Abstract
Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease.
Highlights
Congenital chylothorax (CC), or fetal chylothorax (FC), is a rare condition, characterized by accumulation of lymphocyte-rich fluid in the pleural cavity [1]
Even though genes involved in lymphangiogenesis have been extensively studied in a mouse model [8], only a few homologous genes, including vascular endothelial growth factor receptor type 3 (VEGFR3), integrina9 (ITGA9), Tyrosine-protein phosphatase non-receptor type 11 (PTPN11), and Forkhead box protein C2 (FOXC2), were reported in humans affected with hereditary lymphedema [5], [9]
ACGH Two segmental microduplications were identified in the 59-end of ITGA9 of the index case (Ind) fetus; the first was over the exon 1-intron 1 boundary, arr 3p21.3 (37,493,992–37,494,056)63, with a length of 64 base pairs, and the second was located at the 59end of the intron 1, arr 3p21.3 (37,494,150–37,494,255)63, and was 100 bp (Figures 2A and 2B)
Summary
Congenital chylothorax (CC), or fetal chylothorax (FC), is a rare condition (estimated incidence, 1 in 12 000), characterized by accumulation of lymphocyte-rich fluid in the pleural cavity [1]. Even though genes involved in lymphangiogenesis have been extensively studied in a mouse model [8], only a few homologous genes, including vascular endothelial growth factor receptor type 3 (VEGFR3), integrina (ITGA9), Tyrosine-protein phosphatase non-receptor type 11 (PTPN11), and Forkhead box protein C2 (FOXC2), were reported in humans affected with hereditary lymphedema [5], [9]. Among these causative loci, ITGA9, which has an important role in lymphatic valve morphogenesis (in knockout mice), is a candidate gene of autosomal-recessive primary lymphedema caused by lymphatic valve defects [7], [10]. Fetuses carrying mutations in the hereditary lymphedema-associated gene loci had a grave prognosis in our recent series of cases involving fetal OK-432 pleurodesis [4]
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