Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders

Vincent, Marie‐Françoise; Karolak, Justyna A.; Deutsch, Gail H.; Gambin, Tomasz; Popek, Edwina J.; Isidor, Bertrand; Szafrański, Przemysław; Caignec, Cédric Le; Stankiewicz, Paweł

doi:10.1164/rccm.201903-0495tr

Cited by 62 publications

(77 citation statements)

References 74 publications

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“…Recently, we and others have described heterozygous recurrent and nonrecurrent CNV deletions on 17q23.1q23.2, involving TBX2 and TBX4, as well as de novo heterozygous missense TBX4 variants [30][31][32][33] in patients with PH and other lethal pulmonary abnormal growth conditions. PH is a group of rare lung developmental diseases histopathologically characterized by a reduction of the number and size of bronchioles and alveoli [43,44]. While PH is usually secondary to underlying disorders limiting fetal lung growth (i.e.…”

Section: Discussionmentioning

confidence: 99%

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A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

et al. 2020

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Background: Application of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.2 or 16p11.2, respectively. Case presentation: Here, we report a deceased newborn with pulmonary hypertension and pulmonary interstitial emphysema with features suggestive of pulmonary hypoplasia, resulting in respiratory failure and neonatal death soon after birth. Using the array comparative genomic hybridization and WGS, two heterozygous recurrent CNV deletions:~2.2 Mb on 17q23.1q23.2, involving TBX4, and~600 kb on 16p11.2, involving TBX6, that both arose de novo on maternal chromosomes were identified. In the predicted lung-specific enhancer upstream to TBX4, we have detected seven novel putative regulatory non-coding SNVs that were absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. Conclusions: Our findings further support a recently reported model of complex compound inheritance of LLDD in which both non-coding and coding heterozygous TBX4 variants contribute to the lung phenotype. In addition, this is the first report of a patient with combined de novo heterozygous recurrent 17q23.1q23.2 and 16p11.2 CNV deletions.

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Section: Discussionmentioning

confidence: 99%

“…diaphragmatic hernia, skeletal abnormalities, or oligohydramnios), primary PH (MIM# 265430) is related to an embryologic defect of lung branching morphogenesis and vasculogenesis [45,46]. The consequence of PH is severe respiratory distress and PAH, typically refractory to therapy [44].…”

Section: Discussionmentioning

confidence: 99%

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

et al. 2020

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“…Presentation in the newborn period is with respiratory distress proceeding rapidly to intubation and mechanical ventilation, usually in a term baby, with remorseless deterioration. SP gene mutations should be considered alongside other commoner causes such as congenital infection and aspiration syndromes, and rarer conditions such as alveolar capillary dysplasia with misaligned pulmonary veins and related conditions [ 74 , 75 ]. In older children, presentation is more usually with cough, progressive breathlessness and respiratory distress, but first presentation may as a child who has been intubated for type I respiratory failure (carbon dioxide elimination is rarely an issue).…”

Section: Clinical Presentationmentioning

confidence: 99%

“…The differential diagnosis of chILD presenting in the newborn period [ 74 ] includes the alveolar capillary dysplasia spectrum and genetic testing, especially for FOXF1 and TBX4 , should be performed [ 75 ]. The differential diagnosis of later presentations encompasses almost all paediatric respirology, and in particular the other causes of chILD.…”

Section: Differential Diagnosismentioning

confidence: 99%

Pulmonary alveolar proteinosis in children

Bush

Pabary

2020

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Pulmonary alveolar proteinosis (PAP) is an umbrella term for a wide spectrum of conditions that have a very characteristic appearance on computed tomography. There is outlining of the secondary pulmonary lobules on the background of ground-glass shadowing and pathologically, filling of the alveolar spaces with normal or abnormal surfactant. PAP is rare and the common causes in children are very different from those seen in adults; autoimmune PAP is rare and macrophage blockade not described in children. There are many genetic causes of PAP, the best known of which are mutations in the genes encoding surfactant protein (SP)-B, SP-C, thyroid transcription factor 1, ATP-binding cassette protein 3, and the granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor α- and β- chains. PAP may also be a manifestation of rheumatological and metabolic disease, congenital immunodeficiency, and haematological malignancy. Precise diagnosis of the underlying cause is essential in planning treatment, as well as for genetic counselling. The evidence base for treatment is poor. Some forms of PAP respond well to whole-lung lavage, and autoimmune PAP, which is much commoner in adults, responds to inhaled or subcutaneous GM-CSF. Emerging therapies based on studies in murine models of PAP include stem-cell transplantation for GM-CSF receptor mutations.Educational aimsTo understand when to suspect that a child has pulmonary alveolar proteinosis (PAP) and how to confirm that this is the cause of the presentation.To show that PAP is an umbrella term for conditions characterised by alveolar filling by normal or abnormal surfactant, and that this term is the start, not the end, of the diagnostic journey.To review the developmental differences in the spectrum of conditions that may cause PAP, and specifically to understand the differences between causes in adults and children.To discuss when to treat PAP with whole-lung lavage and/or granulocyte–macrophage colony-stimulating factor, and review potential promising new therapies.

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“…In some infants, the lung circulation fails to achieve or sustain the normal decrease in pulmonary vascular resistance, leading to hypoxemic respiratory failure with pulmonary hypertension, which is known as persistent pulmonary hypertension of the newborn. Despite advances in care, however, a subgroup of term or near-term infants present with persistent pulmonary hypertension of the newborn physiology that is poorly responsive to these interventions, and die in the first days of life with evidence of lethal congenital lung disease (3–6). In this highly fatal subgroup, lung biopsy or autopsy findings often reveal a striking disruption of distal lung development, including signs of decreased alveolar architecture, reduced vascular density, signature hypertensive remodeling of arteries and microvasculature, and other features (3–9).…”

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confidence: 99%

Mechanistic Insights into Lethal Lung Developmental Disorders. The Rare Informs the Common

Sun

2019

Am J Respir Crit Care Med

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Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders

Cited by 62 publications

References 74 publications

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

Pulmonary alveolar proteinosis in children

Mechanistic Insights into Lethal Lung Developmental Disorders. The Rare Informs the Common

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