We report, to the best of our knowledge, the second and third cases of PIG associated with CHD. Both patients presented with either clinical evidence (patient no. 1) or documentation (patient no. 2) of perioperative pulmonary hypertension that was clinically significant and unresponsive to inhaled nitric oxide. Interestingly, in patient no. 1, systemic steroid therapy was initiated before the diagnosis of PIG was made. Steroids were given for suspected, and subsequently disproved, adrenal insufficiency and were associated with clinical improvement. In patient no. 2, clinical improvement was gradual without steroid administration. Both cases demonstrated the hallmark PIG histologic finding of diffuse, uniform interstitial thickening due to the presence of immature interstitial cells containing abundant cytoplasmic glycogen. Moreover, both cases demonstrated evidence of increased pulmonary pressures, which led to the administration of inhaled nitric oxide and, in the second case, long-term treatment with sildenafil.
Persistent pulmonary hypertension of the newborn is not a single disease but rather a pathophysiologic condition. It is a clinical syndrome that manifests when the normal transition from the fetal to the postnatal pulmonary circulation fails to occur. In other words, the acronym “PPHN” encompasses the spectrum of diseases in which the normal sharp decrease in pulmonary vascular resistance and increase in pulmonary blood flow, with concomitant decrease in extrapulmonary shunting across the foramen ovale and DA, is significantly delayed . The pathophysiologic mechanisms that prevent the normal pulmonary vascular remodeling and vasodilation at birth remain unclear, but they are most likely multifactorial in etiology. Several conditions, including sepsis, meconium aspiration syndrome, and lung hypoplasia, have been associated with PPHN [2, 10]. Not surprisingly, the response to therapy varies across etiologies and depends in part on the condition of the lung parenchyma and pulmonary vasculature. Moreover, some conditions that cause PPHN—such as alveolar capillary dysplasia (ACD) and pulmonary lymphangiectasias, particularly when it persists beyond the neonatal period as in seen patient no. 2—are almost entirely unresponsive to therapy. Thus, the ability to distinguish between the various conditions that result in PPHN to plan appropriate diagnostic studies, tailor therapies, and predict outcome remains crucial. It is recognized that PPHN may be an independent complicating factor in the preoperative and postoperative course of some neonates with CHD with severe hypoxemia and hemodynamic instability . To date, potential etiologies for the independent association between PPHN and CHD have not been recognized.
Deutsch et al.  reported the first and only other documented case of PIG in a neonate with CHD. Similar to our cases, that neonate presented with severe pulmonary hypertension in the newborn period that could not be explained by the diagnosed CHD of hypoplastic aortic arch and PDA. Preoperative lung biopsy specimen demonstrated PIG, and systemic steroid therapy was initiated with marked clinical improvement. Interestingly, follow-up biopsy specimen at 2 months of age demonstrated resolution of the pathology.
We report two additional cases of PIG in neonates with CHD and evidence of unexplained pulmonary hypertension of the newborn. Because histologic examination is required to establish the diagnosis, we speculate that PIG, although rare, may be underrecognized in neonates presenting with PPHN in the setting of CHD. Moreover, although corticosteroids are the “gold-standard” therapy in biopsy-confirmed PIG, the consequences of this treatment, i.e., potential neurodevelopmental aberrations, immunosuppression, poor wound healing, and potential decreased pulmonary alveolarization in patients suffering from concomitant lung growth anomalies, must be considered because PIG is often a self-limited disease process.