chest imaging findings of NEHI with a brief review of the literature.

8.
Pediatr Pulmonol ; 51(9): 921-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27145217

RESUMO

BACKGROUND: Heterozygous mutations in the FOXF1 transcription factor gene are implicated in alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a developmental disorder of the lungs classically presenting with pulmonary hypertension and early demise. Evidence has suggested haploinsufficiency and partial paternal imprinting. We present a family with several affected members with an extremely variable phenotype. PATIENTS: The index patient presented several hours after birth with severe pulmonary hypertension. She is now 3-years old, thriving on maximal pulmonary hypertension therapy, chronic steroids, and oxygen. One of the patient's siblings died at 16 days with pulmonary hypertension and an annular pancreas, consistent with classical ACDMPV. METHODS: Whole exome sequencing was performed in the index case. The identified variant was confirmed by Sanger sequencing, and tested in the remaining family members. Parental origin was determined by PCR amplification and cloning, sequencing, and identification of adjacent single nucleotide polymorphisms. Echocardiography was performed in the asymptomatic carriers. RESULTS: Whole exome analysis revealed a novel, predictably pathogenic heterozygous missense mutation, g.chr16:86544406 C>A NM_001451, c.C231A, p.F77L, in the FOXF1 gene. The mutation arose in the father, de novo, early postzygotically, with 70% somatic mosaicism in the blood, on the grandpaternal chromosome. It was also present in the proband's asymptomatic sister, found to have partial anomalous pulmonary venous return. CONCLUSION: FOXF1 mutations may have an extremely variable phenotype, possibly as a result of somatic mosaicism and complex gene regulation including unorthodox imprinting of the gene locus. The prolonged survival of the proband suggests the need for aggressive treatment. Pediatr Pulmonol. 2016; 51:921-927. © 2016 Wiley Periodicals, Inc.


Assuntos
Fatores de Transcrição Forkhead/genética , Mutação de Sentido Incorreto , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Pré-Escolar , Feminino , Heterozigoto , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Masculino , Mosaicismo , Linhagem , Fenótipo , Veias Pulmonares/anormalidades , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/genética
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