Two patients with FOXF1 mutations with alveolar capillary dysplasia with misalignment of pulmonary veins and other malformations: Two different presentations and outcomes

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) describes a group of developmental disorders affecting the lungs with its pulmonary vasculature. Mutations in the FOXF1 gene have been reported in most cases, and extrapulmonary findings were described.We present two patients with ACDMPV and FOXF1 mutations that illustrate the variability in presentation and outcome of their disease. Patient 1 was a full-term infant with imperforate anus and pulmonary hypertension. He required Extracorporeal Membrane Oxygenation on day of life (DOL) 3, and passed away on DOL 13 after no clinical improvement. Postmortem findings were consistent with ACDMPV. FOXF1 testing revealed a heterozygous pathogenic frameshift de novo mutation, c.1057_1078dup, p.(Gly360Valfs*58). Patient 2 is a 6-month-old female, with a small omphalocele. She had intermittent retractions at 1 week of age. She was admitted with pulmonary hypertension at 7 weeks of age. Lung biopsy confirmed ACDMPV. FOXF1 testing revealed a de novo, heterozygous likely pathogenic missense mutation c.253T>C, p.(Phe85Leu]).Our two patients had different presentations, ages of onset, and progression of their disease.Our second patient had patchy lung involvement on biopsy, which may explain the relatively delayed onset and longer survival. ACDMPV is an important consideration for full-term infants with worsening pulmonary hypertension early in life. K E Y W O R D S alveolar capillary dysplasia with misalignment of pulmonary veins, FOXF1, pulmonary hypertension

Lung biopsies in infants and children in critical care situation

“…[16][17][18][19][20] FOXF1, mostly associated with fatal forms of ACD, has also been reported in patients with prolonged survival (with or without lung transplantation). [21][22][23][24] Conversely, some mutations lead to a more homogeneous and unfavorable prognosis such as SFTPB mutations that are associated with fatal forms of chILD in newborns. [25][26][27] In case where these genes are involved in newborns with severe initial respiratory distress requiring invasive ventilation, a poor outcome can be predicted with a high degree of confidence.…”

“…Additionally, even for the same mutation, NKX2‐1 and TBX4 mutations are associated with extreme variations in phenotypes 16–20 . FOXF1 , mostly associated with fatal forms of ACD, has also been reported in patients with prolonged survival (with or without lung transplantation) 21–24 . Conversely, some mutations lead to a more homogeneous and unfavorable prognosis such as SFTPB mutations that are associated with fatal forms of chILD in newborns 25–27 .…”

High‐level gonosomal mosaicism for a pathogenic non‐coding CNV deletion of the lung‐specific FOXF1 enhancer in an unaffected mother of an infant with ACDMPV

“…Heterozygous SNVs in the FOXF1 gene on chromosome 16q24.1 or CNV deletions involving FOXF1 (MIM# 601089) and/or its distant lung-specific enhancer, located ~286 kb upstream, are found in 80%-90% of patients with ACDMPV. To date, more than 64 distinct pathogenic or likely pathogenic SNVs (missense and nonsense), 29 indels (frameshift) and 70 CNV deletions have been reported (Abu-El-Haija et al, 2018;Everett et al, 2017;Hayasaka et al, 2018;Ma et al, 2017;Nagano et al, 2016;Pradhan et al, 2019;Sen et al, 2013;Stankiewicz et al, 2009;Szafranski et al, 2013Szafranski et al, , 2014Szafranski et al, , 2016Szafranski et al, , 2019Szafranski et al, , 2022Yildiz Bolukbasi et al, 2022).…”

Ultrasound findings in neonates with alveolar capillary dysplasia with misalignment of the pulmonary veins: report of two cases

“… 1 – 4 Since the description of the first autopsy case of a term infant with alveolar capillary dysplasia in 1981, 5 approximately 200 cases have been reported worldwide, and these cases showed a relatively even geographical distribution. 6 – 29 Because the prenatal histories in these cases were generally normal and no characteristic manifestations were noted in the imaging examinations, 30 – 33 clinical evidence for diagnosis is still lacking. With the development of ultrasound, lung ultrasound (LUS) has become an extremely important bedside imaging tool in the neonatal intensive care unit (NICU).…”