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      A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation

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          Abstract

          Background

          Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients.

          Case presentation

          We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2–40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels.

          Conclusions

          Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

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          Most cited references 18

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          Expanding the phenotype of alveolar capillary dysplasia (ACD).

          To define the phenotype of congenital alveolar capillary dysplasia (ACD) as a first step toward mapping the responsible gene(s). Analysis of pathology reports and microscopic slides of 23 subjects with ACD and sequence analysis of two candidate genes. Our review of the pre- and postmortem records delineates both the natural history of this condition and the associated anomalies. Our collection of families corroborates the likely autosomal recessive nature of this condition in some families and provides additional data for genetic and prenatal counseling. Anomalies of many organ systems were detected either in the prenatal period or during the hospital course. However, some major anomalies were not detected until postmortem examination. Left-right asymmetry and gastrointestinal malrotation emerge as important, previously recognized but underappreciated phenotypic features of ACD. Finally, we used sequence analysis to exclude mutations in the coding region of two candidate genes, bone morphogenetic protein type II receptor (BMPR2) and endothelial monocyte-activating polypeptide II (EMAP II), as candidates for ACD. Understanding the clinical spectrum of ACD and the cloning of an "ACD gene" both have implications for counseling, for prenatal testing, and for understanding the molecular pathophysiology of ACD and other organ malformations that are associated with this condition.
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            Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

            Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. © 2013 Wiley Periodicals, Inc.
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              Alveolar capillary dysplasia.

              Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants. This review aims to address recent findings in the etiology and genetics of ACD/MPV and to raise awareness of this poorly known disease, which may also present as milder, unclassified forms. Successively discussed are what is known about the epidemiology, pathogenesis, pathophysiology, diagnostic indicators and approaches, genetic testing, treatment, and cases of delayed onset. The review concludes with suggestions for future directions to answer the many unknowns about this disorder.
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                Author and article information

                Contributors
                minami@kuhp.kyoto-u.ac.jp
                Journal
                Diagn Pathol
                Diagn Pathol
                Diagnostic Pathology
                BioMed Central (London )
                1746-1596
                9 May 2020
                9 May 2020
                2020
                : 15
                Affiliations
                [1 ]GRID grid.411217.0, ISNI 0000 0004 0531 2775, Department of Diagnostic Pathology, , Kyoto University Hospital, ; 54 Kawahara-cho, Sakyo-ku, Kyoto, 606-8507 Japan
                [2 ]GRID grid.437848.4, ISNI 0000 0004 0569 8970, Department of Pathology and Laboratory Medicine, , Nagoya University Hospital, ; Nagoya, Japan
                [3 ]GRID grid.258799.8, ISNI 0000 0004 0372 2033, Department of Pediatrics, Graduate School of Medicine, , Kyoto University, ; Kyoto, Japan
                [4 ]GRID grid.437848.4, ISNI 0000 0004 0569 8970, Division of Neonatology, Center for Maternal-Neonatal Care, , Nagoya University Hospital, ; Nagoya, Japan
                [5 ]GRID grid.27476.30, ISNI 0000 0001 0943 978X, Department of Pediatrics, , Nagoya University Graduate School of Medicine, ; Nagoya, Japan
                [6 ]GRID grid.411217.0, ISNI 0000 0004 0531 2775, Clinical Genetics Unit, , Kyoto University Hospital, ; Kyoto, Japan
                [7 ]GRID grid.412167.7, ISNI 0000 0004 0378 6088, Maternity and Perinatal Care Center, , Hokkaido University Hospital, ; Sapporo, Japan
                [8 ]GRID grid.416697.b, ISNI 0000 0004 0569 8102, Department of Clinical Research, , Saitama Children’s Medical Center, ; Saitama, Japan
                Article
                972
                10.1186/s13000-020-00972-6
                7211333
                32386508
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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                © The Author(s) 2020

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