Incidence of alveolar capillary dysplasia with misalignment of pulmonary veins in infants with unexplained severe pulmonary hypertension: The roles of clinical, pathological, and genetic testing

Early Hum Dev. 2021 Apr:155:105323. doi: 10.1016/j.earlhumdev.2021.105323. Epub 2021 Jan 26.


Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare and fatal disorder that occurs in the developing fetal lungs; at birth, infants exhibit an oxygenation disorder accompanied by severe pulmonary hypertension (PH) and have a very short life span. ACDMPV is definitively diagnosed by pathological findings, and infants born with unexplained severe PH may not be properly diagnosed without a biopsy or autopsy.

Methods: Japanese infants with unexplained severe PH were enrolled in this study. Genetic analyses were performed on DNA extracted from peripheral blood leukocytes. Sanger sequencing or next-generation sequencing was performed by coding exons and introns for FOXF1 in all samples. For individuals without pathogenic exonic variants, multiplex ligation-dependent probe amplification was performed to identify copy number variations (CNVs) in exons, introns, and in the upstream region of FOXF1.

Results: This study included 30 infants who were diagnosed over the course of nine years. Four individuals had the pathogenic variations on the exon 1 of FOXF1, including two frameshift and two missense variations. Pathogenic CNVs were found in another five individuals.

Conclusion: In the pathologically proven ACDMPV patients, the ratios of cases with exonic variations, CNVs, and no genetic findings were reported as 45%, 45% and 10%, respectively. We estimate that about 30% (10 (9 + 1) out of 30) of individuals with unexplained severe PH had ACDMPV.

Keywords: Alveolar capillary dysplasia with misalignment of pulmonary veins; Copy number variations; Forkhead box F1; Pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Copy Number Variations
  • Forkhead Transcription Factors / genetics
  • Genetic Testing
  • Humans
  • Hypertension, Pulmonary* / epidemiology
  • Hypertension, Pulmonary* / genetics
  • Incidence
  • Infant
  • Infant, Newborn
  • Persistent Fetal Circulation Syndrome* / epidemiology
  • Persistent Fetal Circulation Syndrome* / genetics


  • FOXF1 protein, human
  • Forkhead Transcription Factors