Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV, MIM 265380) is a lethal neonatal developmental lung disorder characterized by reduced number of pulmonary capillaries, muscular thickening in small pulmonary arterioles, and abnormally situated pulmonary veins running alongside pulmonary arterioles [1, 2]. Patients with ACDMPV present with respiratory distress usually accompanied by pulmonary hypertension and often by extra-pulmonary anomalies [3, 4].
In the vast majority of patients with ACDMPV, heterozygous de novo point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its distant enhancer region on chromosome 16q24.1 have been identified [4–7]. FOXF1 is a transcription factor involved, among others, in maintaining the endothelial barrier through activation of the S1P/S1PR1 signaling required for the integrity of adherens junctions .
An ~60 kb distant tissue-specific enhancer region (chr16:86,212,040-86,271,919; hg19) located 270 kb upstream of FOXF1 has been defined following alignment of ACDMPV causative deletion CNVs that did not include FOXF1 . This region encodes fetal lung-expressed long non-coding RNAs, LINC01081 and LINC01082, and encompasses binding sites for numerous transcriptional regulators, including CEBP/p300, CTCF, and GLI2 [4, 7]. Both LINC01081 and GLI2 have been shown to positively control FOXF1 expression in human fetal lung fibroblasts [7, 9]. Recently, in vivo studies of the mouse syntenic region have shown that it likewise harbors a Foxf1 enhancer . Of note, 30 of 31 genomic deletions pathogenic for ACDMPV, for which parental origin was determined, occurred de novo on the maternal chromosome 16, suggesting genomic imprinting of the FOXF1 locus . Importantly, some of the GLI2-binding sites located in the enhancer region have been found to reside in a partially methylated CpG island, and their function has been shown to be methylation sensitive . Moreover, the putative promoter region of the LINC01081 gene also includes a CpG island that could potentially be involved in its epigenetic regulation.
Here, we present a patient (144.3) manifesting full phenotype of ACDMPV caused by a deletion CNV involving only a portion of the 60-kb enhancer region that enabled us to identify its critical 15-kb core interval.
The patient was a full-term baby boy, appropriate for gestational age, born via normal spontaneous vaginal delivery with meconium-stained amniotic fluid to a 22-year-old, G2, P2 mother. Pregnancy was uncomplicated. The mother had prenatal care and denied use of tobacco, alcohol, or drugs. Neonatal resuscitation was routine. Birth weight was 3.6 kg. Apgar scores were 8 and 9 at 1 and 5 min of life, respectively.
The patient’s early neonatal course was unremarkable until approximately 8 h of life, when he developed respiratory distress associated with oxygen saturations in the 80’s on room air, prompting admission to the neonatal intensive care unit (NICU). Chest X-ray revealed small bilateral pneumothoraxes and was not consistent with meconium aspiration syndrome. Echocardiogram showed patent foramen ovale with moderate right to left shunting, small patent ductus arteriosus with little flow into the pulmonary artery, mildly dilated right ventricle, mildly dilated right atrium, and severe pulmonary hypertension (3/4 systemic) while on inhaled nitric oxide (iNO) via nasal cannula at 12 h of life.
Upon admission to the NICU, the patient was started on iNO, initially via high flow nasal cannula without significant improvement prompting intubation and mechanical ventilation, first conventional followed by high-frequency oscillatory ventilation (HFOV) at approximately 24 h of life. The patient was transferred to HFOV plus iNO because of worsening hypoxemia complicated by systemic hypotension. Follow-up CXR showed well-expanded lungs and resolution of bilateral pneumothoraxes. The patient did not show significant improvement despite good alveolar recruitment on HFOV, optimization of systemic blood pressure with vasopressor medication, and iNO therapy. At approximately 48 h of life, he was placed on VV extracorporeal membrane oxygenation (ECMO) due to refractory hypoxemic respiratory failure. He remained relatively stable for 4 days on ECMO until he developed a right pneumothorax, which required chest tube placement. On day 7 of the ECMO run, the patient developed a left pneumothorax complicated by large hemothorax, pulmonary hemorrhage, disseminated intravascular coagulation, and tamponade physiology, including severe metabolic/lactic acidosis despite maximal ECMO and vasopressor support. On day 8 of the ECMO run, day 10 of life, the family decided to withdraw support given the patient’s severe clinical deterioration and grim prognosis.
Histopathological evaluation at autopsy confirmed the diagnosis of ACDMPV. The major pathological findings in the lungs included congested pulmonary veins adjacent to pulmonary arteries, thickened alveolar septae with decreased numbers of centrally located capillaries, and arteriolar hypertrophy of lungs.