Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal cause of refractory pulmonary hypertension of the newborn. We describe the clinical course of a neonate with refractory pulmonary hypertension diagnosed with ACD/MPV, aortic coarctation and other not previously reported associated malformations.
Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal cause of refractory pulmonary hypertension of the newborn.1 Newborns without typical risk factors present within first days of life with refractory pulmonary hypertension.
ACD/MVP is associated in up to 80% of cases to gastrointestinal, genitourinary, cardiovascular and right-left laterality anomalies.2
We present a newborn with refractory pulmonary hypertension, diagnosed postmortem with ACD/MPV, deletion of the FOXF1 gene and other not previously reported associated malformations.
A 1-week-old male, born at 38 weeks, was transferred to our institution with recurrent hypoxemic episodes.
Shortly after uneventful delivery, he had developed progressive respiratory distress syndrome with hypoxemia, requiring mechanical ventilation at 24 h of life. He was weaned from ventilator on day 3 but subsequently suffered from hypoxemic episodes. Persistent pulmonary hypertension was suspected and he was transferred to our unit.
Two-dimensional echo showed an aortic coarctation with arch hypoplasia, signs of pulmonary hypertension and a large patent ductus arteriosus. Drainage of pulmonary veins (PVs) into the left atrium seemed normal, but a levoatriocardinal vein connecting PV to the innominate vein was also suspected and confirmed with angio computed tomography.
Non-invasive respiratory support, supplementary oxygen and prostaglandin infusion were started.
Aortic arch repair (side-to-end anastomosis) and levoatriocardinal vein ligation were performed at 15 days of age. After surgery, the patient suffered from severe pulmonary hypertensive crises, unresponsive to maximum ventilator therapy and pulmonary vasodilator treatment.
Cardiac catheterization demonstrated suprasystemic pulmonary artery pressure with normal pulmonary wedge pressure. Angiograms of the pulmonary arteries showed normal PV drainage into the left atrium with very slow progression of the contrast medium through the pulmonary vascular bed (Supplementary Videos 1 and 2).
Rapid deterioration of the patient did not allow extracorporeal membrane oxygenation (ECMO) support to be initiated and pulmonary biopsy to be performed, and the patient died due to multiorgan failure at 22 days of life.
Macroscopic examination revealed an incomplete form of left-sidedness bilateral isomerism (Figure 1a). In addition, the heart showed surgically corrected coarctation of the aorta and a bicuspid aortic valve.
The lungs showed two distinct patterns of microscopic developmental anomalies: congenital alveolar dysplasia (Figure 1b) and alveolar capillary dysplasia with misalignment of PVs (Figure 1c). Vascular lesions due to pulmonary hypertension were also found (Figure 1d).
In the white matter of the cerebellum, several groups of disorganized cortical cells were found bilaterally (cerebellar heterotopia).
A customized oligonucleotide acute comparative genomic hybridization was perfomed detecting a 1.65-Mb de novo hemizygous deletion of chromosome 16q24.1-q24. This deletion contained four annotated genes (FOXF1, FOXC2, FOXL1 and JPH3) and this region has not been previously reported to show copy number variation in normal individuals. No other potentially pathogenic copy number alterations were observed elsewhere in the genome.
Fluorescent in situ hybridization analysis of parental samples using BAC probe RP11–278A23 mapping to 16q24.2 revealed two copies and no rearrangements of that region.
We report the case of an infant with clinical, histopathological and genetic findings consistent with ADC/MPV. Furthermore, our patient showed findings of both ACD/MVP and congenital alveolar dysplasia, which support the hypothesis that both entities are part of the same spectrum.3,4,5
Histological findings of ACD/MPV are the result of a disorganized pulmonary maldevelopment in the sacular and alveolar phases that lead to an altered development of the blood-air barrier.6 Hypoxemia usually starts soon after birth but may appear after several months.7
Coexistence of congenital heart defects, particularly left heart outflow tract obstructive lesions, may act as a confounder and limit further studies. In fact, our patient’s atypical course with a honeymoon period and the presence of aortic coarctation led us not to indicate open lung biopsy before or during surgery.
As far as we know, cerebellar heterotopia had not been previously reported in association to ACD. It is caused by a displacement of gray matter into the white matter8 and is usually associated with genetic and malformative syndromes.
Mutations or deletions in or upstream to the FOXF1 gene are present in 40% of cases. In previously reported cases, those with inactivating mutations of the FOXF1 gene disclosed a phenotype of ACD/MPV with intestinal malrotation and urinary tract malfomations, usually without cardiac malformations, whereas those with deletions harboring FOXF1 and the neighboring FOXC2 and FOXL1 had, in addition to ACD/MPV, distinct malformations such as congenital heart defects and gastrointestinal atresias. Our patient had ACD/MPV associated to a congenital heart malformation but, interestingly and in contrast to previously reported cases, showed intestinal malrotation but no gut atresia.
ACD/MPV is diagnosed at necropsy in more than 90% of reported cases.9 Most cases had been misdiagnosed as idiopathic persistent pulmonary hypertension of the newborn. If clinically suspected, diagnosis requires histopathological evaluation by means of an open pulmonary biopsy.
As there is no beneficial effect of medical treatment, in vivo diagnosis should lead to consider limiting aggressive therapies such as ECMO or cardiac surgery.
To the best of our knowledge, this is the first reported association between ACD/MVP with cerebellar heterotopia. In addition, the coexistence of congenital alveolar dysplasia, and the unexpected presence of intestinal malrotation and lack of gut atresia according to genetic findings, are distinctive features of this case.
ACD/MVP must be suspected in infants who develop refractory hypoxemia with pulmonary hypertension, especially in the absence of risk factors for pulmonary hypertension. The coexistence of congenital cardiac disease is common and must not mislead our clinical suspicion. Lung biopsy should be carried out in order to consider limiting further invasive procedures and provide compassionate care. ECMO therapy can be instituted before definitive diagnosis is achieved because reversible conditions can mimic this clinical presentation and might benefit from it.
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The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Journal of Perinatology website
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Arreo del Val, V., Avila-Alvarez, A., Schteffer, L. et al. Alveolar capillary dysplasia with misalignment of the pulmonary veins associated with aortic coarctation and intestinal malrotation. J Perinatol 34, 795–797 (2014). https://doi.org/10.1038/jp.2014.94
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