A Case of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (ACD/MPV): The Importance of Early Genetic Testing

Abstract

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, lethal condition caused by irregular pulmonary vascular maturation. Almost all cases present in the newborn period with ensuing respiratory decline within a couple days of life, ultimately leading to nearly 100% neonatal mortality. While the gold standard for diagnosis is lung biopsy, the identification of the Forkhead Box F1 (FOXF1) gene as the main genetic cause of ACD/MPV has allowed for a definitive diagnosis to be made without performing a high-risk procedure in a critically-ill neonate. This case report describes an ACD/MPV patient with hyperinsulinemia and refractory hypoglycemia as well as multiple anomalies who was found to have a novel pathogenic variant in the FOXF1 gene, identified via exome with copy number analysis, which results in premature protein termination (NM 001451.2 c.637 dup, p.Val213Glyfs*82). Our patient showcases the importance of early genetic testing to diagnose ACD/MPV given the substantial risk in obtaining a lung biopsy in a patient with hypoxemic respiratory failure, severe pulmonary hypertension, and vasodilator-induced pulmonary edema.

Haploinsufficiencies of FOXF1, FOXC2 and FOXL1 genes originated from deleted 16q24.1q24.2 fragment related with alveolar capillary dysplasia with misalignment of pulmonary veins and lymphedema-distichiasis syndrome: relationship to phenotype

“…In this report, although the characteristic phenotypes associated with LDS may be atypical in the fetal stage, CNV-seq detection confirms the diagnosis of LDS. Therefore, genetic detection should be recommended as a first-line diagnostic tool for the fetuses with suspected ACDMPV and/or LDS early during the fetal period [ 30 ]. In addition, the disease-causing variant of FOXL1 gene is mainly related with gastrointestinal manifestations, as has been confirmed in mice with FOXL1 gene knocked out [ 31 ].…”

Haploinsufficiencies of FOXF1, FOXC2 and FOXL1 genes originated from deleted 16q24.1q24.2 fragment related with alveolar capillary dysplasia with misalignment of pulmonary veins and lymphedema–distichiasis syndrome: relationship to phenotype

“…In this report, the characteristic phenotypes associated with LDS may be atypical due to the fetal stage, however, the pathogenic variant by molecular genetic testing con rms the diagnosis of LDS. Therefore, genetic detection should be recommended as a rst-line diagnostic tool for the fetuses with suspected ACD/MPV and / or LDS early during the fetal period [24]. Although clinical manifestations of the individuals in the table 1 are very different, there are no one who presented ACD/MPV and LDS simultaneously.…”