Persistent pulmonary hypertension (PPHN) in the neonates is commonly seen with parenchymal lung diseases (pneumonia, meconium aspiration syndrome) and congenital cardiac diseases. When these are not the underlying cause of pulmonary hypertension, and if it is refractory to usual medical therapies, it presents a diagnostic challenge. We report a late preterm neonate operated for esophageal atresia with severe persistent pulmonary hypertension where the diagnosis was made on post-mortem lung biopsy.

Cystic fibrosis screening was negative including the common mutation analysis. High resolution chest CT was done to rule out other possibilities like idiopathic pulmonary fibrosis, pulmonary lymphagiectasia and structural malformations; it showed bilateral lower lobe collapse, hyperinflated upper lung fields with mild septal prominence and a small airspace cavity in the right paracardiac area, signs of bronchopulmonary dysplasia. Baby remained critically ill with extensive intensive care support, eventually developed cardio-respiratory failure and died on day 103 of life. Histopathological examination of lung was performed after consent from parents; it revealed features consistent with alveolar capillary dysplasia (Fig. 1).

Fig. 1 Misaligned pulmonary veins, scarce dilated pulmonary capillaries located away from alveolar epithelium, absent alveolo-capillary barrier and museularisation of distal arterioles. (See color image at website).

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and universally fatal disorder leading to respiratory failure early in life [1]. Most of affected infants present shortly after birth or within 48 hrs of life with hypoxic respiratory failure and are refractory to all medical therapies [2]. Newborns affected with ACD/MPV present with minimal or no parenchymal lung disease and severe idiopathic PPHN. Profound hypoxemia, with partial pressures of oxygen in arterial blood less than 30 mm Hg, and severe metabolic acidosis consistent with pulmonary hypertensive crisis and right ventricular failure are nearly always present. ACD/MPV should be suspected in neonates with primary/idiopathic PPHN who fail to respond to pulmonary vasodilator therapy including nitric oxide therapy and ECMO. While most of the affected babies present in neonatal period and expire early; so far four reports have been published of infants presenting with fulminant disease later (5 week to 7 month age) [3-6]. Two of them presented with symptoms serious enough to warrant brief periods of respiratory observation in a neonatal intensive care unit before discharge [3,6], the remaining two appeared asymptomatic and were discharged home as well babies [4,5]. Survival beyond three months after the onset is rare. Diagnosis of ACD/MPV is made only on histological grounds, characterized by misaligned pulmonary veins, scarce dilated pulmonary capillaries located away from alveolar epithelium, absent alveolo-capillary barrier, and muscularization of distal arterioles.

Newborns with ACD/MPV have multiple other congenital malformations of gastrointestinal tract, cardiovascular system, and genitourinary system in almost 80% of cases. PAPVC with esophageal atresia and tracheoesophageal fistula in our case with progressive pulmonary insufficiency prompted us to perform lung biopsy to rule out ACD/MPV. Antemortem lung biopsy was offered to parents; however it was not performed because of unstable clinical condition. Early diagnosis of this condition would prevent the newborn with ACD/MPV to undergo invasive therapies. However, CT scan performed showed dilated central pulmonary arteries; this finding was not given much importance and could have helped us in early diagnosis [7].

About 10% of alveolar capillary dysplasia are reported to have familial association [8]. Candidate gene involvement is now being researched and some case reports showed haplo-insufficincy for the fork-head FOX transcription factor gene cluster which may present in 40% of cases [9]. Genetic testing was not performed in our case.

The clinical approach to newborns with ACD/MPV is on the same lines as that for persistent primary pulmonary hypertension [10]. Index of suspicion should be high if a neonate with idiopathic PPHN is a non-responder to usual medical therapies and especially if there are any associated anomalies of the gastrointestinal, genitourinary, and cardiovascular systems. Early diagnosis by histologic evaluation of antemortem lung biopsy in these neonates warrants against unnecessary therapies and prolongation of medical treatment.

Contributors: All authors were involved in patient-management, and contributed to the review of literature. All authors approved the final version of the manuscript.

Funding: None; Competing interests: None stated.

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