INTRODUCTION:
Bronchopulmonary dysplasia (BPD), the chronic lung disease of
prematurity, contributes to significant morbidities and mortality,
especially in extremely low gestational-age newborns. Despite advances
in perinatal care, BPD remains a major sequel of prematurity, often
leading to the prolonged need for mechanical ventilation, pulmonary
hypertension (PH), other co-morbidities, and
mortality.1,2 Further, there has been a growing
recognition that some preterm infants develop severe BPD (sBPD), and
this subgroup has been identified as having a much higher risk for poor
outcomes, including late mortality and PH.3-5
Compromised alveolar development with impaired lung vascular growth and
hypertensive remodeling are histologic hallmarks of sBPD, as well as
genetic lethal lung developmental disorders (LLDD), including alveolar
capillary dysplasia with misalignment of pulmonary veins
(ACDMPV).6,7 Extensive work has shown that loss ofFOXF1 expression is the genetic basis for
ACDMPV,.8 As with sBPD, ACDMPV is characterized by
marked disruption of the alveolar capillary network, which causes severe
neonatal respiratory distress and PH, leading to nearly uniform
mortality despite aggressive cardiopulmonary
therapies.6,7 Additional studies of ACDMPV have shown
that the “MPV,” are actually bronchial veins and represent recruitment
of intrapulmonary bronchopulmonary anastomoses (IBA), which connect the
pulmonary vasculature with bronchial vessels.8 The
presence of prominent IBAs have similarly been identified in fatal
sBPD,11 suggesting that overlapping features between
ACDMPV and sBPD exist, and that these conditions may share pathogenetic
mechanisms. Such a link has been suggested in extensive laboratory
studies that demonstrated impaired FoxF1 expression in neonatal
mice exposed to hyperoxia, a common experimental model for
BPD.12
Although multiple mechanisms are associated with high risk for BPD,
outcomes remain highly variable and mechanisms that increase
susceptibility for this challenging subgroup of preterm infants with
sBPD and PH remain poorly understood.2 In this report,
we present the case of a preterm infant who died with sBPD and PH,
andhad striking histologic features compatible with the diagnosis of
ACDMPV but had negative genetic findings for FOXF1 . We further
demonstrate dramatic reductions in lung FOXF1 content in sBPD,
suggesting common mechanistic links between ACDMPV and sBPD with
impaired FOXF1 signaling.