A NovelDe NovoPathogenic Variant inFOXF1in a Newborn with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is an autosomal dominant, fatal developmental disorder of the lungs, with a mortality rate of about 100%. ACD/MPV is caused by mutations in FOXF1. Herein, we describe a newborn boy with ACD/MPV carrying a novel pathogenic variant of FOXF1. The patient developed respiratory distress and severe pulmonary hypertension on the first day of life. Despite aggressive cardiorespiratory management, including veno-venous extracorporeal membrane oxygenation, his condition deteriorated rapidly, and he died within the first month of his life. Lung histology showed the characteristic features of ACD/MPV at autopsy. Sequence analysis of FOXF1 from genomic DNA obtained from autopsied lung tissue revealed that the patient was heterozygous for a novel missense variant (c.305T>C; p.Leu102Pro). Further analysis of both parents confirmed the de novo occurrence of the variant. To the best of our knowledge, this is the first report of genetically confirmed ACD/MPV in Korea.

Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects

“… 1 , 6 , 7 In up to 80% of the cases, associated malformations are found for which surgery is occasionally needed. 3 , 8 – 14 These malformations predominantly affect the gastrointestinal tract, but also affect the cardiovascular and urogenital system. 2 – 5 , 9 , 15 , 16 Irrespective of the co-morbidities, the mortality of ACD/MPV is almost 100%.…”

“…Yet, the vast majority of ACD/MPV patients cannot be weaned from ECMO, while ECMO itself is invasive, comes with risks of complications, and is expensive. 1 , 4 , 7 , 8 , 19 , 23 , 28 , 29 , 37 Ideally, an open lung biopsy is performed before ECMO therapy has started or at least before a “second-run” ECMO therapy is considered. 7 , 14 , 27 , 28 On the other hand, ECMO therapy can provide an excellent bridge to lung transplantation in ACD/MPV patients with a mild phenotype.…”

“…49 Additionally, a variety of heterozygous genomic variants in the FOXF1 locus of ACD/MPV patients have been reported by other research groups. 8,16,20 Most of the variants are collected in the Leiden Open Variation Database (LOVD). 52 FOXF1, first described by Pierrou et al in 1994, is a member of the Forkhead box transcription factors (TFs) and plays a role during embryonic development, specifically in lung development.…”

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

“…2 Found on chromosome 16p24.1, 6 this gene is responsible for encoding a transcription factor critical in pulmonary morphogenesis and vascular development. 2, 7 Given that FOXF1 is a major transcription factor affecting mesenchymal development, it is not surprising that multiple congenital anomalies are typical. 4 FOXF1 is a member of the FOX family, which is recognized by a conserved DNA-binding domain.…”

A recurrent 8 bp frameshifting indel in FOXF1 defines a novel mutation hotspot associated with alveolar capillary dysplasia with misalignment of pulmonary veins

“…Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV, MIM# 265380) is a rare neonatal developmental lung disease, lethal due to severe respiratory distress and refractory pulmonary hypertension (PAH) (Bishop, Stankiewicz, & Steinhorn, 2011). To date, more than 70 distinct ACDMPV-related FOXF1 heterozygous point mutations and 60 copy-number variant (CNV) deletions involving FOXF1 and/or its upstream lung-specific enhancer at 16q24.1 have been identified in 80–90% of ACDMPV patients (Abu-El-Haija et al, 2018; Everett, Ataliotis, Chioza, Shaw-Smith, & Chung, 2017; Hayasaka et al, 2018; Ma et al, 2017; Nagano, Yoshikawa, Hosono, Takahashi, & Nakayama, 2016; Pradhan et al, 2019; Sen, Gerychova, et al, 2013; Stankiewicz et al, 2009; Szafranski et al, 2013, 2014, 2016). FOXF1 (Forkhead box F1, MIM#601089) encodes a transcription factor of the fork-head family, and is regulated by the sonic hedgehog (SHH) signaling pathway during lung development (Fernandes-Silva, Correia-Pinto, & Moura, 2017; Kalinichenko et al, 2001).…”